Comprehensive Physiology Wiley Online Library

Thick Filament Protein Network, Functions, and Disease Association

Full Article on Wiley Online Library



ABSTRACT

Sarcomeres consist of highly ordered arrays of thick myosin and thin actin filaments along with accessory proteins. Thick filaments occupy the center of sarcomeres where they partially overlap with thin filaments. The sliding of thick filaments past thin filaments is a highly regulated process that occurs in an ATP‐dependent manner driving muscle contraction. In addition to myosin that makes up the backbone of the thick filament, four other proteins which are intimately bound to the thick filament, myosin binding protein‐C, titin, myomesin, and obscurin play important structural and regulatory roles. Consistent with this, mutations in the respective genes have been associated with idiopathic and congenital forms of skeletal and cardiac myopathies. In this review, we aim to summarize our current knowledge on the molecular structure, subcellular localization, interacting partners, function, modulation via posttranslational modifications, and disease involvement of these five major proteins that comprise the thick filament of striated muscle cells. © 2018 American Physiological Society. Compr Physiol 8:631‐709, 2018.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Schematic representation of a half sarcomere depicting the position of the Z‐disk, I‐band, A‐band, and M‐band. Myosin thick filaments and associated proteins are shown in color including myosin heads (green), myosin rods (petrol), regulatory light chains (magenta), essential light chains (peach), MyBP‐C (purple), myomesin (orange), titin (yellow), and obscurin (light blue), while actin thin filaments and the surrounding sarcoplasmic reticulum are shown in different shades of grey; the structure of the half sarcomere was generated by e‐heart.org bearing minor modifications.
Figure 2. Figure 2. Domain organization of MyHC, ELC, and RLC. (A) The NH2‐terminus of sarcomeric MyHC contains an SH3‐like domain, followed by the motor head domain containing the converter segment, a lever arm consisting of two IQ motifs, and a coiled‐coil region. Proteolytic cleavage of MyHC yields three fragments: HMM‐S1, HMM‐S2, and LMM. The S1 segment contains the SH3‐like domain, the motor head domain and the lever arm. The S2 and LMM fragments contain the NH2‐ and COOH‐terminal portions of the coiled‐coil region, respectively. (B) Both ELC and RLC contain EF‐hand motifs. ELC isoforms may contain two EF‐hand motifs, such as MYL1, or one EF‐hand motif, such as MYL3 and MYL4; however, all RLC isoforms carry two EF‐hand motifs, with MYL2 containing longer EF‐hand motifs compared to MYL7 and MYLPF.
Figure 3. Figure 3. Binding partners of myosin heavy and light chains in striated muscles. (A) A number of interacting partners have been identified for MyHC, including actin binding to the motor head domain, MyBP‐C and MyBP‐H binding to the coiled‐coil region containing both the S2 and LMM fragments, myomesin binding to the coiled‐coil LMM region, titin binding to S1 and LMM, nonerythroid 4.1R, MuRF1 and MuRF3 binding to HMM, and AMPD binding to S2. ELC and RLC bind to the NH2‐ and COOH‐terminal IQ motifs of MyHC, respectively, via their EF‐hand motifs. Although Akt2, HspB2, and caspase‐3 interact with MyHC, the exact binding sites have not been characterized yet. (B) The binding partners of ELC and RLC are less studied; ELC interacts with actin via its nonmodular NH2‐terminus, and RLC interacts with cardiac MyBP‐C, MuRF1, and MuRF2, however the exact binding sites have yet to be determined.
Figure 4. Figure 4. Schematic representation of the generation of power stroke. (A) Actomyosin interaction is inhibited upon binding of ATP to myosin. At this stage, the myosin ATPase site is partially open and inactive. (B) During recovery stroke, the converter segment of myosin is subjected to a 65° rotation resulting in closing of the myosin ATPase site and ATP hydrolysis. (C) While the hydrolysis products, ADP and inorganic phosphate, are still bound to the myosin globular head domain, the head domain weakly associates with actin and triggers the release of inorganic phosphate. Concomitantly, conformational changes of the head domain lead to enhanced actin binding, followed by release of ADP, the generation of power stroke, and muscle contraction. (D) The globular head domain of myosin is still attached to actin postpower stroke awaiting the addition of another ATP molecule and the initiation of a new cycle.
Figure 5. Figure 5. Posttranslational modifications of human myosin heavy and light chains. Given that only acetylation and phosphorylation sites are known for the human isoforms, the figure only denotes those; Tables 4 and 5 however includes additional modifications identified in other mammalian species. (A) Acetylation (Ac) and phosphorylation (P) sites of the human myosin heavy and light chains are depicted onto the myosin domains; color coding was used to note the different isoforms. With the exception of MYH7, acetylation and phosphorylation sites are mainly concentrated in the LMM coiled‐coil region. In MYH7, however, acetylation and phosphorylation sites are present throughout the entire length of the protein. (B) Acetrylation and phosphorylation sites are concentrated in the nonmodular NH2‐terminus and the first EF‐hand motif of MYL1, but only in the nonmodular NH2‐terminus of MYL3; no posttranslational modifications have been identified for MYL4. (C) Acetylation and phosphorylation sites are scattered across the entire length of MYL2 and MYLPF; similar to MYL4, there are no known posttranslational modifications for MYL7.
Figure 6. Figure 6. Number of mutations identified to date in individual domains of the myosin heavy (A) and light chain [(B) and (C)] isoforms expressed in human striated muscles. The total count noted includes missense mutations and single amino acid duplications and deletions, since these types of mutations account for >90% of the total number of mutations identified in the myosin family.
Figure 7. Figure 7. Schematic representation of the three MyBP‐C isoforms. The black and white horizontal rectangles correspond to the Pro/Ala rich region and the M‐motif, while the yellow and dark blue vertical rectangles represent Ig and FnIII domains, respectively. Colored zigzagged lines in sMyBP‐C represent alternatively spliced insertions. fMyBP‐C and cMyBP‐C share a conserved linker region between C4 and C5, denoted in red. C0 and cardiac specific regions in cMyBP‐C are shown in light blue.
Figure 8. Figure 8. Binding partners of the three MyBP‐C isoforms. Binding regions are shown on the cMyBP‐C isoform to also include interactions mediated by C0. Binding to all partners has been determined for both cMyBP‐C and sMyBP‐C unless binding is located within a cardiac specific region (light blue) or noted only for sMyBP‐C. Much less research has focused on confirming or identifying binding partners of fMyBP‐C.
Figure 9. Figure 9. Posttranslational modifications identified in cMyBP‐C and sMyBP‐C. Phosphorylation sites in sMyBP‐C and cMyBP‐C (green) are located within their NH2‐terminal regions. Acetylation of lysine residues in cMyBP‐C (purple) is primarily located in the NH2‐terminus and Ig domain C7. S‐glutathiolation of cMyBP‐C (orange) occurs in the central region of the protein within Ig domains C3‐C5. One citrulination site (blue) and one S‐nitrosylation site (gray) are located within the COOH‐terminus of cMyBP‐C. There are no known posttranslational modifications in fMyBP‐C.
Figure 10. Figure 10. Illustration of the individual (sMyBP‐C and fMyBP‐C) or number and type (cMyBP‐C) of mutations per domain that have been identified to date in the MyBP‐C family.
Figure 11. Figure 11. Domain schematic of titin within the thick filament. The various domains are depicted as differently colored rectangles with Ig domains shown in yellow, FnIII domains in dark blue, the kinase domain in pink, and interdomain sequences in orange. The two titin super repeats are also illustrated with the first one denoted by a single and the second one by a double zigzagged line connecting the respective Ig and FNIII domains.
Figure 12. Figure 12. Binding partners of titin in the thick filament. In the A‐band, the FnIII domains of titin's super repeats bind to the myosin S1 and LMM regions. Titin also provides regularly spaced binding sites for MyBPC in the first Ig domain of each second super repeat, leading to its periodic localization in the C‐zone of the A‐band. The Ig and FnIII domains located directly COOH terminally to the second super repeat mediate binding to MuRF‐1 and ‐2. In the M‐band, the titin kinase interacts with Ca2+/calmodulin and Nbr1/p62. The rest of the M‐band portion of titin provides binding sites for DRAL/FHL2, myomesin, Bin1, myospryn, calpain‐3, obscurin, and obsl1. The exact binding site for M‐protein in the COOH‐terminus of titin has not yet been identified.
Figure 13. Figure 13. Posttranslational modifications of titin within the thick filament. The only known phosphorylation sites within this region are localized to the M‐band, and include phosphorylation of the four Ser residues (Ser35236, Ser35243, Ser35249, and Ser35255; NP_001254479.2) located in the four KSP motifis present in Is4, and of Tyr‐170 located in the P+1 loop of the titin kinase domain. Moreover, eight arginylation sites are spread throughout the A‐ and M‐band portions of titin. Four of these sites (Glu14609, Glu19156, Asp19159, and Asp27727; NP_035782.3) are found within FnIII domains of the first and second super‐repeat regions, while the fifth site (Asp32535; NP_035782.3) is located in Is3. The remaining three arginylation sites are present in Ig domains in the first and second super‐repeat regions (L7960 and V15013; NP_082280.2) and the titin kinase (C24818; NP_082280.2).
Figure 14. Figure 14. Number of mutations identified to date in individual domains of titin within the thick filament. The number of missense, nonsense, indel, or splice mutations present in each domain is depicted below the schematic.
Figure 15. Figure 15. Schematic representation of the three myomesin isoforms: myomesin, M‐protein, and myomesin‐3. The yellow and dark blue rectangles correspond to Ig and FnIII domains, respectively, the black zigzagged line represents the nonmodular NH2‐terminal domain, and the red curvy line between domains My6 and My7 illustrates the Ser/Pro‐rich insertion present in EH‐myomesin.
Figure 16. Figure 16. Interacting partners of the myomesin isoforms and their respective binding sites. All three proteins form homotypic dimers via their COOH‐terminal Ig domain My13. Moreover, a number of binding sites have been identified primarily on myomesin that mediate binding to other M‐band proteins. These include the nonmodular My1 region of myomesin and Ig domains My2‐My3 of M‐protein that bind to LMM, the FnIII domains My7‐My8 of myomesin and My6‐My8 of M‐protein that interact with M‐CK, the linker region between FnIII domains My4‐My5 of myomesin that binds to the Ig3 domain of obscurin and obsl‐1, and the FnIII My4‐My6 region of myomesin that interacts with the Ig domain M4 of titin.
Figure 17. Figure 17. Illustration of the mutations that have been identified in MYOM1 encoding myomesin and their location. There are no known myopathy‐causing mutations for MYOM2 encoding M‐protein and MYOM3 encoding myomesin‐3.
Figure 18. Figure 18. Schematic representation of giant obscurin‐A and obscurin‐B and small double kinase and single kinase. Domains are shown as colored rectangles: Ig (yellow), FnIII (dark blue), IQ (green), SH3 (red), RhoGEF (purple), PH (light blue), and kinase (pink). The nonmodular region at the extreme COOH‐terminus of obscurin A is denoted as black line.
Figure 19. Figure 19. Interacting partners of obscurins in striated muscles. The NH2‐terminus of obscurins provides binding sites for several proteins residing in the M‐band, including the extreme COOH‐terminus of titin (obscurin Ig1/titin M10), sMyBP‐C v1 (obscurin Ig2/sMyBP‐C v1 C10) and myomesin (obscurin Ig3/My4‐5). Obscurin Ig58/Ig59 domains also interact with titin ZIg9/ZIg10 domains at the level of Z/I junctions. Moreover, a number of binding partners have been identified for the obscurin signaling motifs. Accordingly, the obscurin RhoGEF motif mediates binding to GTPases RhoA and TC10 and the anchoring protein RanBP9, and the obscurin IQ domain binds calmodulin in a Ca2+‐independent manner. Notably, isoform‐specific interactions have also been characterized, including the presence of multiple ankyrin binding sites in the nonmodular COOH‐terminus of obscurin‐A, and the ability of Kinase1 and Kinase2 of obscurin‐B to interact with the cytoplasmic domain of N‐cadherin and the extracellular domain of the NKA‐β1 subunit, respectively. The binding partners of the invertebrate obscurin orthlogue UNC89 are also shown in red color, although these have not yet been confirmed in vertebrates; please note that the structural architecture of the invertebrate UNC‐89 isoforms is different from the vertebrate obscurins, however the domains per se are conserved.
Figure 20. Figure 20. Posttranslational modifications of obscurins. To date, the only known modification that obscurins undergo is phosphorylation. A number of phosphorylation sites (shown in green) have been identified via phosphoproteomic analysis that exhibit a preferential accumulation within or proximal to the signaling motifs present in the COOH‐terminus. However, these have not been confirmed via biochemical or molecular methods with the exception of a phosphorylation event involving Ser4829 that is mediated by GSK‐3β and was identified in a tachypacing‐induced heart failure model.
Figure 21. Figure 21. Illustration of the OBSCN mutations and their location that have been linked with the development of different forms of cardiomyopathy. Mutations associated with HCM are shown in red, mutations associated with DCM are shown in blue, and mutations associated with LVNC are shown in black. Three additional polymorphisms have been described as compound heterozygous, and are shown in green; fs: frameshift.


Figure 1. Schematic representation of a half sarcomere depicting the position of the Z‐disk, I‐band, A‐band, and M‐band. Myosin thick filaments and associated proteins are shown in color including myosin heads (green), myosin rods (petrol), regulatory light chains (magenta), essential light chains (peach), MyBP‐C (purple), myomesin (orange), titin (yellow), and obscurin (light blue), while actin thin filaments and the surrounding sarcoplasmic reticulum are shown in different shades of grey; the structure of the half sarcomere was generated by e‐heart.org bearing minor modifications.


Figure 2. Domain organization of MyHC, ELC, and RLC. (A) The NH2‐terminus of sarcomeric MyHC contains an SH3‐like domain, followed by the motor head domain containing the converter segment, a lever arm consisting of two IQ motifs, and a coiled‐coil region. Proteolytic cleavage of MyHC yields three fragments: HMM‐S1, HMM‐S2, and LMM. The S1 segment contains the SH3‐like domain, the motor head domain and the lever arm. The S2 and LMM fragments contain the NH2‐ and COOH‐terminal portions of the coiled‐coil region, respectively. (B) Both ELC and RLC contain EF‐hand motifs. ELC isoforms may contain two EF‐hand motifs, such as MYL1, or one EF‐hand motif, such as MYL3 and MYL4; however, all RLC isoforms carry two EF‐hand motifs, with MYL2 containing longer EF‐hand motifs compared to MYL7 and MYLPF.


Figure 3. Binding partners of myosin heavy and light chains in striated muscles. (A) A number of interacting partners have been identified for MyHC, including actin binding to the motor head domain, MyBP‐C and MyBP‐H binding to the coiled‐coil region containing both the S2 and LMM fragments, myomesin binding to the coiled‐coil LMM region, titin binding to S1 and LMM, nonerythroid 4.1R, MuRF1 and MuRF3 binding to HMM, and AMPD binding to S2. ELC and RLC bind to the NH2‐ and COOH‐terminal IQ motifs of MyHC, respectively, via their EF‐hand motifs. Although Akt2, HspB2, and caspase‐3 interact with MyHC, the exact binding sites have not been characterized yet. (B) The binding partners of ELC and RLC are less studied; ELC interacts with actin via its nonmodular NH2‐terminus, and RLC interacts with cardiac MyBP‐C, MuRF1, and MuRF2, however the exact binding sites have yet to be determined.


Figure 4. Schematic representation of the generation of power stroke. (A) Actomyosin interaction is inhibited upon binding of ATP to myosin. At this stage, the myosin ATPase site is partially open and inactive. (B) During recovery stroke, the converter segment of myosin is subjected to a 65° rotation resulting in closing of the myosin ATPase site and ATP hydrolysis. (C) While the hydrolysis products, ADP and inorganic phosphate, are still bound to the myosin globular head domain, the head domain weakly associates with actin and triggers the release of inorganic phosphate. Concomitantly, conformational changes of the head domain lead to enhanced actin binding, followed by release of ADP, the generation of power stroke, and muscle contraction. (D) The globular head domain of myosin is still attached to actin postpower stroke awaiting the addition of another ATP molecule and the initiation of a new cycle.


Figure 5. Posttranslational modifications of human myosin heavy and light chains. Given that only acetylation and phosphorylation sites are known for the human isoforms, the figure only denotes those; Tables 4 and 5 however includes additional modifications identified in other mammalian species. (A) Acetylation (Ac) and phosphorylation (P) sites of the human myosin heavy and light chains are depicted onto the myosin domains; color coding was used to note the different isoforms. With the exception of MYH7, acetylation and phosphorylation sites are mainly concentrated in the LMM coiled‐coil region. In MYH7, however, acetylation and phosphorylation sites are present throughout the entire length of the protein. (B) Acetrylation and phosphorylation sites are concentrated in the nonmodular NH2‐terminus and the first EF‐hand motif of MYL1, but only in the nonmodular NH2‐terminus of MYL3; no posttranslational modifications have been identified for MYL4. (C) Acetylation and phosphorylation sites are scattered across the entire length of MYL2 and MYLPF; similar to MYL4, there are no known posttranslational modifications for MYL7.


Figure 6. Number of mutations identified to date in individual domains of the myosin heavy (A) and light chain [(B) and (C)] isoforms expressed in human striated muscles. The total count noted includes missense mutations and single amino acid duplications and deletions, since these types of mutations account for >90% of the total number of mutations identified in the myosin family.


Figure 7. Schematic representation of the three MyBP‐C isoforms. The black and white horizontal rectangles correspond to the Pro/Ala rich region and the M‐motif, while the yellow and dark blue vertical rectangles represent Ig and FnIII domains, respectively. Colored zigzagged lines in sMyBP‐C represent alternatively spliced insertions. fMyBP‐C and cMyBP‐C share a conserved linker region between C4 and C5, denoted in red. C0 and cardiac specific regions in cMyBP‐C are shown in light blue.


Figure 8. Binding partners of the three MyBP‐C isoforms. Binding regions are shown on the cMyBP‐C isoform to also include interactions mediated by C0. Binding to all partners has been determined for both cMyBP‐C and sMyBP‐C unless binding is located within a cardiac specific region (light blue) or noted only for sMyBP‐C. Much less research has focused on confirming or identifying binding partners of fMyBP‐C.


Figure 9. Posttranslational modifications identified in cMyBP‐C and sMyBP‐C. Phosphorylation sites in sMyBP‐C and cMyBP‐C (green) are located within their NH2‐terminal regions. Acetylation of lysine residues in cMyBP‐C (purple) is primarily located in the NH2‐terminus and Ig domain C7. S‐glutathiolation of cMyBP‐C (orange) occurs in the central region of the protein within Ig domains C3‐C5. One citrulination site (blue) and one S‐nitrosylation site (gray) are located within the COOH‐terminus of cMyBP‐C. There are no known posttranslational modifications in fMyBP‐C.


Figure 10. Illustration of the individual (sMyBP‐C and fMyBP‐C) or number and type (cMyBP‐C) of mutations per domain that have been identified to date in the MyBP‐C family.


Figure 11. Domain schematic of titin within the thick filament. The various domains are depicted as differently colored rectangles with Ig domains shown in yellow, FnIII domains in dark blue, the kinase domain in pink, and interdomain sequences in orange. The two titin super repeats are also illustrated with the first one denoted by a single and the second one by a double zigzagged line connecting the respective Ig and FNIII domains.


Figure 12. Binding partners of titin in the thick filament. In the A‐band, the FnIII domains of titin's super repeats bind to the myosin S1 and LMM regions. Titin also provides regularly spaced binding sites for MyBPC in the first Ig domain of each second super repeat, leading to its periodic localization in the C‐zone of the A‐band. The Ig and FnIII domains located directly COOH terminally to the second super repeat mediate binding to MuRF‐1 and ‐2. In the M‐band, the titin kinase interacts with Ca2+/calmodulin and Nbr1/p62. The rest of the M‐band portion of titin provides binding sites for DRAL/FHL2, myomesin, Bin1, myospryn, calpain‐3, obscurin, and obsl1. The exact binding site for M‐protein in the COOH‐terminus of titin has not yet been identified.


Figure 13. Posttranslational modifications of titin within the thick filament. The only known phosphorylation sites within this region are localized to the M‐band, and include phosphorylation of the four Ser residues (Ser35236, Ser35243, Ser35249, and Ser35255; NP_001254479.2) located in the four KSP motifis present in Is4, and of Tyr‐170 located in the P+1 loop of the titin kinase domain. Moreover, eight arginylation sites are spread throughout the A‐ and M‐band portions of titin. Four of these sites (Glu14609, Glu19156, Asp19159, and Asp27727; NP_035782.3) are found within FnIII domains of the first and second super‐repeat regions, while the fifth site (Asp32535; NP_035782.3) is located in Is3. The remaining three arginylation sites are present in Ig domains in the first and second super‐repeat regions (L7960 and V15013; NP_082280.2) and the titin kinase (C24818; NP_082280.2).


Figure 14. Number of mutations identified to date in individual domains of titin within the thick filament. The number of missense, nonsense, indel, or splice mutations present in each domain is depicted below the schematic.


Figure 15. Schematic representation of the three myomesin isoforms: myomesin, M‐protein, and myomesin‐3. The yellow and dark blue rectangles correspond to Ig and FnIII domains, respectively, the black zigzagged line represents the nonmodular NH2‐terminal domain, and the red curvy line between domains My6 and My7 illustrates the Ser/Pro‐rich insertion present in EH‐myomesin.


Figure 16. Interacting partners of the myomesin isoforms and their respective binding sites. All three proteins form homotypic dimers via their COOH‐terminal Ig domain My13. Moreover, a number of binding sites have been identified primarily on myomesin that mediate binding to other M‐band proteins. These include the nonmodular My1 region of myomesin and Ig domains My2‐My3 of M‐protein that bind to LMM, the FnIII domains My7‐My8 of myomesin and My6‐My8 of M‐protein that interact with M‐CK, the linker region between FnIII domains My4‐My5 of myomesin that binds to the Ig3 domain of obscurin and obsl‐1, and the FnIII My4‐My6 region of myomesin that interacts with the Ig domain M4 of titin.


Figure 17. Illustration of the mutations that have been identified in MYOM1 encoding myomesin and their location. There are no known myopathy‐causing mutations for MYOM2 encoding M‐protein and MYOM3 encoding myomesin‐3.


Figure 18. Schematic representation of giant obscurin‐A and obscurin‐B and small double kinase and single kinase. Domains are shown as colored rectangles: Ig (yellow), FnIII (dark blue), IQ (green), SH3 (red), RhoGEF (purple), PH (light blue), and kinase (pink). The nonmodular region at the extreme COOH‐terminus of obscurin A is denoted as black line.


Figure 19. Interacting partners of obscurins in striated muscles. The NH2‐terminus of obscurins provides binding sites for several proteins residing in the M‐band, including the extreme COOH‐terminus of titin (obscurin Ig1/titin M10), sMyBP‐C v1 (obscurin Ig2/sMyBP‐C v1 C10) and myomesin (obscurin Ig3/My4‐5). Obscurin Ig58/Ig59 domains also interact with titin ZIg9/ZIg10 domains at the level of Z/I junctions. Moreover, a number of binding partners have been identified for the obscurin signaling motifs. Accordingly, the obscurin RhoGEF motif mediates binding to GTPases RhoA and TC10 and the anchoring protein RanBP9, and the obscurin IQ domain binds calmodulin in a Ca2+‐independent manner. Notably, isoform‐specific interactions have also been characterized, including the presence of multiple ankyrin binding sites in the nonmodular COOH‐terminus of obscurin‐A, and the ability of Kinase1 and Kinase2 of obscurin‐B to interact with the cytoplasmic domain of N‐cadherin and the extracellular domain of the NKA‐β1 subunit, respectively. The binding partners of the invertebrate obscurin orthlogue UNC89 are also shown in red color, although these have not yet been confirmed in vertebrates; please note that the structural architecture of the invertebrate UNC‐89 isoforms is different from the vertebrate obscurins, however the domains per se are conserved.


Figure 20. Posttranslational modifications of obscurins. To date, the only known modification that obscurins undergo is phosphorylation. A number of phosphorylation sites (shown in green) have been identified via phosphoproteomic analysis that exhibit a preferential accumulation within or proximal to the signaling motifs present in the COOH‐terminus. However, these have not been confirmed via biochemical or molecular methods with the exception of a phosphorylation event involving Ser4829 that is mediated by GSK‐3β and was identified in a tachypacing‐induced heart failure model.


Figure 21. Illustration of the OBSCN mutations and their location that have been linked with the development of different forms of cardiomyopathy. Mutations associated with HCM are shown in red, mutations associated with DCM are shown in blue, and mutations associated with LVNC are shown in black. Three additional polymorphisms have been described as compound heterozygous, and are shown in green; fs: frameshift.
References
 1.Ababou A, Gautel M, Pfuhl M. Dissecting the N‐terminal myosin binding site of human cardiac myosin‐binding protein C. Structure and myosin binding of domain C2. J Biol Chem 282: 9204‐9215, 2007.
 2.Ababou A, Rostkova E, Mistry S, Le Masurier C, Gautel M, Pfuhl M. Myosin binding protein C positioned to play a key role in regulation of muscle contraction: Structure and interactions of domain C1. J Mol Biol 384: 615‐630, 2008.
 3.Abdelaziz AI, Pagel I, Schlegel WP, Kott M, Monti J, Haase H, Morano I. Human atrial myosin light chain 1 expression attenuates heart failure. Adv Exp Med Biol 565: 283‐292; discussion 292, 405‐215, 2005.
 4.Abdul‐Hussein S, van der Ven PF, Tajsharghi H. Expression profiles of muscle disease‐associated genes and their isoforms during differentiation of cultured human skeletal muscle cells. BMC Musculoskelet Disord 13: 262, 2012.
 5.Abraham WT, Gilbert EM, Lowes BD, Minobe WA, Larrabee P, Roden RL, Dutcher D, Sederberg J, Lindenfeld JA, Wolfel EE, Shakar SF, Ferguson D, Volkman K, Linseman JV, Quaife RA, Robertson AD, Bristow MR. Coordinate changes in myosin heavy chain isoform gene expression are selectively associated with alterations in dilated cardiomyopathy phenotype. Mol Med 8: 750‐760, 2002.
 6.Ackermann M, Kontrogianni‐Konstantopoulos A. Cardiomyopathies: When the goliaths of heart muscle hurt. In: Milei J, Ambrosio G, editors. Cardiomyopathies. London, United Kingdom: Intech, 2013.
 7.Ackermann MA, Hu LY, Bowman AL, Bloch RJ, Kontrogianni‐Konstantopoulos A. Obscurin interacts with a novel isoform of MyBP‐C slow at the periphery of the sarcomeric M‐band and regulates thick filament assembly. Mol Biol Cell 20: 2963‐2978, 2009.
 8.Ackermann MA, King B, Lieberman NAP, Bobbili PJ, Rudloff M, Berndsen CE, Wright NT, Hecker PA, Kontrogianni‐Konstantopoulos A. Novel obscurins mediate cardiomyocyte adhesion and size via the PI3K/AKT/mTOR signaling pathway. J Mol Cell Cardiol 111: 27‐39, 2017.
 9.Ackermann MA, Kontrogianni‐Konstantopoulos A. Myosin binding protein‐C slow: An intricate subfamily of proteins. J Biomed Biotechnol 2010: 652065, 2010.
 10.Ackermann MA, Kontrogianni‐Konstantopoulos A. Myosin binding protein‐C slow is a novel substrate for protein kinase A (PKA) and C (PKC) in skeletal muscle. J Proteome Res 10: 4547‐4555, 2011.
 11.Ackermann MA, Kontrogianni‐Konstantopoulos A. Myosin binding protein‐C: A regulator of actomyosin interaction in striated muscle. J Biomed Biotechnol 2011: 636403, 2011.
 12.Ackermann MA, Kontrogianni‐Konstantopoulos A. Myosin binding protein‐C slow: A multifaceted family of proteins with a complex expression profile in fast and slow twitch skeletal muscles. Front Physiol 4: 391, 2013.
 13.Ackermann MA, Patel PD, Valenti J, Takagi Y, Homsher E, Sellers JR, Kontrogianni‐Konstantopoulos A. Loss of actomyosin regulation in distal arthrogryposis myopathy due to mutant myosin binding protein‐C slow. FASEB J 27: 3217‐3228, 2013.
 14.Ackermann MA, Shriver M, Perry NA, Hu LY, Kontrogianni‐Konstantopoulos A. Obscurins: Goliaths and Davids take over non‐muscle tissues. PLoS One 9: e88162, 2014.
 15.Ackermann MA, Ward CW, Gurnett C, Kontrogianni‐Konstantopoulos A. Myosin binding protein‐C slow phosphorylation is altered in Duchenne dystrophy and arthrogryposis myopathy in fast‐twitch skeletal muscles. Sci Rep 5: 13235, 2015.
 16.Agarkova I, Auerbach D, Ehler E, Perriard JC. A novel marker for vertebrate embryonic heart, the EH‐myomesin isoform. J Biol Chem 275: 10256‐10264, 2000.
 17.Agarkova I, Perriard JC. The M‐band: An elastic web that crosslinks thick filaments in the center of the sarcomere. Trends Cell Biol 15: 477‐485, 2005.
 18.Agarkova I, Schoenauer R, Ehler E, Carlsson L, Carlsson E, Thornell LE, Perriard JC. The molecular composition of the sarcomeric M‐band correlates with muscle fiber type. Eur J Cell Biol 83: 193‐204, 2004.
 19.Agbulut O, Noirez P, Beaumont F, Butler‐Browne G. Myosin heavy chain isoforms in postnatal muscle development of mice. Biol Cell 95: 399‐406, 2003.
 20.Al‐Khayat HA. Three‐dimensional structure of the human myosin thick filament: Clinical implications. Glob Cardiol Sci Pract 2013: 280‐302, 2013.
 21.Alyonycheva T, Cohen‐Gould L, Siewert C, Fischman DA, Mikawa T. Skeletal muscle‐specific myosin binding protein‐H is expressed in Purkinje fibers of the cardiac conduction system. Circ Res 80: 665‐672, 1997.
 22.Ao W, Pilgrim D. Caenorhabditis elegans UNC‐45 is a component of muscle thick filaments and colocalizes with myosin heavy chain B, but not myosin heavy chain A. J Cell Biol 148: 375‐384, 2000.
 23.Arimura T, Matsumoto Y, Okazaki O, Hayashi T, Takahashi M, Inagaki N, Hinohara K, Ashizawa N, Yano K, Kimura A. Structural analysis of obscurin gene in hypertrophic cardiomyopathy. Biochem Biophys Res Commun 362: 281‐287, 2007.
 24.Arimura T, Suematsu N, Zhou YB, Nishimura J, Satoh S, Takeshita A, Kanaide H, Kimura A. Identification, characterization, and functional analysis of heart‐specific myosin light chain phosphatase small subunit. J Biol Chem 276: 6073‐6082, 2001.
 25.Armani A, Galli S, Giacomello E, Bagnato P, Barone V, Rossi D, Sorrentino V. Molecular interactions with obscurin are involved in the localization of muscle‐specific small ankyrin1 isoforms to subcompartments of the sarcoplasmic reticulum. Exp Cell Res 312: 3546‐3558, 2006.
 26.Arrell DK, Neverova I, Fraser H, Marban E, Van Eyk JE. Proteomic analysis of pharmacologically preconditioned cardiomyocytes reveals novel phosphorylation of myosin light chain 1. Circ Res 89: 480‐487, 2001.
 27.Aryal B, Jeong J, Rao VA. Doxorubicin‐induced carbonylation and degradation of cardiac myosin binding protein C promote cardiotoxicity. Proc Natl Acad Sci U S A 111: 2011‐2016, 2014.
 28.Ashby B, Frieden C. Interaction of AMP‐aminohydrolase with myosin and its subfragments. J Biol Chem 252: 1869‐1872, 1977.
 29.Aslanidis C, Jansen G, Amemiya C, Shutler G, Mahadevan M, Tsilfidis C, Chen C, Alleman J, Wormskamp NG, Vooijs M, et al. Cloning of the essential myotonic dystrophy region and mapping of the putative defect. Nature 355: 548‐551, 1992.
 30.Auckland LM, Lambert SJ, Cummins P. Cardiac myosin light and heavy chain isotypes in tetralogy of Fallot. Cardiovasc Res 20: 828‐836, 1986.
 31.Auerbach D, Bantle S, Keller S, Hinderling V, Leu M, Ehler E, Perriard JC. Different domains of the M‐band protein myomesin are involved in myosin binding and M‐band targeting. Mol Biol Cell 10: 1297‐1308, 1999.
 32.Bagnato P, Barone V, Giacomello E, Rossi D, Sorrentino V. Binding of an ankyrin‐1 isoform to obscurin suggests a molecular link between the sarcoplasmic reticulum and myofibrils in striated muscles. J Cell Biol 160: 245‐253, 2003.
 33.Bahler M, Eppenberger HM, Wallimann T. Novel thick filament protein of chicken pectoralis muscle: The 86 kd protein. I. Purification and characterization. J Mol Biol 186: 381‐391, 1985.
 34.Baines AJ, Lu HC, Bennett PM. The Protein 4.1 family: Hub proteins in animals for organizing membrane proteins. Biochim Biophys Acta 1838: 605‐619, 2014.
 35.Bamshad M, Van Heest AE, Pleasure D. Arthrogryposis: A review and update. J Bone Joint Surg Am 91 (Suppl 4): 40‐46, 2009.
 36.Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M, McNabb M, Witt CC, Labeit D, Gregorio CC, Granzier H, Labeit S. The complete gene sequence of titin, expression of an unusual approximately 700‐kDa titin isoform, and its interaction with obscurin identify a novel Z‐line to I‐band linking system. Circ Res 89: 1065‐1072, 2001.
 37.Bansal D, Campbell KP. Dysferlin and the plasma membrane repair in muscular dystrophy. Trends Cell Biol 14: 206‐213, 2004.
 38.Bar‐Lavan Y, Shemesh N, Ben‐Zvi A. Chaperone families and interactions in metazoa. Essays Biochem 60: 237‐253, 2016.
 39.Barbet JP, Thornell LE, Butler‐Browne GS. Immunocytochemical characterisation of two generations of fibers during the development of the human quadriceps muscle. Mech Dev 35: 3‐11, 1991.
 40.Bardswell SC, Cuello F, Rowland AJ, Sadayappan S, Robbins J, Gautel M, Walker JW, Kentish JC, Avkiran M. Distinct sarcomeric substrates are responsible for protein kinase D‐mediated regulation of cardiac myofilament Ca2+ sensitivity and cross‐bridge cycling. J Biol Chem 285: 5674‐5682, 2010.
 41.Barefield D, Kumar M, Gorham J, Seidman JG, Seidman CE, de Tombe PP, Sadayappan S. Haploinsufficiency of MYBPC3 exacerbates the development of hypertrophic cardiomyopathy in heterozygous mice. J Mol Cell Cardiol 79: 234‐243, 2015.
 42.Barefield D, Sadayappan S. Phosphorylation and function of cardiac myosin binding protein‐C in health and disease. J Mol Cell Cardiol 48: 866‐875, 2010.
 43.Barral JM, Bauer CC, Ortiz I, Epstein HF. Unc‐45 mutations in Caenorhabditis elegans implicate a CRO1/She4p‐like domain in myosin assembly. J Cell Biol 143: 1215‐1225, 1998.
 44.Barral JM, Hutagalung AH, Brinker A, Hartl FU, Epstein HF. Role of the myosin assembly protein UNC‐45 as a molecular chaperone for myosin. Science 295: 669‐671, 2002.
 45.Bashir R, Britton S, Strachan T, Keers S, Vafiadaki E, Lako M, Richard I, Marchand S, Bourg N, Argov Z, Sadeh M, Mahjneh I, Marconi G, Passos‐Bueno MR, Moreira Ede S, Zatz M, Beckmann JS, Bushby K. A gene related to Caenorhabditis elegans spermatogenesis factor fer‐1 is mutated in limb‐girdle muscular dystrophy type 2B. Nat Genet 20: 37‐42, 1998.
 46.Bayram Y, Karaca E, Coban Akdemir Z, Yilmaz EO, Tayfun GA, Aydin H, Torun D, Bozdogan ST, Gezdirici A, Isikay S, Atik MM, Gambin T, Harel T, El‐Hattab AW, Charng WL, Pehlivan D, Jhangiani SN, Muzny DM, Karaman A, Celik T, Yuregir OO, Yildirim T, Bayhan IA, Boerwinkle E, Gibbs RA, Elcioglu N, Tuysuz B, Lupski JR. Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin. J Clin Invest 126: 762‐778, 2016.
 47.Begay RL, Graw S, Sinagra G, Merlo M, Slavov D, Gowan K, Jones KL, Barbati G, Spezzacatene A, Brun F, Di Lenarda A, Smith JE, Granzier HL, Mestroni L, Taylor M, Registry FC. Role of titin missense variants in dilated cardiomyopathy. J Am Heart Assoc 4: 1‐9, 2015.
 48.Behrmann E, Muller M, Penczek PA, Mannherz HG, Manstein DJ, Raunser S. Structure of the rigor actin‐tropomyosin‐myosin complex. Cell 150: 327‐338, 2012.
 49.Benian GM, Tinley TL, Tang X, Borodovsky M. The Caenorhabditis elegans gene unc‐89, required fpr muscle M‐line assembly, encodes a giant modular protein composed of Ig and signal transduction domains. J Cell Biol 132: 835‐848, 1996.
 50.Bennett P, Craig R, Starr R, Offer G. The ultrastructural location of C‐protein, X‐protein and H‐protein in rabbit muscle. J Muscle Res Cell Motil 7: 550‐567, 1986.
 51.Bennett PM, Gautel M. Titin domain patterns correlate with the axial disposition of myosin at the end of the thick filament. J Mol Biol 259: 896‐903, 1996.
 52.Benson MA, Tinsley CL, Blake DJ. Myospryn is a novel binding partner for dysbindin in muscle. J Biol Chem 279: 10450‐10458, 2004.
 53.Berkemeier F, Bertz M, Xiao S, Pinotsis N, Wilmanns M, Grater F, Rief M. Fast‐folding alpha‐helices as reversible strain absorbers in the muscle protein myomesin. Proc Natl Acad Sci U S A 108: 14139‐14144, 2011.
 54.Bezold KL, Shaffer JF, Khosa JK, Hoye ER, Harris SP. A gain‐of‐function mutation in the M‐domain of cardiac myosin‐binding protein‐C increases binding to actin. J Biol Chem 288: 21496‐21505, 2013.
 55.Bhuiyan MS, Gulick J, Osinska H, Gupta M, Robbins J. Determination of the critical residues responsible for cardiac myosin binding protein C's interactions. J Mol Cell Cardiol 53: 838‐847, 2012.
 56.Bicer S, Reiser PJ. Myosin light chain isoform expression among single mammalian skeletal muscle fibers: Species variations. J Muscle Res Cell Motil 25: 623‐633, 2004.
 57.Bloemink MJ, Deacon JC, Resnicow DI, Leinwand LA, Geeves MA. The superfast human extraocular myosin is kinetically distinct from the fast skeletal IIa, IIb, and IId isoforms. J Biol Chem 288: 27469‐27479, 2013.
 58.Bloemink MJ, Melkani GC, Bernstein SI, Geeves MA. The relay/converter interface influences hydrolysis of ATP by skeletal muscle myosin II. J Biol Chem 291: 1763‐1773, 2016.
 59.Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294: 1704‐1708, 2001.
 60.Bogomolovas J, Gasch A, Simkovic F, Rigden DJ, Labeit S, Mayans O. Titin kinase is an inactive pseudokinase scaffold that supports MuRF1 recruitment to the sarcomeric M‐line. Open Biol 4: 140041, 2014.
 61.Bonne G, Carrier L, Bercovici J, Cruaud C, Richard P, Hainque B, Gautel M, Labeit S, James M, Beckmann J, Weissenbach J, Vosberg HP, Fiszman M, Komajda M, Schwartz K. Cardiac myosin binding protein‐C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy. Nat Genet 11: 438‐440, 1995.
 62.Borisov AB, Kontrogianni‐Konstantopoulos A, Bloch RJ, Westfall MV, Russell MW. Dynamics of obscurin localization during differentiation and remodeling of cardiac myocytes: Obscurin as an integrator of myofibrillar structure. J Histochem Cytochem 52: 1117‐1127, 2004.
 63.Borisov AB, Martynova MG, Russell MW. Early incorporation of obscurin into nascent sarcomeres: Implication for myofibril assembly during cardiac myogenesis. Histochem Cell Biol 129: 463‐478, 2008.
 64.Borisov AB, Raeker MO, Kontrogianni‐Konstantopoulos A, Yang K, Kurnit DM, Bloch RJ, Russell MW. Rapid response of cardiac obscurin gene cluster to aortic stenosis: Differential activation of Rho‐GEF and MLCK and involvement in hypertrophic growth. Biochem Biophys Res Commun 310: 910‐918, 2003.
 65.Borisov AB, Raeker MO, Russell MW. Developmental expression and differential cellular localization of obscurin and obscurin‐associated kinase in cardiac muscle cells. J Cell Biochem 103: 1621‐1635, 2008.
 66.Borzok MA, Catino DH, Nicholson JD, Kontrogianni‐Konstantopoulos A, Bloch RJ. Mapping the binding site on small ankyrin 1 for obscurin. J Biol Chem 282: 32384‐32396, 2007.
 67.Bott‐Flugel L, Weig HJ, Uhlein H, Nabauer M, Laugwitz KL, Seyfarth M. Quantitative analysis of apoptotic markers in human end‐stage heart failure. Eur J Heart Fail 10: 129‐132, 2008.
 68.Bowman AL, Catino DH, Strong JC, Randall WR, Kontrogianni‐Konstantopoulos A, Bloch RJ. The rho‐guanine nucleotide exchange factor domain of obscurin regulates assembly of titin at the Z‐disk through interactions with Ran binding protein 9. Mol Biol Cell 19: 3782‐3792, 2008.
 69.Bowman AL, Kontrogianni‐Konstantopoulos A, Hirsch SS, Geisler SB, Gonzalez‐Serratos H, Russell MW, Bloch RJ. Different obscurin isoforms localize to distinct sites at sarcomeres. FEBS Lett 581: 1549‐1554, 2007.
 70.Brenner B, Hahn N, Hanke E, Matinmehr F, Scholz T, Steffen W, Kraft T. Mechanical and kinetic properties of beta‐cardiac/slow skeletal muscle myosin. J Muscle Res Cell Motil 33: 403‐417, 2012.
 71.Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K, Stanton VP, Thirion JP, Hudson T, et al. Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 68: 799‐808, 1992.
 72.Bujalowski PJ, Nicholls P, Oberhauser AF. UNC‐45B chaperone: The role of its domains in the interaction with the myosin motor domain. Biophys J 107: 654‐661, 2014.
 73.Burke M, Sivaramakrishnam M, Kamalakannan V. On the mode of the alkali light chain association to the heavy chain of myosin subfragment 1. Evidence for the involvement of the carboxyl‐terminal region of the heavy chain. Biochemistry 22: 3046‐3053, 1983.
 74.Busby B, Oashi T, Willis CD, Ackermann MA, Kontrogianni‐Konstantopoulos A, Mackerell AD, Jr., Bloch RJ. Electrostatic interactions mediate binding of obscurin to small ankyrin 1: Biochemical and molecular modeling studies. J Mol Biol 408: 321‐334, 2011.
 75.Busby B, Willis CD, Ackermann MA, Kontrogianni‐Konstantopoulos A, Bloch RJ. Characterization and comparison of two binding sites on obscurin for small ankyrin 1. Biochemistry 49: 9948‐9956, 2010.
 76.Buxton J, Shelbourne P, Davies J, Jones C, Van Tongeren T, Aslanidis C, de Jong P, Jansen G, Anvret M, Riley B, et al. Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy. Nature 355: 547‐548, 1992.
 77.Cahill TJ, Ashrafian H, Watkins H. Genetic cardiomyopathies causing heart failure. Circ Res 113: 660‐675, 2013.
 78.Caremani M, Dantzig J, Goldman YE, Lombardi V, Linari M. Effect of inorganic phosphate on the force and number of myosin cross‐bridges during the isometric contraction of permeabilized muscle fibers from rabbit psoas. Biophys J 95: 5798‐5808, 2008.
 79.Caremani M, Melli L, Dolfi M, Lombardi V, Linari M. The working stroke of the myosin II motor in muscle is not tightly coupled to release of orthophosphate from its active site. J Physiol 591: 5187‐5205, 2013.
 80.Carlsson E, Grove BK, Wallimann T, Eppenberger HM, Thornell LE. Myofibrillar M‐band proteins in rat skeletal muscles during development. Histochemistry 95: 27‐35, 1990.
 81.Carlsson L, Yu JG, Thornell LE. New aspects of obscurin in human striated muscles. Histochem Cell Biol 130: 91‐103, 2008.
 82.Carmignac V, Salih MA, Quijano‐Roy S, Marchand S, Al Rayess MM, Mukhtar MM, Urtizberea JA, Labeit S, Guicheney P, Leturcq F, Gautel M, Fardeau M, Campbell KP, Richard I, Estournet B, Ferreiro A. C‐terminal titin deletions cause a novel early‐onset myopathy with fatal cardiomyopathy. Ann Neurol 61: 340‐351, 2007.
 83.Carrier L, Knoll R, Vignier N, Keller DI, Bausero P, Prudhon B, Isnard R, Ambroisine ML, Fiszman M, Ross J, Jr., Schwartz K, Chien KR. Asymmetric septal hypertrophy in heterozygous cMyBP‐C null mice. Cardiovasc Res 63: 293‐304, 2004.
 84.Carrier L, Mearini G, Stathopoulou K, Cuello F. Cardiac myosin‐binding protein C (MYBPC3) in cardiac pathophysiology. Gene 573: 188‐197, 2015.
 85.Cazorla O, Szilagyi S, Vignier N, Salazar G, Kramer E, Vassort G, Carrier L, Lacampagne A. Length and protein kinase A modulations of myocytes in cardiac myosin binding protein C‐deficient mice. Cardiovasc Res 69: 370‐380, 2006.
 86.Cecconi F, Guardiani C, Livi R. Analyzing pathogenic mutations of C5 domain from cardiac myosin binding protein C through MD simulations. Eur Biophys J 37: 683‐691, 2008.
 87.Centner T, Yano J, Kimura E, McElhinny AS, Pelin K, Witt CC, Bang ML, Trombitas K, Granzier H, Gregorio CC, Sorimachi H, Labeit S. Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domain. J Mol Biol 306: 717‐726, 2001.
 88.Ceyhan‐Birsoy O, Agrawal PB, Hidalgo C, Schmitz‐Abe K, DeChene ET, Swanson LC, Soemedi R, Vasli N, Iannaccone ST, Shieh PB, Shur N, Dennison JM, Lawlor MW, Laporte J, Markianos K, Fairbrother WG, Granzier H, Beggs AH. Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. Neurology 81: 1205‐1214, 2013.
 89.Chan JY, Takeda M, Briggs LE, Graham ML, Lu JT, Horikoshi N, Weinberg EO, Aoki H, Sato N, Chien KR, Kasahara H. Identification of cardiac‐specific myosin light chain kinase. Circ Res 102: 571‐580, 2008.
 90.Chang AN, Battiprolu PK, Cowley PM, Chen G, Gerard RD, Pinto JR, Hill JA, Baker AJ, Kamm KE, Stull JT. Constitutive phosphorylation of cardiac myosin regulatory light chain in vivo. J Biol Chem 290: 10703‐10716, 2015.
 91.Chang AN, Mahajan P, Knapp S, Barton H, Sweeney HL, Kamm KE, Stull JT. Cardiac myosin light chain is phosphorylated by Ca2+/calmodulin‐dependent and ‐independent kinase activities. Proc Natl Acad Sci U S A 113: E3824‐E3833, 2016.
 92.Charton K, Danièle N, Vihola A, Roudaut C, Gicquel E, Monjaret F, Tarrade A, Sarparanta J, Udd B, Richard I. Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies. Hum Mol Genet 19: 4608‐4624, 2010.
 93.Charton K, Sarparanta J, Vihola A, Milic A, Jonson PH, Suel L, Luque H, Boumela I, Richard I, Udd B. CAPN3‐mediated processing of C‐terminal titin replaced by pathological cleavage in titinopathy. Hum Mol Genet 24: 3718‐3731, 2015.
 94.Chauveau C, Bonnemann CG, Julien C, Kho AL, Marks H, Talim B, Maury P, Arne‐Bes MC, Uro‐Coste E, Alexandrovich A, Vihola A, Schafer S, Kaufmann B, Medne L, Hübner N, Foley AR, Santi M, Udd B, Topaloglu H, Moore SA, Gotthardt M, Samuels ME, Gautel M, Ferreiro A. Recessive TTN truncating mutations define novel forms of core myopathy with heart disease. Hum Mol Genet 23: 980‐991, 2014.
 95.Chauveau C, Rowell J, Ferreiro A. A rising titan: TTN review and mutation update. Hum Mutat 35: 1046‐1059, 2014.
 96.Chen D, Li S, Singh R, Spinette S, Sedlmeier R, Epstein HF. Dual function of the UNC‐45b chaperone with myosin and GATA4 in cardiac development. J Cell Sci 125: 3893‐3903, 2012.
 97.Chen J, Kubalak SW, Minamisawa S, Price RL, Becker KD, Hickey R, Ross J, Jr., Chien KR. Selective requirement of myosin light chain 2v in embryonic heart function. J Biol Chem 273: 1252‐1256, 1998.
 98.Chen PP, Patel JR, Rybakova IN, Walker JW, Moss RL. Protein kinase A‐induced myofilament desensitization to Ca(2+) as a result of phosphorylation of cardiac myosin‐binding protein C. J Gen Physiol 136: 615‐627, 2010.
 99.Chen Z, Zhao TJ, Li J, Gao YS, Meng FG, Yan YB, Zhou HM. Slow skeletal muscle myosin‐binding protein‐C (MyBPC1) mediates recruitment of muscle‐type creatine kinase (CK) to myosin. Biochem J 436: 437‐445, 2011.
 100.Cho M, Webster SG, Blau HM. Evidence for myoblast‐extrinsic regulation of slow myosin heavy chain expression during muscle fiber formation in embryonic development. J Cell Biol 121: 795‐810, 1993.
 101.Cieniewski‐Bernard C, Dupont E, Richard E, Bastide B. Phospho‐GlcNAc modulation of slow MLC2 during soleus atrophy through a multienzymatic and sarcomeric complex. Pflugers Arch 466: 2139‐2151, 2014.
 102.Cieniewski‐Bernard C, Montel V, Berthoin S, Bastide B. Increasing O‐GlcNAcylation level on organ culture of soleus modulates the calcium activation parameters of muscle fibers. PLoS One 7: e48218, 2012.
 103.Coisy‐Quivy M, Sanguesa‐Ferrer J, Weill M, Johnson DS, Donnay JM, Hipskind R, Fort P, Philips A. Identification of Rho GTPases implicated in terminal differentiation of muscle cells in ascidia. Biol Cell 98: 577‐588, 2006.
 104.Coisy‐Quivy M, Touzet O, Bourret A, Hipskind RA, Mercier J, Fort P, Philips A. TC10 controls human myofibril organization and is activated by the sarcomeric RhoGEF obscurin. J Cell Sci 122: 947‐956, 2009.
 105.Colegrave M, Peckham M. Structural implications of beta‐cardiac myosin heavy chain mutations in human disease. Anat Rec (Hoboken) 297: 1670‐1680, 2014.
 106.Colson BA, Bekyarova T, Locher MR, Fitzsimons DP, Irving TC, Moss RL. Protein kinase A‐mediated phosphorylation of cMyBP‐C increases proximity of myosin heads to actin in resting myocardium. Circ Res 103: 244‐251, 2008.
 107.Condon K, Silberstein L, Blau HM, Thompson WJ. Development of muscle fiber types in the prenatal rat hindlimb. Dev Biol 138: 256‐274, 1990.
 108.Conibear PB, Bagshaw CR, Fajer PG, Kovacs M, Malnasi‐Csizmadia A. Myosin cleft movement and its coupling to actomyosin dissociation. Nat Struct Biol 10: 831‐835, 2003.
 109.Conti A, Riva N, Pesca M, Iannaccone S, Cannistraci CV, Corbo M, Previtali SC, Quattrini A, Alessio M. Increased expression of myosin binding protein H in the skeletal muscle of amyotrophic lateral sclerosis patients. Biochim Biophys Acta 1842: 99‐106, 2014.
 110.Cooke R. The role of the myosin ATPase activity in adaptive thermogenesis by skeletal muscle. Biophys Rev 3: 33‐45, 2011.
 111.Copeland O, Sadayappan S, Messer AE, Steinen GJ, van der Velden J, Marston SB. Analysis of cardiac myosin binding protein‐C phosphorylation in human heart muscle. J Mol Cell Cardiol 49: 1003‐1011, 2010.
 112.Cornachione AS, Leite FS, Wang J, Leu NA, Kalganov A, Volgin D, Han X, Xu T, Cheng YS, Yates JR, III, Rassier DE, Kashina A. Arginylation of myosin heavy chain regulates skeletal muscle strength. Cell Rep 8: 470‐476, 2014.
 113.Craig R, Lee KH, Mun JY, Torre I, Luther PK. Structure, sarcomeric organization, and thin filament binding of cardiac myosin‐binding protein‐C. Pflugers Arch 466: 425‐431, 2014.
 114.Craig R, Offer G. The location of C‐protein in rabbit skeletal muscle. Proc R Soc Lond B Biol Sci 192: 451‐461, 1976.
 115.Cuello F, Bardswell SC, Haworth RS, Ehler E, Sadayappan S, Kentish JC, Avkiran M. Novel role for p90 ribosomal S6 kinase in the regulation of cardiac myofilament phosphorylation. J Biol Chem 286: 5300‐5310, 2011.
 116.Cunha SR, Le Scouarnec S, Schott JJ, Mohler PJ. Exon organization and novel alternative splicing of the human ANK2 gene: Implications for cardiac function and human cardiac disease. J Mol Cell Cardiol 45: 724‐734, 2008.
 117.Cunha SR, Mohler PJ. Obscurin targets ankyrin‐B and protein phosphatase 2A to the cardiac M‐line. J Biol Chem 283: 31968‐31980, 2008.
 118.Dantzig JA, Goldman YE, Millar NC, Lacktis J, Homsher E. Reversal of the cross‐bridge force‐generating transition by photogeneration of phosphate in rabbit psoas muscle fibres. J Physiol 451: 247‐278, 1992.
 119.Davis JS. Interaction of C‐protein with pH 8.0 synthetic thick filaments prepared from the myosin of vertebrate skeletal muscle. J Muscle Res Cell Motil 9: 174‐183, 1988.
 120.De Cid R, Ben Yaou R, Roudaut C, Charton K, Baulande S, Leturcq F, Romero NB, Malfatti E, Beuvin M, Vihola A, Criqui A, Nelson I, Nectoux J, Ben Aim L, Caloustian C, Olaso R, Udd B, Bonne G, Eymard B, Richard I. A new titinopathy: Childhood‐juvenile onset Emery‐Dreifuss‐like phenotype without cardiomyopathy. Neurology 85: 2126‐2135, 2015.
 121.de Seze J, Udd B, Vermersch P. Tibial muscular dystrophy. A rare form of distal myopathy. Rev Neurol (Paris) 155: 296‐305, 1999.
 122.de Tombe PP. Myosin binding protein C in the heart. Circ Res 98: 1234‐1236, 2006.
 123.Dechesne CA, Leger JO, Leger JJ. Distribution of alpha‐ and beta‐myosin heavy chains in the ventricular fibers of the postnatal developing rat. Dev Biol 123: 169‐178, 1987.
 124.Decker RS, Decker ML, Kulikovskaya I, Nakamura S, Lee DC, Harris K, Klocke FJ, Winegrad S. Myosin‐binding protein C phosphorylation, myofibril structure, and contractile function during low‐flow ischemia. Circulation 111: 906‐912, 2005.
 125.Dhandapany PS, Sadayappan S, Xue Y, Powell GT, Rani DS, Nallari P, Rai TS, Khullar M, Soares P, Bahl A, Tharkan JM, Vaideeswar P, Rathinavel A, Narasimhan C, Ayapati DR, Ayub Q, Mehdi SQ, Oppenheimer S, Richards MB, Price AL, Patterson N, Reich D, Singh L, Tyler‐Smith C, Thangaraj K. A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia. Nat Genet 41: 187‐191, 2009.
 126.Ding P, Huang J, Battiprolu PK, Hill JA, Kamm KE, Stull JT. Cardiac myosin light chain kinase is necessary for myosin regulatory light chain phosphorylation and cardiac performance in vivo. J Biol Chem 285: 40819‐40829, 2010.
 127.Dixon DM, Choi J, El‐Ghazali A, Park SY, Roos KP, Jordan MC, Fishbein MC, Comai L, Reddy S. Loss of muscleblind‐like 1 results in cardiac pathology and persistence of embryonic splice isoforms. Sci Rep 5: 9042, 2015.
 128.Dow MR, Mains PE. Genetic and molecular characterization of the caenorhabditis elegans gene, mel‐26, a postmeiotic negative regulator of mei‐1, a meiotic‐specific spindle component. Genetics 150: 119‐128, 1998.
 129.Du A, Sanger JM, Sanger JW. Cardiac myofibrillogenesis inside intact embryonic hearts. Dev Biol 318: 236‐246, 2008.
 130.Edström L, Thornell LE, Albo J, Landin S, Samuelsson M. Myopathy with respiratory failure and typical myofibrillar lesions. J Neurol Sci 96: 211‐228, 1990.
 131.Ehler E, Gautel M. The sarcomere and sarcomerogenesis. Adv Exp Med Biol 642: 1‐14, 2008.
 132.Ehler E, Rothen BM, Hämmerle SP, Komiyama M, Perriard JC. Myofibrillogenesis in the developing chicken heart: Assembly of Z‐disk, M‐line and the thick filaments. J Cell Sci 112 (Pt 10): 1529‐1539, 1999.
 133.Ehlermann P, Weichenhan D, Zehelein J, Steen H, Pribe R, Zeller R, Lehrke S, Zugck C, Ivandic BT, Katus HA. Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene. BMC Med Genet 9: 95, 2008.
 134.Einheber S, Fischman DA. Isolation and characterization of a cDNA clone encoding avian skeletal muscle C‐protein: An intracellular member of the immunoglobulin superfamily. Proc Natl Acad Sci U S A 87: 2157‐2161, 1990.
 135.Ekabe CJ, Kehbila J, Sama CB, Kadia BM, Abanda MH, Monekosso GL. Occurrence of Emery‐Dreifuss muscular dystrophy in a rural setting of Cameroon: A case report and review of the literature. BMC Res Notes 10: 36, 2017.
 136.Ekhilevitch N, Kurolap A, Oz‐Levi D, Mory A, Hershkovitz T, Ast G, Mandel H, Baris HN. Expanding the MYBPC1 phenotypic spectrum: A novel homozygous mutation causes arthrogryposis multiplex congenita. Clin Genet 90: 84‐89, 2016.
 137.Engelhardt WA, Ljubimowa, MN. Myosine and adenosinetriphosphatase. Nature 144: 668‐669, 1939.
 138.England J, Loughna S. Heavy and light roles: Myosin in the morphogenesis of the heart. Cell Mol Life Sci 70: 1221‐1239, 2013.
 139.Eppenberger HM, Perriard JC, Rosenberg UB, Strehler EE. The Mr 165,000 M‐protein myomesin: A specific protein of cross‐striated muscle cells. J Cell Biol 89: 185‐193, 1981.
 140.Evilä A, Vihola A, Sarparanta J, Raheem O, Palmio J, Sandell S, Eymard B, Illa I, Rojas‐Garcia R, Hankiewicz K, Negrão L, Löppönen T, Nokelainen P, Kärppä M, Penttilä S, Screen M, Suominen T, Richard I, Hackman P, Udd B. Atypical phenotypes in titinopathies explained by second titin mutations. Ann Neurol 75: 230‐240, 2014.
 141.Fernando P, Sandoz JS, Ding W, de Repentigny Y, Brunette S, Kelly JF, Kothary R, Megeney LA. Bin1 SRC homology 3 domain acts as a scaffold for myofiber sarcomere assembly. J Biol Chem 284: 27674‐27686, 2009.
 142.Ferrari R, Ceconi C, Curello S, Guarnieri C, Caldarera CM, Albertini A, Visioli O. Oxygen‐mediated myocardial damage during ischaemia and reperfusion: Role of the cellular defences against oxygen toxicity. J Mol Cell Cardiol 17: 937‐945, 1985.
 143.Fert‐Bober J, Sokolove J. Proteomics of citrullination in cardiovascular disease. Proteomics Clin Appl 8: 522‐533, 2014.
 144.Fewell JG, Hewett TE, Sanbe A, Klevitsky R, Hayes E, Warshaw D, Maughan D, Robbins J. Functional significance of cardiac myosin essential light chain isoform switching in transgenic mice. J Clin Invest 101: 2630‐2639, 1998.
 145.Fielitz J, Kim MS, Shelton JM, Latif S, Spencer JA, Glass DJ, Richardson JA, Bassel‐Duby R, Olson EN. Myosin accumulation and striated muscle myopathy result from the loss of muscle RING finger 1 and 3. J Clin Invest 117: 2486‐2495, 2007.
 146.Fielitz J, van Rooij E, Spencer JA, Shelton JM, Latif S, van der Nagel R, Bezprozvannaya S, de Windt L, Richardson JA, Bassel‐Duby R, Olson EN. Loss of muscle‐specific RING‐finger 3 predisposes the heart to cardiac rupture after myocardial infarction. Proc Natl Acad Sci U S A 104: 4377‐4382, 2007.
 147.Finley NL, Cuperman TI. Cardiac myosin binding protein‐C: A structurally dynamic regulator of myocardial contractility. Pflugers Arch 466: 433‐438, 2014.
 148.Fischer S, Windshugel B, Horak D, Holmes KC, Smith JC. Structural mechanism of the recovery stroke in the myosin molecular motor. Proc Natl Acad Sci U S A 102: 6873‐6878, 2005.
 149.Fisher SJ, Helliwell JR, Khurshid S, Govada L, Redwood C, Squire JM, Chayen NE. An investigation into the protonation states of the C1 domain of cardiac myosin‐binding protein C. Acta Crystallogr D Biol Crystallogr 64: 658‐664, 2008.
 150.Fitzsimons DP, Patel JR, Moss RL. Aging‐dependent depression in the kinetics of force development in rat skinned myocardium. Am J Physiol 276: H1511‐H1519, 1999.
 151.Flashman E, Korkie L, Watkins H, Redwood C, Moolman‐Smook JC. Support for a trimeric collar of myosin binding protein C in cardiac and fast skeletal muscle, but not in slow skeletal muscle. FEBS Lett 582: 434‐438, 2008.
 152.Flashman E, Redwood C, Moolman‐Smook J, Watkins H. Cardiac myosin binding protein C: Its role in physiology and disease. Circ Res 94: 1279‐1289, 2004.
 153.Flashman E, Watkins H, Redwood C. Localization of the binding site of the C‐terminal domain of cardiac myosin‐binding protein‐C on the myosin rod. Biochem J 401: 97‐102, 2007.
 154.Flix B, de la Torre C, Castillo J, Casal C, Illa I, Gallardo E. Dysferlin interacts with calsequestrin‐1, myomesin‐2 and dynein in human skeletal muscle. Int J Biochem Cell Biol 45: 1927‐1938, 2013.
 155.Ford‐Speelman DL, Roche JA, Bowman AL, Bloch RJ. The rho‐guanine nucleotide exchange factor domain of obscurin activates rhoA signaling in skeletal muscle. Mol Biol Cell 20: 3905‐3917, 2009.
 156.Fougerousse F, Delezoide AL, Fiszman MY, Schwartz K, Beckmann JS, Carrier L. Cardiac myosin binding protein C gene is specifically expressed in heart during murine and human development. Circ Res 82: 130‐133, 1998.
 157.Franaszczyk M, Chmielewski P, Truszkowska G, Stawinski P, Michalak E, Rydzanicz M, Sobieszczanska‐Malek M, Pollak A, Szczygieł J, Kosinska J, Parulski A, Stoklosa T, Tarnowska A, Machnicki MM, Foss‐Nieradko B, Szperl M, Sioma A, Kusmierczyk M, Grzybowski J, Zielinski T, Ploski R, Bilinska ZT. Titin truncating variants in dilated cardiomyopathy—Prevalence and genotype‐phenotype correlations. PLoS One 12: e0169007, 2017.
 158.Franco D, Markman MM, Wagenaar GT, Ya J, Lamers WH, Moorman AF. Myosin light chain 2a and 2v identifies the embryonic outflow tract myocardium in the developing rodent heart. Anat Rec 254: 135‐146, 1999.
 159.Frank G, Weeds AG. The amino‐acid sequence of the alkali light chains of rabbit skeletal‐muscle myosin. Eur J Biochem 44: 317‐334, 1974.
 160.Freiburg A, Gautel M. A molecular map of the interactions between titin and myosin‐binding protein C. Implications for sarcomeric assembly in familial hypertrophic cardiomyopathy. Eur J Biochem 235: 317‐323, 1996.
 161.Fujioka M, Takahashi N, Odai H, Araki S, Ichikawa K, Feng J, Nakamura M, Kaibuchi K, Hartshorne DJ, Nakano T, Ito M. A new isoform of human myosin phosphatase targeting/regulatory subunit (MYPT2): cDNA cloning, tissue expression, and chromosomal mapping. Genomics 49: 59‐68, 1998.
 162.Fukuzawa A, Idowu S, Gautel M. Complete human gene structure of obscurin: Implications for isoform generation by differential splicing. J Muscle Res Cell Motil 26: 427‐434, 2005.
 163.Fukuzawa A, Lange S, Holt M, Vihola A, Carmignac V, Ferreiro A, Udd B, Gautel M. Interactions with titin and myomesin target obscurin and obscurin‐like 1 to the M‐band: Implications for hereditary myopathies. J Cell Sci 121: 1841‐1851, 2008.
 164.Fürst DO, Osborn M, Nave R, Weber K. The organization of titin filaments in the half‐sarcomere revealed by monoclonal antibodies in immunoelectron microscopy: A map of ten nonrepetitive epitopes starting at the Z line extends close to the M line. J Cell Biol 106: 1563‐1572, 1988.
 165.Furst DO, Vinkemeier U, Weber K. Mammalian skeletal muscle C‐protein: Purification from bovine muscle, binding to titin and the characterization of a full‐length human cDNA. J Cell Sci 102 (Pt 4): 769‐778, 1992.
 166.Fusi L, Huang Z, Irving M. The Conformation of myosin heads in relaxed skeletal muscle: Implications for myosin‐based regulation. Biophys J 109: 783‐792, 2015.
 167.Fusi L, Percario V, Brunello E, Caremani M, Bianco P, Powers JD, Reconditi M, Lombardi V, Piazzesi G. Minimum number of myosin motors accounting for shortening velocity under zero load in skeletal muscle. J Physiol 595: 1127‐1142, 2017.
 168.Gautel M. The super‐repeats of titin/connectin and their interactions: Glimpses at sarcomeric assembly. Adv Biophys 33: 27‐37, 1996.
 169.Gautel M. Cytoskeletal protein kinases: Titin and its relations in mechanosensing. Pflugers Arch 462: 119‐134, 2011.
 170.Gautel M. The sarcomeric cytoskeleton: Who picks up the strain? Curr Opin Cell Biol 23: 39‐46, 2011.
 171.Gautel M, Djinovic‐Carugo K. The sarcomeric cytoskeleton: From molecules to motion. J Exp Biol 219: 135‐145, 2016.
 172.Gautel M, Furst DO, Cocco A, Schiaffino S. Isoform transitions of the myosin binding protein C family in developing human and mouse muscles: Lack of isoform transcomplementation in cardiac muscle. Circ Res 82: 124‐129, 1998.
 173.Gautel M, Leonard K, Labeit S. Phosphorylation of KSP motifs in the C‐terminal region of titin in differentiating myoblasts. EMBO J 12: 3827‐3834, 1993.
 174.Gautel M, Zuffardi O, Freiburg A, Labeit S. Phosphorylation switches specific for the cardiac isoform of myosin binding protein‐C: A modulator of cardiac contraction? EMBO J 14: 1952‐1960, 1995.
 175.Ge Y, Rybakova IN, Xu Q, Moss RL. Top‐down high‐resolution mass spectrometry of cardiac myosin binding protein C revealed that truncation alters protein phosphorylation state. Proc Natl Acad Sci U S A 106: 12658‐12663, 2009.
 176.Geeves MA, Holmes KC. Structural mechanism of muscle contraction. Annu Rev Biochem 68: 687‐728, 1999.
 177.Geisler SB, Robinson D, Hauringa M, Raeker MO, Borisov AB, Westfall MV, Russell MW. Obscurin‐like 1, OBSL1, is a novel cytoskeletal protein related to obscurin. Genomics 89: 521‐531, 2007.
 178.Gerull B. The rapidly evolving role of titin in cardiac physiology and cardiomyopathy. Can J Cardiol 31: 1351‐1359, 2015.
 179.Gerull B, Atherton J, Geupel A, Sasse‐Klaassen S, Heuser A, Frenneaux M, McNabb M, Granzier H, Labeit S, Thierfelder L. Identification of a novel frameshift mutation in the giant muscle filament titin in a large Australian family with dilated cardiomyopathy. J Mol Med (Berl) 84: 478‐483, 2006.
 180.Gerull B, Gramlich M, Atherton J, McNabb M, Trombitas K, Sasse‐Klaassen S, Seidman JG, Seidman C, Granzier H, Labeit S, Frenneaux M, Thierfelder L. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet 30: 201‐204, 2002.
 181.Giacomello E, Sorrentino V. Localization of ank1.5 in the sarcoplasmic reticulum precedes that of SERCA and RyR: Relationship with the organization of obscurin in developing sarcomeres. Histochem Cell Biol 131: 371‐382, 2009.
 182.Gigli M, Begay RL, Morea G, Graw SL, Sinagra G, Taylor MR, Granzier H, Mestroni L. A review of the giant protein titin in clinical molecular diagnostics of cardiomyopathies. Front Cardiovasc Med 3: 21, 2016.
 183.Gilbert R, Cohen JA, Pardo S, Basu A, Fischman DA. Identification of the A‐band localization domain of myosin binding proteins C and H (MyBP‐C, MyBP‐H) in skeletal muscle. J Cell Sci 112 (Pt 1): 69‐79, 1999.
 184.Goel HL, Dey CS. Insulin‐mediated tyrosine phosphorylation of myosin heavy chain and concomitant enhanced association of C‐terminal SRC kinase during skeletal muscle differentiation. Cell Biol Int 26: 557‐561, 2002.
 185.Golenhofen N, Perng MD, Quinlan RA, Drenckhahn D. Comparison of the small heat shock proteins alphaB‐crystallin, MKBP, HSP25, HSP20, and cvHSP in heart and skeletal muscle. Histochem Cell Biol 122: 415‐425, 2004.
 186.Gollapudi SK, Gallon CE, Chandra M. The tropomyosin binding region of cardiac troponin T modulates crossbridge recruitment dynamics in rat cardiac muscle fibers. J Mol Biol 425: 1565‐1581, 2013.
 187.Gollapudi SK, Mamidi R, Mallampalli SL, Chandra M. The N‐terminal extension of cardiac troponin T stabilizes the blocked state of cardiac thin filament. Biophys J 103: 940‐948, 2012.
 188.Gordon AM, Homsher E, Regnier M. Regulation of contraction in striated muscle. Physiol Rev 80: 853‐924, 2000.
 189.Govindan S, McElligott A, Muthusamy S, Nair N, Barefield D, Martin JL, Gongora E, Greis KD, Luther PK, Winegrad S, Henderson KK, Sadayappan S. Cardiac myosin binding protein‐C is a potential diagnostic biomarker for myocardial infarction. J Mol Cell Cardiol 52: 154‐164, 2012.
 190.Gramlich M, Pane LS, Zhou Q, Chen Z, Murgia M, Schotterl S, Goedel A, Metzger K, Brade T, Parrotta E, Schaller M, Gerull B, Thierfelder L, Aartsma‐Rus A, Labeit S, Atherton JJ, McGaughran J, Harvey RP, Sinnecker D, Mann M, Laugwitz KL, Gawaz MP, Moretti A. Antisense‐mediated exon skipping: A therapeutic strategy for titin‐based dilated cardiomyopathy. EMBO Mol Med 7: 562‐576, 2015.
 191.Granzier H, Labeit S. Cardiac titin: An adjustable multi‐functional spring. J Physiol 541: 335‐342, 2002.
 192.Granzier HL, Labeit S. The giant protein titin: A major player in myocardial mechanics, signaling, and disease. Circ Res 94: 284‐295, 2004.
 193.Granzier HL, Labeit S. The giant muscle protein titin is an adjustable molecular spring. Exerc Sport Sci Rev 34: 50‐53, 2006.
 194.Grassie ME, Moffat LD, Walsh MP, MacDonald JA. The myosin phosphatase targeting protein (MYPT) family: A regulated mechanism for achieving substrate specificity of the catalytic subunit of protein phosphatase type 1delta. Arch Biochem Biophys 510: 147‐159, 2011.
 195.Grater F, Shen J, Jiang H, Gautel M, Grubmuller H. Mechanically induced titin kinase activation studied by force‐probe molecular dynamics simulations. Biophys J 88: 790‐804, 2005.
 196.Gregorich ZR, Peng Y, Cai W, Jin Y, Wei L, Chen AJ, McKiernan SH, Aiken JM, Moss RL, Diffee GM, Ge Y. Top‐down targeted proteomics reveals decrease in myosin regulatory light‐chain phosphorylation that contributes to sarcopenic muscle dysfunction. J Proteome Res 15: 2706‐2716, 2016.
 197.Gregorio CC, Granzier H, Sorimachi H, Labeit S. Muscle assembly: A titanic achievement? Curr Opin Cell Biol 11: 18‐25, 1999.
 198.Gregorio CC, Perry CN, McElhinny AS. Functional properties of the titin/connectin‐associated proteins, the muscle‐specific RING finger proteins (MURFs), in striated muscle. J Muscle Res Cell Motil 26: 389‐400, 2005.
 199.Gresham KS, Stelzer JE. The contributions of cardiac myosin binding protein C and troponin I phosphorylation to beta‐adrenergic enhancement of in vivo cardiac function. J Physiol 594: 669‐686, 2016.
 200.Grimm M, Haas P, Willipinski‐Stapelfeldt B, Zimmermann WH, Rau T, Pantel K, Weyand M, Eschenhagen T. Key role of myosin light chain (MLC) kinase‐mediated MLC2a phosphorylation in the alpha 1‐adrenergic positive inotropic effect in human atrium. Cardiovasc Res 65: 211‐220, 2005.
 201.Grimm M, Mahnecke N, Soja F, El‐Armouche A, Haas P, Treede H, Reichenspurner H, Eschenhagen T. The MLCK‐mediated alpha1‐adrenergic inotropic effect in atrial myocardium is negatively modulated by PKCepsilon signaling. Br J Pharmacol 148: 991‐1000, 2006.
 202.Grose JH, Langston K, Wang X, Squires S, Mustafi SB, Hayes W, Neubert J, Fischer SK, Fasano M, Saunders GM, Dai Q, Christians E, Lewandowski ED, Ping P, Benjamin IJ. Characterization of the cardiac overexpression of HSPB2 reveals mitochondrial and myogenic roles supported by a cardiac HspB2 interactome. PLoS One 10: e0133994, 2015.
 203.Grove BK, Cerny L, Perriard JC, Eppenberger HM. Myomesin and M‐protein: Expression of two M‐band proteins in pectoral muscle and heart during development. J Cell Biol 101: 1413‐1421, 1985.
 204.Grove BK, Cerny L, Perriard JC, Eppenberger HM, Thornell LE. Fiber type‐specific distribution of M‐band proteins in chicken muscle. J Histochem Cytochem 37: 447‐454, 1989.
 205.Grove BK, Holmbom B, Thornell LE. Myomesin and M protein: Differential expression in embryonic fibers during pectoral muscle development. Differentiation 34: 106‐114, 1987.
 206.Grove BK, Kurer V, Lehner C, Doetschman TC, Perriard JC, Eppenberger HM. A new 185,000‐dalton skeletal muscle protein detected by monoclonal antibodies. J Cell Biol 98: 518‐524, 1984.
 207.Gruen M, Gautel M. Mutations in beta‐myosin S2 that cause familial hypertrophic cardiomyopathy (FHC) abolish the interaction with the regulatory domain of myosin‐binding protein‐C. J Mol Biol 286: 933‐949, 1999.
 208.Gruen M, Prinz H, Gautel M. cAPK‐phosphorylation controls the interaction of the regulatory domain of cardiac myosin binding protein C with myosin‐S2 in an on‐off fashion. FEBS Lett 453: 254‐259, 1999.
 209.Guan K, Rohwedel J, Wobus AM. Embryonic stem cell differentiation models: Cardiogenesis, myogenesis, neurogenesis, epithelial and vascular smooth muscle cell differentiation in vitro. Cytotechnology 30: 211‐226, 1999.
 210.Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, Besenbacher S, Magnusson G, Halldorsson BV, Hjartarson E, Sigurdsson GT, Stacey SN, Frigge ML, Holm H, Saemundsdottir J, Helgadottir HT, Johannsdottir H, Sigfusson G, Thorgeirsson G, Sverrisson JT, Gretarsdottir S, Walters GB, Rafnar T, Thjodleifsson B, Bjornsson ES, Olafsson S, Thorarinsdottir H, Steingrimsdottir T, Gudmundsdottir TS, Theodors A, Jonasson JG, Sigurdsson A, Bjornsdottir G, Jonsson JJ, Thorarensen O, Ludvigsson P, Gudbjartsson H, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Arnar DO, Magnusson OT, Kong A, Masson G, Thorsteinsdottir U, Helgason A, Sulem P, Stefansson K. Large‐scale whole‐genome sequencing of the Icelandic population. Nat Genet 47: 435‐444, 2015.
 211.Guellich A, Negroni E, Decostre V, Demoule A, Coirault C. Altered cross‐bridge properties in skeletal muscle dystrophies. Front Physiol 5: 393, 2014.
 212.Guhathakurta P, Prochniewicz E, Thomas DD. Amplitude of the actomyosin power stroke depends strongly on the isoform of the myosin essential light chain. Proc Natl Acad Sci U S A 112: 4660‐4665, 2015.
 213.Gupta MK, Robbins J. Post‐translational control of cardiac hemodynamics through myosin binding protein C. Pflugers Arch 466: 231‐236, 2014.
 214.Gurnett CA, Desruisseau DM, McCall K, Choi R, Meyer ZI, Talerico M, Miller SE, Ju JS, Pestronk A, Connolly AM, Druley TE, Weihl CC, Dobbs MB. Myosin binding protein C1: A novel gene for autosomal dominant distal arthrogryposis type 1. Hum Mol Genet 19: 1165‐1173, 2010.
 215.Hackman P, Marchand S, Sarparanta J, Vihola A, Pénisson‐Besnier I, Eymard B, Pardal‐Fernández JM, Hammouda e‐H, Richard I, Illa I, Udd B. Truncating mutations in C‐terminal titin may cause more severe tibial muscular dystrophy (TMD). Neuromuscul Disord 18: 922‐928, 2008.
 216.Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, Labeit S, Witt C, Peltonen L, Richard I, Udd B. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal‐muscle protein titin. Am J Hum Genet 71: 492‐500, 2002.
 217.Hall JG. Genetic aspects of arthrogryposis. Clin Orthop Relat Res: 44‐53, 1985.
 218.Han YS, Geiger PC, Cody MJ, Macken RL, Sieck GC. ATP consumption rate per cross bridge depends on myosin heavy chain isoform. J Appl Physiol (1985) 94: 2188‐2196, 2003.
 219.Han Z, Hendrickson EA, Bremner TA, Wyche JH. A sequential two‐step mechanism for the production of the mature p17:p12 form of caspase‐3 in vitro. J Biol Chem 272: 13432‐13436, 1997.
 220.Haravuori H, Vihola A, Straub V, Auranen M, Richard I, Marchand S, Voit T, Labeit S, Somer H, Peltonen L, Beckmann JS, Udd B. Secondary calpain3 deficiency in 2q‐linked muscular dystrophy: Titin is the candidate gene. Neurology 56: 869‐877, 2001.
 221.Harley HG, Brook JD, Rundle SA, Crow S, Reardon W, Buckler AJ, Harper PS, Housman DE, Shaw DJ. Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature 355: 545‐546, 1992.
 222.Harris SP, Bartley CR, Hacker TA, McDonald KS, Douglas PS, Greaser ML, Powers PA, Moss RL. Hypertrophic cardiomyopathy in cardiac myosin binding protein‐C knockout mice. Circ Res 90: 594‐601, 2002.
 223.Harris SP, Lyons RG, Bezold KL. In the thick of it: HCM‐causing mutations in myosin binding proteins of the thick filament. Circ Res 108: 751‐764, 2011.
 224.Hartzell HC. Effects of phosphorylated and unphosphorylated C‐protein on cardiac actomyosin ATPase. J Mol Biol 186: 185‐195, 1985.
 225.Hayashibara T, Miyanishi T. Binding of the amino‐terminal region of myosin alkali 1 light chain to actin and its effect on actin‐myosin interaction. Biochemistry 33: 12821‐12827, 1994.
 226.He ZH, Bottinelli R, Pellegrino MA, Ferenczi MA, Reggiani C. ATP consumption and efficiency of human single muscle fibers with different myosin isoform composition. Biophys J 79: 945‐961, 2000.
 227.Hedberg C, Melberg A, Dahlbom K, Oldfors A. Hereditary myopathy with early respiratory failure is caused by mutations in the titin FN3 119 domain. Brain 137: e270, 2014.
 228.Hedberg C, Toledo AG, Gustafsson CM, Larson G, Oldfors A, Macao B. Hereditary myopathy with early respiratory failure is associated with misfolding of the titin fibronectin III 119 subdomain. Neuromuscul Disord 24: 373‐379, 2014.
 229.Hedou J, Bastide B, Page A, Michalski JC, Morelle W. Mapping of O‐linked beta‐N‐acetylglucosamine modification sites in key contractile proteins of rat skeletal muscle. Proteomics 9: 2139‐2148, 2009.
 230.Hedou J, Cieniewski‐Bernard C, Leroy Y, Michalski JC, Mounier Y, Bastide B. O‐linked N‐acetylglucosaminylation is involved in the Ca2+ activation properties of rat skeletal muscle. J Biol Chem 282: 10360‐10369, 2007.
 231.Heissler SM, Sellers JR. Myosin light chains: Teaching old dogs new tricks. Bioarchitecture 4: 169‐188, 2014.
 232.Heissler SM, Sellers JR. Various themes of myosin regulation. J Mol Biol 428: 1927‐1946, 2016.
 233.Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG, Seidman CE. Truncations of titin causing dilated cardiomyopathy. N Engl J Med 366: 619‐628, 2012.
 234.Herring BP, England PJ. The turnover of phosphate bound to myosin light chain‐2 in perfused rat heart. Biochem J 240: 205‐214, 1986.
 235.Hidalgo C, Granzier H. Tuning the molecular giant titin through phosphorylation: Role in health and disease. Trends Cardiovasc Med 23: 165‐171, 2013.
 236.Hisatome I, Morisaki T, Kamma H, Sugama T, Morisaki H, Ohtahara A, Holmes EW. Control of AMP deaminase 1 binding to myosin heavy chain. Am J Physiol 275: C870‐C881, 1998.
 237.Hofmann PA, Greaser ML, Moss RL. C‐protein limits shortening velocity of rabbit skeletal muscle fibres at low levels of Ca2+ activation. J Physiol 439: 701‐715, 1991.
 238.Hojlund K, Bowen BP, Hwang H, Flynn CR, Madireddy L, Geetha T, Langlais P, Meyer C, Mandarino LJ, Yi Z. In vivo phosphoproteome of human skeletal muscle revealed by phosphopeptide enrichment and HPLC‐ESI‐MS/MS. J Proteome Res 8: 4954‐4965, 2009.
 239.Holmes KC, Angert I, Kull FJ, Jahn W, Schroder RR. Electron cryo‐microscopy shows how strong binding of myosin to actin releases nucleotide. Nature 425: 423‐427, 2003.
 240.Homburger JR, Green EM, Caleshu C, Sunitha MS, Taylor RE, Ruppel KM, Metpally RP, Colan SD, Michels M, Day SM, Olivotto I, Bustamante CD, Dewey FE, Ho CY, Spudich JA, Ashley EA. Multidimensional structure‐function relationships in human beta‐cardiac myosin from population‐scale genetic variation. Proc Natl Acad Sci U S A 113: 6701‐6706, 2016.
 241.Hooijman P, Stewart MA, Cooke R. A new state of cardiac myosin with very slow ATP turnover: A potential cardioprotective mechanism in the heart. Biophys J 100: 1969‐1976, 2011.
 242.Hornemann T, Kempa S, Himmel M, Hayess K, Furst DO, Wallimann T. Muscle‐type creatine kinase interacts with central domains of the M‐band proteins myomesin and M‐protein. J Mol Biol 332: 877‐887, 2003.
 243.Hornemann T, Stolz M, Wallimann T. Isoenzyme‐specific interaction of muscle‐type creatine kinase with the sarcomeric M‐line is mediated by NH(2)‐terminal lysine charge‐clamps. J Cell Biol 149: 1225‐1234, 2000.
 244.Hoskins AC, Jacques A, Bardswell SC, McKenna WJ, Tsang V, dos Remedios CG, Ehler E, Adams K, Jalilzadeh S, Avkiran M, Watkins H, Redwood C, Marston SB, Kentish JC. Normal passive viscoelasticity but abnormal myofibrillar force generation in human hypertrophic cardiomyopathy. J Mol Cell Cardiol 49: 737‐745, 2010.
 245.Houdusse A, Sweeney HL. How myosin generates force on actin filaments. Trends Biochem Sci 41: 989‐997, 2016.
 246.Houmeida A, Holt J, Tskhovrebova L, Trinick J. Studies of the interaction between titin and myosin. J Cell Biol 131: 1471‐1481, 1995.
 247.Hu LY, Ackermann MA, Kontrogianni‐Konstantopoulos A. The sarcomeric M‐region: A molecular command center for diverse cellular processes. Biomed Res Int 2015: 714197, 2015.
 248.Hu LY, Kontrogianni‐Konstantopoulos A. The kinase domains of obscurin interact with intercellular adhesion proteins. FASEB J 27: 2001‐2012, 2013.
 249.Hu LYR, Ackermann MA, Hecker PA, Prosser BL, King B, O’ Connell KA, Grogan A, Meyer LC, Berndsen CE, Wright NT, Lederer WJ, Kontrogianni‐Konstantopoulos A. Deregulated Ca2+ cycling underlies the development of arrhythmia and heart disease due to mutant obscurin. Sci Adv 3: e1603081, 2017.
 250.Hu Z, Yang B, Lu W, Zhou W, Zeng L, Li T, Wang X. HSPB2/MKBP, a novel and unique member of the small heat‐shock protein family. J Neurosci Res 86: 2125‐2133, 2008.
 251.Huang C, Sheikh F, Hollander M, Cai C, Becker D, Chu PH, Evans S, Chen J. Embryonic atrial function is essential for mouse embryogenesis, cardiac morphogenesis and angiogenesis. Development 130: 6111‐6119, 2003.
 252.Huang SC, Zhou A, Nguyen DT, Zhang HS, Benz EJ, Jr. Protein 4.1R influences myogenin protein stability and skeletal muscle differentiation. J Biol Chem 291: 25591‐25607, 2016.
 253.Huang W, Szczesna‐Cordary D. Molecular mechanisms of cardiomyopathy phenotypes associated with myosin light chain mutations. J Muscle Res Cell Motil 36: 433‐445, 2015.
 254.Hughes SM, Cho M, Karsch‐Mizrachi I, Travis M, Silberstein L, Leinwand LA, Blau HM. Three slow myosin heavy chains sequentially expressed in developing mammalian skeletal muscle. Dev Biol 158: 183‐199, 1993.
 255.Huxley AF, Niedergerke R. Structural changes in muscle during contraction; interference microscopy of living muscle fibres. Nature 173: 971‐973, 1954.
 256.Huxley H, Hanson J. Changes in the cross‐striations of muscle during contraction and stretch and their structural interpretation. Nature 173: 973‐976, 1954.
 257.Huxley HE, Brown W. The low‐angle x‐ray diagram of vertebrate striated muscle and its behaviour during contraction and rigor. J Mol Biol 30: 383‐434, 1967.
 258.Idowu SM, Gautel M, Perkins SJ, Pfuhl M. Structure, stability and dynamics of the central domain of cardiac myosin binding protein C (MyBP‐C): Implications for multidomain assembly and causes for cardiomyopathy. J Mol Biol 329: 745‐761, 2003.
 259.Isaacs WB, Kim IS, Struve A, Fulton AB. Association of titin and myosin heavy chain in developing skeletal muscle. Proc Natl Acad Sci U S A 89: 7496‐7500, 1992.
 260.Izumi R, Niihori T, Aoki Y, Suzuki N, Kato M, Warita H, Takahashi T, Tateyama M, Nagashima T, Funayama R, Abe K, Nakayama K, Aoki M, Matsubara Y. Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure. J Hum Genet 58: 259‐266, 2013.
 261.Jacques A, Hoskins AC, Kentish JC, Marston SB. From genotype to phenotype: A longitudinal study of a patient with hypertrophic cardiomyopathy due to a mutation in the MYBPC3 gene. J Muscle Res Cell Motil 29: 239‐246, 2008.
 262.James J, Robbins J. Signaling and myosin‐binding protein C. J Biol Chem 286: 9913‐9919, 2011.
 263.Jansweijer JA, Nieuwhof K, Russo F, Hoorntje ET, Jongbloed JD, Lekanne Deprez RH, Postma AV, Bronk M, van Rijsingen IA, de Haij S, Biagini E, van Haelst PL, van Wijngaarden J, van den Berg MP, Wilde AA, Mannens MM, de Boer RA, van Spaendonck‐Zwarts KY, van Tintelen JP, Pinto YM. Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy. Eur J Heart Fail 19(4): 512‐521, 2017.
 264.Jeffries CM, Whitten AE, Harris SP, Trewhella J. Small‐angle X‐ray scattering reveals the N‐terminal domain organization of cardiac myosin binding protein C. J Mol Biol 377: 1186‐1199, 2008.
 265.Jiang BH, Aoki M, Zheng JZ, Li J, Vogt PK. Myogenic signaling of phosphatidylinositol 3‐kinase requires the serine‐threonine kinase Akt/protein kinase B. Proc Natl Acad Sci U S A 96: 2077‐2081, 1999.
 266.Jiang J, Burgon PG, Wakimoto H, Onoue K, Gorham JM, O'Meara CC, Fomovsky G, McConnell BK, Lee RT, Seidman JG, Seidman CE. Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis. Proc Natl Acad Sci U S A 112: 9046‐9051, 2015.
 267.Johansen T, Lamark T. Selective autophagy mediated by autophagic adapter proteins. Autophagy 7: 279‐296, 2011.
 268.Kabsch W, Mannherz HG, Suck D, Pai EF, Holmes KC. Atomic structure of the actin:DNase I complex. Nature 347: 37‐44, 1990.
 269.Kamm KE, Stull JT. Dedicated myosin light chain kinases with diverse cellular functions. J Biol Chem 276: 4527‐4530, 2001.
 270.Kamm KE, Stull JT. Signaling to myosin regulatory light chain in sarcomeres. J Biol Chem 286: 9941‐9947, 2011.
 271.Kampourakis T, Sun YB, Irving M. Myosin light chain phosphorylation enhances contraction of heart muscle via structural changes in both thick and thin filaments. Proc Natl Acad Sci U S A 113: E3039‐E3047, 2016.
 272.Karsai A, Kellermayer MS, Harris SP. Mechanical unfolding of cardiac myosin binding protein‐C by atomic force microscopy. Biophys J 101: 1968‐1977, 2011.
 273.Kass DA, Chen CH, Curry C, Talbot M, Berger R, Fetics B, Nevo E. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 99: 1567‐1573, 1999.
 274.Kassem H, Azer RS, Saber‐Ayad M, Moharem‐Elgamal S, Magdy G, Elguindy A, Cecchi F, Olivotto I, Yacoub MH. Early results of sarcomeric gene screening from the Egyptian National BA‐HCM Program. J Cardiovasc Transl Res 6: 65‐80, 2013.
 275.Katzemich A, Kreiskother N, Alexandrovich A, Elliott C, Schock F, Leonard K, Sparrow J, Bullard B. The function of the M‐line protein obscurin in controlling the symmetry of the sarcomere in the flight muscle of Drosophila. J Cell Sci 125: 3367‐3379, 2012.
 276.Katzemich A, West RJ, Fukuzawa A, Sweeney ST, Gautel M, Sparrow J, Bullard B. Binding partners of the kinase domains in Drosophila obscurin and their effect on the structure of the flight muscle. J Cell Sci 128: 3386‐3397, 2015.
 277.Kazmierczak K, Xu Y, Jones M, Guzman G, Hernandez OM, Kerrick WG, Szczesna‐Cordary D. The role of the N‐terminus of the myosin essential light chain in cardiac muscle contraction. J Mol Biol 387: 706‐725, 2009.
 278.Kenyon GL, Reed GH. Creatine kinase: Structure‐activity relationships. Adv Enzymol Relat Areas Mol Biol 54: 367‐426, 1983.
 279.Kiani FA, Fischer S. ATP‐dependent interplay between local and global conformational changes in the myosin motor. Cytoskeleton (Hoboken) 73: 643‐651, 2016.
 280.Kimura S, Maruyama K, Huang YP. Interactions of muscle beta‐connectin with myosin, actin, and actomyosin at low ionic strengths. J Biochem 96: 499‐506, 1984.
 281.Kirk JA, Holewinski RJ, Kooij V, Agnetti G, Tunin RS, Witayavanitkul N, de Tombe PP, Gao WD, Van Eyk J, Kass DA. Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK‐3beta. J Clin Invest 124: 129‐138, 2014.
 282.Klemp P, Hall JG. Dominant distal arthrogryposis in a Maori family with marked variability of expression. Am J Med Genet 55: 414‐419, 1995.
 283.Kockskamper J, Khafaga M, Grimm M, Elgner A, Walther S, Kockskamper A, von Lewinski D, Post H, Grossmann M, Dorge H, Gottlieb PA, Sachs F, Eschenhagen T, Schondube FA, Pieske B. Angiotensin II and myosin light‐chain phosphorylation contribute to the stretch‐induced slow force response in human atrial myocardium. Cardiovasc Res 79: 642‐651, 2008.
 284.Koebis M, Ohsawa N, Kino Y, Sasagawa N, Nishino I, Ishiura S. Alternative splicing of myomesin 1 gene is aberrantly regulated in myotonic dystrophy type 1. Genes Cells 16: 961‐972, 2011.
 285.Kohr MJ, Aponte AM, Sun J, Wang G, Murphy E, Gucek M, Steenbergen C. Characterization of potential S‐nitrosylation sites in the myocardium. Am J Physiol Heart Circ Physiol 300: H1327‐H1335, 2011.
 286.Kolmerer B, Olivieri N, Witt CC, Herrmann BG, Labeit S. Genomic organization of M line titin and its tissue‐specific expression in two distinct isoforms. J Mol Biol 256: 556‐563, 1996.
 287.Kontrogianni‐Konstantopoulos A, Ackermann MA, Bowman AL, Yap SV, Bloch RJ. Muscle giants: Molecular scaffolds in sarcomerogenesis. Physiol Rev 89: 1217‐1267, 2009.
 288.Kontrogianni‐Konstantopoulos A, Bloch RJ. Obscurin: A multitasking muscle giant. J Muscle Res Cell Motil 26: 419‐426, 2005.
 289.Kontrogianni‐Konstantopoulos A, Catino DH, Strong JC, Bloch RJ. De novo myofibrillogenesis in C2C12 cells: Evidence for the independent assembly of M bands and Z disks. Am J Physiol Cell Physiol 290: C626‐C637, 2006.
 290.Kontrogianni‐Konstantopoulos A, Catino DH, Strong JC, Randall WR, Bloch RJ. Obscurin regulates the organization of myosin into A bands. Am J Physiol Cell Physiol 287: C209‐C217, 2004.
 291.Kontrogianni‐Konstantopoulos A, Catino DH, Strong JC, Sutter S, Borisov AB, Pumplin DW, Russell MW, Bloch RJ. Obscurin modulates the assembly and organization of sarcomeres and the sarcoplasmic reticulum. FASEB J 20: 2102‐2111, 2006.
 292.Kontrogianni‐Konstantopoulos A, Huang SC, Benz EJ, Jr. A nonerythroid isoform of protein 4.1R interacts with components of the contractile apparatus in skeletal myofibers. Mol Biol Cell 11: 3805‐3817, 2000.
 293.Kontrogianni‐Konstantopoulos A, Jones EM, Van Rossum DB, Bloch RJ. Obscurin is a ligand for small ankyrin 1 in skeletal muscle. Mol Biol Cell 14: 1138‐1148, 2003.
 294.Kramerova I, Kudryashova E, Tidball JG, Spencer MJ. Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro. Hum Mol Genet 13: 1373‐1388, 2004.
 295.Kruger M, Kotter S. Titin, a central mediator for hypertrophic signaling, exercise‐induced mechanosignaling and skeletal muscle remodeling. Front Physiol 7: 76, 2016.
 296.Kubalak SW, Miller‐Hance WC, O'Brien TX, Dyson E, Chien KR. Chamber specification of atrial myosin light chain‐2 expression precedes septation during murine cardiogenesis. J Biol Chem 269: 16961‐16970, 1994.
 297.Kuhne W. Untersuchungen uber das Protoplasma und die Contractilitat. Leipzig: W. Engelmann, 1864.
 298.Kulikovskaya I, McClellan G, Flavigny J, Carrier L, Winegrad S. Effect of MyBP‐C binding to actin on contractility in heart muscle. J Gen Physiol 122: 761‐774, 2003.
 299.Kulikovskaya I, McClellan G, Levine R, Winegrad S. Effect of extraction of myosin binding protein C on contractility of rat heart. Am J Physiol Heart Circ Physiol 285: H857‐H865, 2003.
 300.Kulkarni KP, Panigrahi I, Ray M, Marwaha RK. Distal arthrogryposis syndrome. Indian J Hum Genet 14: 67‐69, 2008.
 301.Kunst G, Kress KR, Gruen M, Uttenweiler D, Gautel M, Fink RH. Myosin binding protein C, a phosphorylation‐dependent force regulator in muscle that controls the attachment of myosin heads by its interaction with myosin S2. Circ Res 86: 51‐58, 2000.
 302.Kurasawa M, Sato N, Matsuda A, Koshida S, Totsuka T, Obinata T. Differential expression of C‐protein isoforms in developing and degenerating mouse striated muscles. Muscle Nerve 22: 196‐207, 1999.
 303.Kurosaka S, Leu NA, Pavlov I, Han X, Ribeiro PA, Xu T, Bunte R, Saha S, Wang J, Cornachione A, Mai W, Yates JR, III, Rassier DE, Kashina A. Arginylation regulates myofibrils to maintain heart function and prevent dilated cardiomyopathy. J Mol Cell Cardiol 53: 333‐341, 2012.
 304.Kuster DW, Sadayappan S. MYBPC3’s alternate ending: Consequences and therapeutic implications of a highly prevalent 25 bp deletion mutation. Pflugers Arch 466: 207‐213, 2014.
 305.Kuster DW, Sequeira V, Najafi A, Boontje NM, Wijnker PJ, Witjas‐Paalberends ER, Marston SB, Dos Remedios CG, Carrier L, Demmers JA, Redwood C, Sadayappan S, van der Velden J. GSK3beta phosphorylates newly identified site in the proline‐alanine‐rich region of cardiac myosin‐binding protein C and alters cross‐bridge cycling kinetics in human: Short communication. Circ Res 112: 633‐639, 2013.
 306.Labeit S, Gautel M, Lakey A, Trinick J. Towards a molecular understanding of titin. EMBO J 11: 1711‐1716, 1992.
 307.Labeit S, Kolmerer B. Titins: Giant proteins in charge of muscle ultrastructure and elasticity. Science 270: 293‐296, 1995.
 308.Lamark T, Perander M, Outzen H, Kristiansen K, Øvervatn A, Michaelsen E, Bjørkøy G, Johansen T. Interaction codes within the family of mammalian Phox and Bem1p domain‐containing proteins. J Biol Chem 278: 34568‐34581, 2003.
 309.Lamont PJ, Wallefeld W, Hilton‐Jones D, Udd B, Argov Z, Barboi AC, Bonneman C, Boycott KM, Bushby K, Connolly AM, Davies N, Beggs AH, Cox GF, Dastgir J, DeChene ET, Gooding R, Jungbluth H, Muelas N, Palmio J, Penttilä S, Schmedding E, Suominen T, Straub V, Staples C, Van den Bergh PY, Vilchez JJ, Wagner KR, Wheeler PG, Wraige E, Laing NG. Novel mutations widen the phenotypic spectrum of slow skeletal/β‐cardiac myosin (MYH7) distal myopathy. Hum Mutat 35: 868‐879, 2014.
 310.Lange S, Auerbach D, McLoughlin P, Perriard E, Schafer BW, Perriard JC, Ehler E. Subcellular targeting of metabolic enzymes to titin in heart muscle may be mediated by DRAL/FHL‐2. J Cell Sci 115: 4925‐4936, 2002.
 311.Lange S, Edström L, Udd B, Gautel M. Reply: Hereditary myopathy with early respiratory failure is caused by mutations in the titin FN3 119 domain. Brain 137: e279, 2014.
 312.Lange S, Himmel M, Auerbach D, Agarkova I, Hayess K, Furst DO, Perriard JC, Ehler E. Dimerisation of myomesin: Implications for the structure of the sarcomeric M‐band. J Mol Biol 345: 289‐298, 2005.
 313.Lange S, Ouyang K, Meyer G, Cui L, Cheng H, Lieber RL, Chen J. Obscurin determines the architecture of the longitudinal sarcoplasmic reticulum. J Cell Sci 122: 2640‐2650, 2009.
 314.Lange S, Perera S, Teh P, Chen J. Obscurin and KCTD6 regulate cullin‐dependent small ankyrin‐1 (sAnk1.5) protein turnover. Mol Biol Cell 23: 2490‐2504, 2012.
 315.Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova E, Kristensen J, Brandmeier B, Franzen G, Hedberg B, Gunnarsson LG, Hughes SM, Marchand S, Sejersen T, Richard I, Edstrom L, Ehler E, Udd B, Gautel M. The kinase domain of titin controls muscle gene expression and protein turnover. Science 308: 1599‐1603, 2005.
 316.Lecker SH, Jagoe RT, Gilbert A, Gomes M, Baracos V, Bailey J, Price SR, Mitch WE, Goldberg AL. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J 18: 39‐51, 2004.
 317.Lee CF, Melkani GC, Bernstein SI. The UNC‐45 myosin chaperone: From worms to flies to vertebrates. Int Rev Cell Mol Biol 313: 103‐144, 2014.
 318.Lee K, Harris SP, Sadayappan S, Craig R. Orientation of myosin binding protein C in the cardiac muscle sarcomere determined by domain‐specific immuno‐EM. J Mol Biol 427: 274‐286, 2015.
 319.Lee KJ, Ross RS, Rockman HA, Harris AN, O'Brien TX, van Bilsen M, Shubeita HE, Kandolf R, Brem G, Price J, et al. Myosin light chain‐2 luciferase transgenic mice reveal distinct regulatory programs for cardiac and skeletal muscle‐specific expression of a single contractile protein gene. J Biol Chem 267: 15875‐15885, 1992.
 320.Leite FeS, Kashina A, Rassier DE. Posttranslational arginylation regulates striated muscle function. Exerc Sport Sci Rev 44: 98‐103, 2016.
 321.Leite FS, Minozzo FC, Kalganov A, Cornachione AS, Cheng YS, Leu NA, Han X, Saripalli C, Yates JR, III, Granzier H, Kashina AS, Rassier DE. Reduced passive force in skeletal muscles lacking protein arginylation. Am J Physiol Cell Physiol 310: C127‐C135, 2016.
 322.Li M, Andersson‐Lendahl M, Sejersen T, Arner A. Knockdown of fast skeletal myosin‐binding protein C in zebrafish results in a severe skeletal myopathy. J Gen Physiol 147: 309‐322, 2016.
 323.Li M, Zheng W. All‐atom molecular dynamics simulations of actin‐myosin interactions: A comparative study of cardiac alpha myosin, beta myosin, and fast skeletal muscle myosin. Biochemistry 52: 8393‐8405, 2013.
 324.Li TB, Liu XH, Feng S, Hu Y, Yang WX, Han Y, Wang YG, Gong LM. Characterization of MR‐1, a novel myofibrillogenesis regulator in human muscle. Acta Biochim Biophys Sin (Shanghai) 36: 412‐418, 2004.
 325.Li X, Zhong B, Han W, Zhao N, Liu W, Sui Y, Wang Y, Lu Y, Wang H, Li J, Jiang M. Two novel mutations in myosin binding protein C slow causing distal arthrogryposis type 2 in two large Han Chinese families may suggest important functional role of immunoglobulin domain C2. PLoS One 10: e0117158, 2015.
 326.Lin B, Govindan S, Lee K, Zhao P, Han R, Runte KE, Craig R, Palmer BM, Sadayappan S. Cardiac myosin binding protein‐C plays no regulatory role in skeletal muscle structure and function. PLoS One 8: e69671, 2013.
 327.Linari M, Brunello E, Reconditi M, Fusi L, Caremani M, Narayanan T, Piazzesi G, Lombardi V, Irving M. Force generation by skeletal muscle is controlled by mechanosensing in myosin filaments. Nature 528: 276‐279, 2015.
 328.Linari M, Piazzesi G, Dobbie I, Koubassova N, Reconditi M, Narayanan T, Diat O, Irving M, Lombardi V. Interference fine structure and sarcomere length dependence of the axial x‐ray pattern from active single muscle fibers. Proc Natl Acad Sci U S A 97: 7226‐7231, 2000.
 329.Linke WA. Sense and stretchability: The role of titin and titin‐associated proteins in myocardial stress‐sensing and mechanical dysfunction. Cardiovasc Res 77: 637‐648, 2008.
 330.Liu J, Aoki M, Illa I, Wu C, Fardeau M, Angelini C, Serrano C, Urtizberea JA, Hentati F, Hamida MB, Bohlega S, Culper EJ, Amato AA, Bossie K, Oeltjen J, Bejaoui K, McKenna‐Yasek D, Hosler BA, Schurr E, Arahata K, de Jong PJ, Brown RH, Jr. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet 20: 31‐36, 1998.
 331.Liu X, Li T, Sun S, Xu F, Wang Y. Role of myofibrillogenesis regulator‐1 in myocardial hypertrophy. Am J Physiol Heart Circ Physiol 290: H279‐H285, 2006.
 332.Llinas P, Isabet T, Song L, Ropars V, Zong B, Benisty H, Sirigu S, Morris C, Kikuti C, Safer D, Sweeney HL, Houdusse A. How actin initiates the motor activity of myosin. Dev Cell 33: 401‐412, 2015.
 333.Locher MR, Razumova MV, Stelzer JE, Norman HS, Moss RL. Effects of low‐level α‐myosin heavy chain expression on contractile kinetics in porcine myocardium. Am J Physiol Heart Circ Physiol 300: H869‐H878, 2011.
 334.Lompre AM, Schwartz K, d'Albis A, Lacombe G, Van Thiem N, Swynghedauw B. Myosin isoenzyme redistribution in chronic heart overload. Nature 282: 105‐107, 1979.
 335.Lowes BD, Minobe W, Abraham WT, Rizeq MN, Bohlmeyer TJ, Quaife RA, Roden RL, Dutcher DL, Robertson AD, Voelkel NF, Badesch DB, Groves BM, Gilbert EM, Bristow MR. Changes in gene expression in the intact human heart. Downregulation of alpha‐myosin heavy chain in hypertrophied, failing ventricular myocardium. J Clin Invest 100: 2315‐2324, 1997.
 336.Lu Y, Kwan AH, Trewhella J, Jeffries CM. The C0C1 fragment of human cardiac myosin binding protein C has common binding determinants for both actin and myosin. J Mol Biol 413: 908‐913, 2011.
 337.Lundby A, Andersen MN, Steffensen AB, Horn H, Kelstrup CD, Francavilla C, Jensen LJ, Schmitt N, Thomsen MB, Olsen JV. In vivo phosphoproteomics analysis reveals the cardiac targets of beta‐adrenergic receptor signaling. Sci Signal 6: rs11, 2013.
 338.Lundby A, Lage K, Weinert BT, Bekker‐Jensen DB, Secher A, Skovgaard T, Kelstrup CD, Dmytriyev A, Choudhary C, Lundby C, Olsen JV. Proteomic analysis of lysine acetylation sites in rat tissues reveals organ specificity and subcellular patterns. Cell Rep 2: 419‐431, 2012.
 339.Lundby A, Secher A, Lage K, Nordsborg NB, Dmytriyev A, Lundby C, Olsen JV. Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues. Nat Commun 3: 876, 2012.
 340.Luther PK, Bennett PM, Knupp C, Craig R, Padron R, Harris SP, Patel J, Moss RL. Understanding the organisation and role of myosin binding protein C in normal striated muscle by comparison with MyBP‐C knockout cardiac muscle. J Mol Biol 384: 60‐72, 2008.
 341.Lynch TLt, Sivaguru M, Velayutham M, Cardounel AJ, Michels M, Barefield D, Govindan S, dos Remedios C, van der Velden J, Sadayappan S. Oxidative stress in dilated cardiomyopathy caused by MYBPC3 mutation. Oxid Med Cell Longev 2015: 424751, 2015.
 342.Lyon RC, Lange S, Sheikh F. Breaking down protein degradation mechanisms in cardiac muscle. Trends Mol Med 19: 239‐249, 2013.
 343.Lyons GE, Ontell M, Cox R, Sassoon D, Buckingham M. The expression of myosin genes in developing skeletal muscle in the mouse embryo. J Cell Biol 111: 1465‐1476, 1990.
 344.Lyons GE, Schiaffino S, Sassoon D, Barton P, Buckingham M. Developmental regulation of myosin gene expression in mouse cardiac muscle. J Cell Biol 111: 2427‐2436, 1990.
 345.Makarenko I, Opitz CA, Leake MC, Neagoe C, Kulke M, Gwathmey JK, del Monte F, Hajjar RJ, Linke WA. Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts. Circ Res 95: 708‐716, 2004.
 346.Malmqvist UP, Aronshtam A, Lowey S. Cardiac myosin isoforms from different species have unique enzymatic and mechanical properties. Biochemistry 43: 15058‐15065, 2004.
 347.Mamidi R, Gresham KS, Verma S, Stelzer JE. Cardiac myosin binding protein‐C phosphorylation modulates myofilament length‐dependent activation. Front Physiol 7: 38, 2016.
 348.Mamidi R, Mallampalli SL, Wieczorek DF, Chandra M. Identification of two new regions in the N‐terminus of cardiac troponin T that have divergent effects on cardiac contractile function. J Physiol 591: 1217‐1234, 2013.
 349.Markus B, Narkis G, Landau D, Birk RZ, Cohen I, Birk OS. Autosomal recessive lethal congenital contractural syndrome type 4 (LCCS4) caused by a mutation in MYBPC1. Hum Mutat 33: 1435‐1438, 2012.
 350.Marques MA, de Oliveira GA. Cardiac troponin and tropomyosin: Structural and cellular perspectives to unveil the hypertrophic cardiomyopathy phenotype. Front Physiol 7: 429, 2016.
 351.Marston S, Copeland O, Gehmlich K, Schlossarek S, Carrier L. How do MYBPC3 mutations cause hypertrophic cardiomyopathy? J Muscle Res Cell Motil 33: 75‐80, 2012.
 352.Marston S, Montgiraud C, Munster AB, Copeland O, Choi O, Dos Remedios C, Messer AE, Ehler E, Knoll R. OBSCN mutations associated with dilated cardiomyopathy and haploinsufficiency. PLoS One 10: e0138568, 2015.
 353.Marston SB. How do mutations in contractile proteins cause the primary familial cardiomyopathies? J Cardiovasc Transl Res 4: 245‐255, 2011.
 354.Martonosi AN. Animal electricity, Ca2+ and muscle contraction. A brief history of muscle research. Acta Biochim Pol 47: 493‐516, 2000.
 355.Martyn DA. Myosin binding protein‐C: Structural and functional complexity. J Mol Cell Cardiol 37: 813‐815, 2004.
 356.Maruyama K. Connectin, an elastic protein from myofibrils. J Biochem 80: 405‐407, 1976.
 357.Maruyama K, Kimura S, Kuroda M, Handa S. Connectin, an elastic protein of muscle. Its abundance in cardiac myofibrils. J Biochem 82: 347‐350, 1977.
 358.Masaki T, Takaiti O. M‐protein. J Biochem 75: 367‐380, 1974.
 359.Mascarello F, Toniolo L, Cancellara P, Reggiani C, Maccatrozzo L. Expression and identification of 10 sarcomeric MyHC isoforms in human skeletal muscles of different embryological origin. Diversity and similarity in mammalian species. Ann Anat 207: 9‐20, 2016.
 360.Mayans O, Benian GM, Simkovic F, Rigden DJ. Mechanistic and functional diversity in the mechanosensory kinases of the titin‐like family. Biochem Soc Trans 41: 1066‐1071, 2013.
 361.Mayans O, Labeit S. MuRFs: Specialized members of the TRIM/RBCC family with roles in the regulation of the trophic state of muscle and its metabolism. Adv Exp Med Biol 770: 119‐129, 2012.
 362.Mayans O, van der Ven PF, Wilm M, Mues A, Young P, Furst DO, Wilmanns M, Gautel M. Structural basis for activation of the titin kinase domain during myofibrillogenesis. Nature 395: 863‐869, 1998.
 363.McClellan G, Kulikovskaya I, Flavigny J, Carrier L, Winegrad S. Effect of cardiac myosin‐binding protein C on stability of the thick filament. J Mol Cell Cardiol 37: 823‐835, 2004.
 364.McClellan G, Kulikovskaya I, Winegrad S. Changes in cardiac contractility related to calcium‐mediated changes in phosphorylation of myosin‐binding protein C. Biophys J 81: 1083‐1092, 2001.
 365.McConnell BK, Jones KA, Fatkin D, Arroyo LH, Lee RT, Aristizabal O, Turnbull DH, Georgakopoulos D, Kass D, Bond M, Niimura H, Schoen FJ, Conner D, Fischman DA, Seidman CE, Seidman JG. Dilated cardiomyopathy in homozygous myosin‐binding protein‐C mutant mice. J Clin Invest 104: 1771, 1999.
 366.McElhinny AS, Perry CN, Witt CC, Labeit S, Gregorio CC. Muscle‐specific RING finger‐2 (MURF‐2) is important for microtubule, intermediate filament and sarcomeric M‐line maintenance in striated muscle development. J Cell Sci 117: 3175‐3188, 2004.
 367.McGrath MJ, Cottle DL, Nguyen MA, Dyson JM, Coghill ID, Robinson PA, Holdsworth M, Cowling BS, Hardeman EC, Mitchell CA, Brown S. Four and a half LIM protein 1 binds myosin‐binding protein C and regulates myosin filament formation and sarcomere assembly. J Biol Chem 281: 7666‐7683, 2006.
 368.McNamara JW, Li A, dos Remedios CG, Cooke R. The role of super‐relaxed myosin in skeletal and cardiac muscle. Biophysical Reviews 7: 5‐14, 2015.
 369.Meder B, Laufer C, Hassel D, Just S, Marquart S, Vogel B, Hess A, Fishman MC, Katus HA, Rottbauer W. A single serine in the carboxyl terminus of cardiac essential myosin light chain‐1 controls cardiomyocyte contractility in vivo. Circ Res 104: 650‐659, 2009.
 370.Messer AE, Jacques AM, Marston SB. Troponin phosphorylation and regulatory function in human heart muscle: Dephosphorylation of Ser23/24 on troponin I could account for the contractile defect in end‐stage heart failure. J Mol Cell Cardiol 42: 247‐259, 2007.
 371.Michael JJ, Gollapudi SK, Ford SJ, Kazmierczak K, Szczesna‐Cordary D, Chandra M. Deletion of 1‐43 amino acids in cardiac myosin essential light chain blunts length dependency of Ca(2+) sensitivity and cross‐bridge detachment kinetics. Am J Physiol Heart Circ Physiol 304: H253‐H259, 2013.
 372.Midde K, Rich R, Marandos P, Fudala R, Li A, Gryczynski I, Borejdo J. Comparison of orientation and rotational motion of skeletal muscle cross‐bridges containing phosphorylated and dephosphorylated myosin regulatory light chain. J Biol Chem 288: 7012‐7023, 2013.
 373.Millar NC, Homsher E. Kinetics of force generation and phosphate release in skinned rabbit soleus muscle fibers. Am J Physiol 262: C1239‐C1245, 1992.
 374.Miller G, Musa H, Gautel M, Peckham M. A targeted deletion of the C‐terminal end of titin, including the titin kinase domain, impairs myofibrillogenesis. J Cell Sci 116: 4811‐4819, 2003.
 375.Miller MS, Palmer BM, Ruch S, Martin LA, Farman GP, Wang Y, Robbins J, Irving TC, Maughan DW. The essential light chain N‐terminal extension alters force and fiber kinetics in mouse cardiac muscle. J Biol Chem 280: 34427‐34434, 2005.
 376.Mitchell EJ, Jakes R, Kendrick‐Jones J. Localisation of light chain and actin binding sites on myosin. Eur J Biochem 161: 25‐35, 1986.
 377.Miyamoto CA, Fischman DA, Reinach FC. The interface between MyBP‐C and myosin: Site‐directed mutagenesis of the CX myosin‐binding domain of MyBP‐C. J Muscle Res Cell Motil 20: 703‐715, 1999.
 378.Miyanishi T, Ishikawa T, Hayashibara T, Maita T, Wakabayashi T. The two actin‐binding regions on the myosin heads of cardiac muscle. Biochemistry 41: 5429‐5438, 2002.
 379.Miyata S, Minobe W, Bristow MR, Leinwand LA. Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ Res 86: 386‐390, 2000.
 380.Mizutani H, Okamoto R, Moriki N, Konishi K, Taniguchi M, Fujita S, Dohi K, Onishi K, Suzuki N, Satoh S, Makino N, Itoh T, Hartshorne DJ, Ito M. Overexpression of myosin phosphatase reduces Ca(2+) sensitivity of contraction and impairs cardiac function. Circ J 74: 120‐128, 2010.
 381.Mohamed AS, Dignam JD, Schlender KK. Cardiac myosin‐binding protein C (MyBP‐C): Identification of protein kinase A and protein kinase C phosphorylation sites. Arch Biochem Biophys 358: 313‐319, 1998.
 382.Moolman‐Smook J, Flashman E, de Lange W, Li Z, Corfield V, Redwood C, Watkins H. Identification of novel interactions between domains of Myosin binding protein‐C that are modulated by hypertrophic cardiomyopathy missense mutations. Circ Res 91: 704‐711, 2002.
 383.Moorhead G, Johnson D, Morrice N, Cohen P. The major myosin phosphatase in skeletal muscle is a complex between the beta‐isoform of protein phosphatase 1 and the MYPT2 gene product. FEBS Lett 438: 141‐144, 1998.
 384.Moos C. Fluorescence microscope study of the binding of added C protein to skeletal muscle myofibrils. J Cell Biol 90: 25‐31, 1981.
 385.Moos C, Mason CM, Besterman JM, Feng IN, Dubin JH. The binding of skeletal muscle C‐protein to F‐actin, and its relation to the interaction of actin with myosin subfragment‐1. J Mol Biol 124: 571‐586, 1978.
 386.Moos C, Offer G, Starr R, Bennett P. Interaction of C‐protein with myosin, myosin rod and light meromyosin. J Mol Biol 97: 1‐9, 1975.
 387.Morano I, Haase H. Different actin affinities of human cardiac essential myosin light chain isoforms. FEBS Lett 408: 71‐74, 1997.
 388.Morano I, Hadicke K, Haase H, Bohm M, Erdmann E, Schaub MC. Changes in essential myosin light chain isoform expression provide a molecular basis for isometric force regulation in the failing human heart. J Mol Cell Cardiol 29: 1177‐1187, 1997.
 389.Morano I, Ritter O, Bonz A, Timek T, Vahl CF, Michel G. Myosin light chain‐actin interaction regulates cardiac contractility. Circ Res 76: 720‐725, 1995.
 390.Morano M, Zacharzowski U, Maier M, Lange PE, Alexi‐Meskishvili V, Haase H, Morano I. Regulation of human heart contractility by essential myosin light chain isoforms. J Clin Invest 98: 467‐473, 1996.
 391.Moretti A, Weig HJ, Ott T, Seyfarth M, Holthoff HP, Grewe D, Gillitzer A, Bott‐Flugel L, Schomig A, Ungerer M, Laugwitz KL. Essential myosin light chain as a target for caspase‐3 in failing myocardium. Proc Natl Acad Sci U S A 99: 11860‐11865, 2002.
 392.Moriscot AS, Baptista IL, Bogomolovas J, Witt C, Hirner S, Granzier H, Labeit S. MuRF1 is a muscle fiber‐type II associated factor and together with MuRF2 regulates type‐II fiber trophicity and maintenance. J Struct Biol 170: 344‐353, 2010.
 393.Mornet D, Bertrand RU, Pantel P, Audemard E, Kassab R. Proteolytic approach to structure and function of actin recognition site in myosin heads. Biochemistry 20: 2110‐2120, 1981.
 394.Moss RL. Cardiac myosin‐binding protein C: A protein once at loose ends finds its regulatory groove. Proc Natl Acad Sci U S A 113: 3133‐3135, 2016.
 395.Moss RL, Fitzsimons DP, Ralphe JC. Cardiac MyBP‐C regulates the rate and force of contraction in mammalian myocardium. Circ Res 116: 183‐192, 2015.
 396.Mouton JM, van der Merwe L, Goosen A, Revera M, Brink PA, Moolman‐Smook JC, Kinnear C. MYBPH acts as modifier of cardiac hypertrophy in hypertrophic cardiomyopathy (HCM) patients. Hum Genet 135: 477‐483, 2016.
 397.Mrosek M, Labeit D, Witt S, Heerklotz H, von Castelmur E, Labeit S, Mayans O. Molecular determinants for the recruitment of the ubiquitin‐ligase MuRF‐1 onto M‐line titin. FASEB J 21: 1383‐1392, 2007.
 398.Muhle‐Goll C, Habeck M, Cazorla O, Nilges M, Labeit S, Granzier H. Structural and functional studies of titin's fn3 modules reveal conserved surface patterns and binding to myosin S1—A possible role in the Frank‐Starling mechanism of the heart. J Mol Biol 313: 431‐447, 2001.
 399.Müller S, Lange S, Gautel M, Wilmanns M. Rigid conformation of an immunoglobulin domain tandem repeat in the A‐band of the elastic muscle protein titin. J Mol Biol 371: 469‐480, 2007.
 400.Mun JY, Previs MJ, Yu HY, Gulick J, Tobacman LS, Beck Previs S, Robbins J, Warshaw DM, Craig R. Myosin‐binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism. Proc Natl Acad Sci U S A 111: 2170‐2175, 2014.
 401.Muretta JM, Petersen KJ, Thomas DD. Direct real‐time detection of the actin‐activated power stroke within the myosin catalytic domain. Proc Natl Acad Sci U S A 110: 7211‐7216, 2013.
 402.Muretta JM, Rohde JA, Johnsrud DO, Cornea S, Thomas DD. Direct real‐time detection of the structural and biochemical events in the myosin power stroke. Proc Natl Acad Sci U S A 112: 14272‐14277, 2015.
 403.Murgia M, Nagaraj N, Deshmukh AS, Zeiler M, Cancellara P, Moretti I, Reggiani C, Schiaffino S, Mann M. Single muscle fiber proteomics reveals unexpected mitochondrial specialization. EMBO Rep 16: 387‐395, 2015.
 404.Murrin LC, Talbot JN. RanBPM, a scaffolding protein in the immune and nervous systems. J Neuroimmune Pharmacol 2: 290‐295, 2007.
 405.Musa H, Meek S, Gautel M, Peddie D, Smith AJ, Peckham M. Targeted homozygous deletion of M‐band titin in cardiomyocytes prevents sarcomere formation. J Cell Sci 119: 4322‐4331, 2006.
 406.Myhre JL, Hills JA, Prill K, Wohlgemuth SL, Pilgrim DB. The titin A‐band rod domain is dispensable for initial thick filament assembly in zebrafish. Dev Biol 387: 93‐108, 2014.
 407.Myhre JL, Pilgrim D. A titan but not necessarily a ruler: Assessing the role of titin during thick filament patterning and assembly. Anat Rec (Hoboken) 297: 1604‐1614, 2014.
 408.Nabeshima Y, Fujii‐Kuriyama Y, Muramatsu M, Ogata K. Alternative transcription and two modes of splicing results in two myosin light chains from one gene. Nature 308: 333‐338, 1984.
 409.Nagueh SF, Shah G, Wu Y, Torre‐Amione G, King NM, Lahmers S, Witt CC, Becker K, Labeit S, Granzier HL. Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy. Circulation 110: 155‐162, 2004.
 410.Narusawa M, Fitzsimons RB, Izumo S, Nadal‐Ginard B, Rubinstein NA, Kelly AM. Slow myosin in developing rat skeletal muscle. J Cell Biol 104: 447‐459, 1987.
 411.Neiva‐Sousa M, Almeida‐Coelho J, Falcao‐Pires I, Leite‐Moreira AF. Titin mutations: The fall of Goliath. Heart Fail Rev 20: 579‐588, 2015.
 412.Neumann J. Altered phosphatase activity in heart failure, influence on Ca2+ movement. Basic Res Cardiol 97 (Suppl 1): I91‐I95, 2002.
 413.Nieznanski K, Nieznanska H, Skowronek K, Kasprzak AA, Stepkowski D. Ca2+ binding to myosin regulatory light chain affects the conformation of the N‐terminus of essential light chain and its binding to actin. Arch Biochem Biophys 417: 153‐158, 2003.
 414.Nishio H, Ichikawa K, Hartshorne DJ. Evidence for myosin‐binding phosphatase in heart myofibrils. Biochem Biophys Res Commun 236: 570‐575, 1997.
 415.Noguchi J, Yanagisawa M, Imamura M, Kasuya Y, Sakurai T, Tanaka T, Masaki T. Complete primary structure and tissue expression of chicken pectoralis M‐protein. J Biol Chem 267: 20302‐20310, 1992.
 416.Oakley CE, Chamoun J, Brown LJ, Hambly BD. Myosin binding protein‐C: Enigmatic regulator of cardiac contraction. Int J Biochem Cell Biol 39: 2161‐2166, 2007.
 417.Obermann WM, Gautel M, Steiner F, van der Ven PF, Weber K, Furst DO. The structure of the sarcomeric M band: Localization of defined domains of myomesin, M‐protein, and the 250‐kD carboxy‐terminal region of titin by immunoelectron microscopy. J Cell Biol 134: 1441‐1453, 1996.
 418.Obermann WM, Gautel M, Weber K, Furst DO. Molecular structure of the sarcomeric M band: Mapping of titin and myosin binding domains in myomesin and the identification of a potential regulatory phosphorylation site in myomesin. EMBO J 16: 211‐220, 1997.
 419.Obermann WM, van der Ven PF, Steiner F, Weber K, Furst DO. Mapping of a myosin‐binding domain and a regulatory phosphorylation site in M‐protein, a structural protein of the sarcomeric M band. Mol Biol Cell 9: 829‐840, 1998.
 420.Offer G, Moos C, Starr R. A new protein of the thick filaments of vertebrate skeletal myofibrils. Extractions, purification and characterization. J Mol Biol 74: 653‐676, 1973.
 421.Ohlsson M, Hedberg C, Brådvik B, Lindberg C, Tajsharghi H, Danielsson O, Melberg A, Udd B, Martinsson T, Oldfors A. Hereditary myopathy with early respiratory failure associated with a mutation in A‐band titin. Brain 135: 1682‐1694, 2012.
 422.Okagaki T, Weber FE, Fischman DA, Vaughan KT, Mikawa T, Reinach FC. The major myosin‐binding domain of skeletal muscle MyBP‐C (C protein) resides in the COOH‐terminal, immunoglobulin C2 motif. J Cell Biol 123: 619‐626, 1993.
 423.Okamoto R, Kato T, Mizoguchi A, Takahashi N, Nakakuki T, Mizutani H, Isaka N, Imanaka‐Yoshida K, Kaibuchi K, Lu Z, Mabuchi K, Tao T, Hartshorne DJ, Nakano T, Ito M. Characterization and function of MYPT2, a target subunit of myosin phosphatase in heart. Cell Signal 18: 1408‐1416, 2006.
 424.Olive M, Abdul‐Hussein S, Oldfors A, Gonzalez‐Costello J, van der Ven PF, Furst DO, Gonzalez L, Moreno D, Torrejon‐Escribano B, Alio J, Pou A, Ferrer I, Tajsharghi H. New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations. Hum Mol Genet 24: 3638‐3650, 2015.
 425.Orlova A, Galkin VE, Jeffries CM, Egelman EH, Trewhella J. The N‐terminal domains of myosin binding protein C can bind polymorphically to F‐actin. J Mol Biol 412: 379‐386, 2011.
 426.Orr N, Arnaout R, Gula LJ, Spears DA, Leong‐Sit P, Li Q, Tarhuni W, Reischauer S, Chauhan VS, Borkovich M, Uppal S, Adler A, Coughlin SR, Stainier DY, Gollob MH. A mutation in the atrial‐specific myosin light chain gene (MYL4) causes familial atrial fibrillation. Nat Commun 7: 11303, 2016.
 427.Palmer BM, McConnell BK, Li GH, Seidman CE, Seidman JG, Irving TC, Alpert NR, Maughan DW. Reduced cross‐bridge dependent stiffness of skinned myocardium from mice lacking cardiac myosin binding protein‐C. Mol Cell Biochem 263: 73‐80, 2004.
 428.Palmio J, Evilä A, Chapon F, Tasca G, Xiang F, Brådvik B, Eymard B, Echaniz‐Laguna A, Laporte J, Kärppä M, Mahjneh I, Quinlivan R, Laforêt P, Damian M, Berardo A, Taratuto AL, Bueri JA, Tommiska J, Raivio T, Tuerk M, Gölitz P, Chevessier F, Sewry C, Norwood F, Hedberg C, Schröder R, Edström L, Oldfors A, Hackman P, Udd B. Hereditary myopathy with early respiratory failure: Occurrence in various populations. J Neurol Neurosurg Psychiatry 85: 345‐353, 2014.
 429.Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Øvervatn A, Bjørkøy G, Johansen T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282: 24131‐24145, 2007.
 430.Patel BG, Wilder T, Solaro RJ. Novel control of cardiac myofilament response to calcium by S‐glutathionylation at specific sites of myosin binding protein C. Front Physiol 4: 336, 2013.
 431.Patra C, Monk KR, Engel FB. The multiple signaling modalities of adhesion G protein‐coupled receptor GPR126 in development. Receptors Clin Investig 1: 79, 2014.
 432.Peng J, Raddatz K, Molkentin JD, Wu Y, Labeit S, Granzier H, Gotthardt M. Cardiac hypertrophy and reduced contractility in hearts deficient in the titin kinase region. Circulation 115: 743‐751, 2007.
 433.Perera S, Holt MR, Mankoo BS, Gautel M. Developmental regulation of MURF ubiquitin ligases and autophagy proteins nbr1, p62/SQSTM1 and LC3 during cardiac myofibril assembly and turnover. Dev Biol 351: 46‐61, 2011.
 434.Periasamy M, Strehler EE, Garfinkel LI, Gubits RM, Ruiz‐Opazo N, Nadal‐Ginard B. Fast skeletal muscle myosin light chains 1 and 3 are produced from a single gene by a combined process of differential RNA transcription and splicing. J Biol Chem 259: 13595‐13604, 1984.
 435.Perry NA, Ackermann MA, Shriver M, Hu LY, Kontrogianni‐Konstantopoulos A. Obscurins: Unassuming giants enter the spotlight. IUBMB Life 65: 479‐486, 2013.
 436.Perry NA, Shriver M, Mameza MG, Grabias B, Balzer E, Kontrogianni‐Konstantopoulos A. Loss of giant obscurins promotes breast epithelial cell survival through apoptotic resistance. FASEB J 26: 2764‐2775, 2012.
 437.Person V, Kostin S, Suzuki K, Labeit S, Schaper J. Antisense oligonucleotide experiments elucidate the essential role of titin in sarcomerogenesis in adult rat cardiomyocytes in long‐term culture. J Cell Sci 113 (Pt 21): 3851‐3859, 2000.
 438.Petzhold D, Lossie J, Keller S, Werner S, Haase H, Morano I. Human essential myosin light chain isoforms revealed distinct myosin binding, sarcomeric sorting, and inotropic activity. Cardiovasc Res 90: 513‐520, 2011.
 439.Petzhold D, Simsek B, Meissner R, Mahmoodzadeh S, Morano I. Distinct interactions between actin and essential myosin light chain isoforms. Biochem Biophys Res Commun 449: 284‐288, 2014.
 440.Pfeffer G, Chinnery PF. Reply: Hereditary myopathy with early respiratory failure is caused by mutations in the titin FN3 119 domain. Brain 137: e280, 2014.
 441.Pfeffer G, Elliott HR, Griffin H, Barresi R, Miller J, Marsh J, Evilä A, Vihola A, Hackman P, Straub V, Dick DJ, Horvath R, Santibanez‐Koref M, Udd B, Chinnery PF. Titin mutation segregates with hereditary myopathy with early respiratory failure. Brain 135: 1695‐1713, 2012.
 442.Pfeffer G, Sambuughin N, Olivé M, Tyndel F, Toro C, Goldfarb LG, Chinnery PF. A new disease allele for the p.C30071R mutation in titin causing hereditary myopathy with early respiratory failure. Neuromuscul Disord 24: 241‐244, 2014.
 443.Piazzesi G, Reconditi M, Linari M, Lucii L, Bianco P, Brunello E, Decostre V, Stewart A, Gore DB, Irving TC, Irving M, Lombardi V. Skeletal muscle performance determined by modulation of number of myosin motors rather than motor force or stroke size. Cell 131: 784‐795, 2007.
 444.Pinder JC, Taylor‐Harris PM, Bennett PM, Carter E, Hayes NV, King MD, Holt MR, Maggs AM, Gascard P, Baines AJ. Isoforms of protein 4.1 are differentially distributed in heart muscle cells: Relation of 4.1R and 4.1G to components of the Ca2+ homeostasis system. Exp Cell Res 318: 1467‐1479, 2012.
 445.Pinotsis N, Chatziefthimiou SD, Berkemeier F, Beuron F, Mavridis IM, Konarev PV, Svergun DI, Morris E, Rief M, Wilmanns M. Superhelical architecture of the myosin filament‐linking protein myomesin with unusual elastic properties. PLoS Biol 10: e1001261, 2012.
 446.Pinotsis N, Lange S, Perriard JC, Svergun DI, Wilmanns M. Molecular basis of the C‐terminal tail‐to‐tail assembly of the sarcomeric filament protein myomesin. EMBO J 27: 253‐264, 2008.
 447.Pizon V, Iakovenko A, Van Der Ven PF, Kelly R, Fatu C, Furst DO, Karsenti E, Gautel M. Transient association of titin and myosin with microtubules in nascent myofibrils directed by the MURF2 RING‐finger protein. J Cell Sci 115: 4469‐4482, 2002.
 448.Pollazzon M, Suominen T, Penttilä S, Malandrini A, Carluccio MA, Mondelli M, Marozza A, Federico A, Renieri A, Hackman P, Dotti MT, Udd B. The first Italian family with tibial muscular dystrophy caused by a novel titin mutation. J Neurol 257: 575‐579, 2010.
 449.Previs MJ, Beck Previs S, Gulick J, Robbins J, Warshaw DM. Molecular mechanics of cardiac myosin‐binding protein C in native thick filaments. Science 337: 1215‐1218, 2012.
 450.Previs MJ, Michalek AJ, Warshaw DM. Molecular modulation of actomyosin function by cardiac myosin‐binding protein C. Pflugers Arch 466: 439‐444, 2014.
 451.Previs MJ, Mun JY, Michalek AJ, Previs SB, Gulick J, Robbins J, Warshaw DM, Craig R. Phosphorylation and calcium antagonistically tune myosin‐binding protein C's structure and function. Proc Natl Acad Sci U S A 113: 3239‐3244, 2016.
 452.Price KM, Littler WA, Cummins P. Human atrial and ventricular myosin light‐chains subunits in the adult and during development. Biochem J 191: 571‐580, 1980.
 453.Price MG, Landsverk ML, Barral JM, Epstein HF. Two mammalian UNC‐45 isoforms are related to distinct cytoskeletal and muscle‐specific functions. J Cell Sci 115: 4013‐4023, 2002.
 454.Puchner EM, Alexandrovich A, Kho AL, Hensen U, Schäfer LV, Brandmeier B, Gräter F, Grubmüller H, Gaub HE, Gautel M. Mechanoenzymatics of titin kinase. Proc Natl Acad Sci U S A 105: 13385‐13390, 2008.
 455.Qadota H, Benian GM. Molecular structure of sarcomere‐to‐membrane attachment at M‐Lines in C. elegans muscle. J Biomed Biotechnol 2010: 864749, 2010.
 456.Qadota H, Blangy A, Xiong G, Benian GM. The DH‐PH region of the giant protein UNC‐89 activates RHO‐1 GTPase in Caenorhabditis elegans body wall muscle. J Mol Biol 383: 747‐752, 2008.
 457.Qadota H, Mayans O, Matsunaga Y, McMurry JL, Wilson KJ, Kwon GE, Stanford R, Deehan K, Tinley TL, Ngwa VM, Benian GM. The SH3 domain of UNC‐89 (obscurin) interacts with paramyosin, a coiled‐coil protein, in Caenorhabditis elegans muscle. Mol Biol Cell 27: 1606‐1620, 2016.
 458.Qadota H, McGaha LA, Mercer KB, Stark TJ, Ferrara TM, Benian GM. A novel protein phosphatase is a binding partner for the protein kinase domains of UNC‐89 (Obscurin) in Caenorhabditis elegans. Mol Biol Cell 19: 2424‐2432, 2008.
 459.Qadota H, Mercer KB, Miller RK, Kaibuchi K, Benian GM. Two LIM domain proteins and UNC‐96 link UNC‐97/pinch to myosin thick filaments in Caenorhabditis elegans muscle. Mol Biol Cell 18: 4317‐4326, 2007.
 460.Raeker MO, Su F, Geisler SB, Borisov AB, Kontrogianni‐Konstantopoulos A, Lyons SE, Russell MW. Obscurin is required for the lateral alignment of striated myofibrils in zebrafish. Dev Dyn 235: 2018‐2029, 2006.
 461.Ramirez‐Correa GA, Jin W, Wang Z, Zhong X, Gao WD, Dias WB, Vecoli C, Hart GW, Murphy AM. O‐linked GlcNAc modification of cardiac myofilament proteins: A novel regulator of myocardial contractile function. Circ Res 103: 1354‐1358, 2008.
 462.Ramirez‐Correa GA, Ma J, Slawson C, Zeidan Q, Lugo‐Fagundo NS, Xu M, Shen X, Gao WD, Caceres V, Chakir K, DeVine L, Cole RN, Marchionni L, Paolocci N, Hart GW, Murphy AM. Removal of abnormal myofilament O‐GlcNAcylation restores Ca2+ sensitivity in diabetic cardiac muscle. Diabetes 64: 3573‐3587, 2015.
 463.Randazzo D, Blaauw B, Paolini C, Pierantozzi E, Spinozzi S, Lange S, Chen J, Protasi F, Reggiani C, Sorrentino V. Exercise‐induced alterations and loss of sarcomeric M‐line organization in the diaphragm muscle of obscurin knockout mice. Am J Physiol Cell Physiol 312: C16‐C28, 2017.
 464.Randazzo D, Giacomello E, Lorenzini S, Rossi D, Pierantozzi E, Blaauw B, Reggiani C, Lange S, Peter AK, Chen J, Sorrentino V. Obscurin is required for ankyrinB‐dependent dystrophin localization and sarcolemma integrity. J Cell Biol 200: 523‐536, 2013.
 465.Ranum LP, Cooper TA. RNA‐mediated neuromuscular disorders. Annu Rev Neurosci 29: 259‐277, 2006.
 466.Rarick HM, Opgenorth TJ, von Geldern TW, Wu‐Wong JR, Solaro RJ. An essential myosin light chain peptide induces supramaximal stimulation of cardiac myofibrillar ATPase activity. J Biol Chem 271: 27039‐27043, 1996.
 467.Ratti J, Rostkova E, Gautel M, Pfuhl M. Structure and interactions of myosin‐binding protein C domain C0: Cardiac‐specific regulation of myosin at its neck? J Biol Chem 286: 12650‐12658, 2011.
 468.Ravenscroft G, Nolent F, Rajagopalan S, Meireles AM, Paavola KJ, Gaillard D, Alanio E, Buckland M, Arbuckle S, Krivanek M, Maluenda J, Pannell S, Gooding R, Ong RW, Allcock RJ, Carvalho ED, Carvalho MD, Kok F, Talbot WS, Melki J, Laing NG. Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita. Am J Hum Genet 96: 955‐961, 2015.
 469.Rayment I, Holden, HM. Myosin subfragment‐1: Structure and function of a molecular motor. Currt Opin Struct Biol 3: 944‐952, 1993.
 470.Rayment I, Rypniewski WR, Schmidt‐Base K, Smith R, Tomchick DR, Benning MM, Winkelmann DA, Wesenberg G, Holden HM. Three‐dimensional structure of myosin subfragment‐1: A molecular motor. Science 261: 50‐58, 1993.
 471.Razumova MV, Shaffer JF, Tu AY, Flint GV, Regnier M, Harris SP. Effects of the N‐terminal domains of myosin binding protein‐C in an in vitro motility assay: Evidence for long‐lived cross‐bridges. J Biol Chem 281: 35846‐35854, 2006.
 472.Reconditi M, Brunello E, Linari M, Bianco P, Narayanan T, Panine P, Piazzesi G, Lombardi V, Irving M. Motion of myosin head domains during activation and force development in skeletal muscle. Proc Natl Acad Sci U S A 108: 7236‐7240, 2011.
 473.Reddy KB, Fox JE, Price MG, Kulkarni S, Gupta S, Das B, Smith DM. Nuclear localization of Myomesin‐1: Possible functions. J Muscle Res Cell Motil 29: 1‐8, 2008.
 474.Reiser PJ, Portman MA, Ning XH, Schomisch Moravec C. Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles. Am J Physiol Heart Circ Physiol 280: H1814‐H1820, 2001.
 475.Rhee D, Sanger JM, Sanger JW. The premyofibril: Evidence for its role in myofibrillogenesis. Cell Motil Cytoskeleton 28: 1‐24, 1994.
 476.Rhoads AR, Friedberg F. Sequence motifs for calmodulin recognition. FASEB J 11: 331‐340, 1997.
 477.Ribeiro PA, Ribeiro JP, Minozzo FC, Pavlov I, Leu NA, Kurosaka S, Kashina A, Rassier DE. Contractility of myofibrils from the heart and diaphragm muscles measured with atomic force cantilevers: Effects of heart‐specific deletion of arginyl‐tRNA‐protein transferase. Int J Cardiol 168: 3564‐3571, 2013.
 478.Rosas PC, Liu Y, Abdalla MI, Thomas CM, Kidwell DT, Dusio GF, Mukhopadhyay D, Kumar R, Baker KM, Mitchell BM, Powers PA, Fitzsimons DP, Patel BG, Warren CM, Solaro RJ, Moss RL, Tong CW. Phosphorylation of cardiac myosin‐binding protein‐C is a critical mediator of diastolic function. Circ Heart Fail 8: 582‐594, 2015.
 479.Rossi AC, Mammucari C, Argentini C, Reggiani C, Schiaffino S. Two novel/ancient myosins in mammalian skeletal muscles: MYH14/7b and MYH15 are expressed in extraocular muscles and muscle spindles. J Physiol 588: 353‐364, 2010.
 480.Rottbauer W, Gautel M, Zehelein J, Labeit S, Franz WM, Fischer C, Vollrath B, Mall G, Dietz R, Kubler W, Katus HA. Novel splice donor site mutation in the cardiac myosin‐binding protein‐C gene in familial hypertrophic cardiomyopathy. Characterization of cardiac transcript and protein. J Clin Invest 100: 475‐482, 1997.
 481.Rowland TJ, Graw SL, Sweet ME, Gigli M, Taylor MR, Mestroni L. Obscurin variants in patients with left ventricular noncompaction. J Am Coll Cardiol 68: 2237‐2238, 2016.
 482.Rubinstein NA, Kelly AM. Development of muscle fiber specialization in the rat hindlimb. J Cell Biol 90: 128‐144, 1981.
 483.Rundell KW, Tullson PC, Terjung RL. AMP deaminase binding in contracting rat skeletal muscle. Am J Physiol 263: C287‐C293, 1992.
 484.Rundell VL, Manaves V, Martin AF, de Tombe PP. Impact of beta‐myosin heavy chain isoform expression on cross‐bridge cycling kinetics. Am J Physiol Heart Circ Physiol 288: H896‐H903, 2005.
 485.Russell MW, Raeker MO, Korytkowski KA, Sonneman KJ. Identification, tissue expression and chromosomal localization of human obscurin‐MLCK, a member of the titin and Dbl families of myosin light chain kinases. Gene 282: 237‐246, 2002.
 486.Rybakova IN, Greaser ML, Moss RL. Myosin binding protein C interaction with actin: Characterization and mapping of the binding site. J Biol Chem 286: 2008‐2016, 2011.
 487.Ryder DJ, Judge SM, Beharry AW, Farnsworth CL, Silva JC, Judge AR. Identification of the acetylation and ubiquitin‐modified proteome during the progression of skeletal muscle atrophy. PLoS One 10: e0136247, 2015.
 488.Sadayappan S, de Tombe PP. Cardiac myosin binding protein‐C: Redefining its structure and function. Biophys Rev 4: 93‐106, 2012.
 489.Sadayappan S, de Tombe PP. Cardiac myosin binding protein‐C as a central target of cardiac sarcomere signaling: A special mini review series. Pflugers Arch 466: 195‐200, 2014.
 490.Sadayappan S, Gulick J, Osinska H, Barefield D, Cuello F, Avkiran M, Lasko VM, Lorenz JN, Maillet M, Martin JL, Brown JH, Bers DM, Molkentin JD, James J, Robbins J. A critical function for Ser‐282 in cardiac myosin binding protein‐C phosphorylation and cardiac function. Circ Res 109: 141‐150, 2011.
 491.Sadayappan S, Gulick J, Osinska H, Martin LA, Hahn HS, Dorn GW, II, Klevitsky R, Seidman CE, Seidman JG, Robbins J. Cardiac myosin‐binding protein‐C phosphorylation and cardiac function. Circ Res 97: 1156‐1163, 2005.
 492.Sadayappan S, Osinska H, Klevitsky R, Lorenz JN, Sargent M, Molkentin JD, Seidman CE, Seidman JG, Robbins J. Cardiac myosin binding protein C phosphorylation is cardioprotective. Proc Natl Acad Sci U S A 103: 16918‐16923, 2006.
 493.Salih MA, Al Rayess M, Cutshall S, Urtizberea JA, Al‐Turaiki MH, Ozo CO, Straub V, Akbar M, Abid M, Andeejani A, Campbell KP. A novel form of familial congenital muscular dystrophy in two adolescents. Neuropediatrics 29: 289‐293, 1998.
 494.Samant SA, Pillai VB, Sundaresan NR, Shroff SG, Gupta MP. Histone deacetylase 3 (HDAC3)‐dependent reversible lysine acetylation of cardiac myosin heavy chain isoforms modulates their enzymatic and motor activity. J Biol Chem 290: 15559‐15569, 2015.
 495.Sanger JW, Kang S, Siebrands CC, Freeman N, Du A, Wang J, Stout AL, Sanger JM. How to build a myofibril. J Muscle Res Cell Motil 26: 343‐354, 2005.
 496.Sanger JW, Wang J, Fan Y, White J, Sanger JM. Assembly and dynamics of myofibrils. J Biomed Biotechnol 2010: 858606, 2010.
 497.Sarparanta J, Blandin G, Charton K, Vihola A, Marchand S, Milic A, Hackman P, Ehler E, Richard I, Udd B. Interactions with M‐band titin and calpain 3 link myospryn (CMYA5) to tibial and limb‐girdle muscular dystrophies. J Biol Chem 285: 30304‐30315, 2010.
 498.Savitskaya MA, Onishchenko GE. Mechanisms of apoptosis. Biochemistry (Mosc) 80: 1393‐1405, 2015.
 499.Schaub MC, Tuchschmid CR, Srihari T, Hirzel HO. Myosin isoenzymes in human hypertrophic hearts. Shift in atrial myosin heavy chains and in ventricular myosin light chains. Eur Heart J 5 (Suppl F): 85‐93, 1984.
 500.Schiaffino S, Reggiani C. Fiber types in mammalian skeletal muscles. Physiol Rev 91: 1447‐1531, 2011.
 501.Schiaffino S, Rossi AC, Smerdu V, Leinwand LA, Reggiani C. Developmental myosins: Expression patterns and functional significance. Skelet Muscle 5: 22, 2015.
 502.Schoenauer R, Bertoncini P, Machaidze G, Aebi U, Perriard JC, Hegner M, Agarkova I. Myomesin is a molecular spring with adaptable elasticity. J Mol Biol 349: 367‐379, 2005.
 503.Schoenauer R, Emmert MY, Felley A, Ehler E, Brokopp C, Weber B, Nemir M, Faggian GG, Pedrazzini T, Falk V, Hoerstrup SP, Agarkova I. EH‐myomesin splice isoform is a novel marker for dilated cardiomyopathy. Basic Res Cardiol 106: 233‐247, 2011.
 504.Schoenauer R, Lange S, Hirschy A, Ehler E, Perriard JC, Agarkova I. Myomesin 3, a novel structural component of the M‐band in striated muscle. J Mol Biol 376: 338‐351, 2008.
 505.Scruggs SB, Hinken AC, Thawornkaiwong A, Robbins J, Walker LA, de Tombe PP, Geenen DL, Buttrick PM, Solaro RJ. Ablation of ventricular myosin regulatory light chain phosphorylation in mice causes cardiac dysfunction in situ and affects neighboring myofilament protein phosphorylation. J Biol Chem 284: 5097‐5106, 2009.
 506.Scruggs SB, Reisdorph R, Armstrong ML, Warren CM, Reisdorph N, Solaro RJ, Buttrick PM. A novel, in‐solution separation of endogenous cardiac sarcomeric proteins and identification of distinct charged variants of regulatory light chain. Mol Cell Proteomics 9: 1804‐1818, 2010.
 507.Seeley M, Huang W, Chen Z, Wolff WO, Lin X, Xu X. Depletion of zebrafish titin reduces cardiac contractility by disrupting the assembly of Z‐discs and A‐bands. Circ Res 100: 238‐245, 2007.
 508.Seibenhener ML, Babu JR, Geetha T, Wong HC, Krishna NR, Wooten MW. Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol 24: 8055‐8068, 2004.
 509.Seibenhener ML, Geetha T, Wooten MW. Sequestosome 1/p62—More than just a scaffold. FEBS Lett 581: 175‐179, 2007.
 510.Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol 65: 1249‐1254, 2015.
 511.Shaffer JF, Kensler RW, Harris SP. The myosin‐binding protein C motif binds to F‐actin in a phosphorylation‐sensitive manner. J Biol Chem 284: 12318‐12327, 2009.
 512.Shama KM, Suzuki A, Harada K, Fujitani N, Kimura H, Ohno S, Yoshida K. Transient up‐regulation of myotonic dystrophy protein kinase‐binding protein, MKBP, and HSP27 in the neonatal myocardium. Cell Struct Funct 24: 1‐4, 1999.
 513.Shamseldin HE, Tulbah M, Kurdi W, Nemer M, Alsahan N, Al Mardawi E, Khalifa O, Hashem A, Kurdi A, Babay Z, Bubshait DK, Ibrahim N, Abdulwahab F, Rahbeeni Z, Hashem M, Alkuraya FS. Identification of embryonic lethal genes in humans by autozygosity mapping and exome sequencing in consanguineous families. Genome Biol 16: 116, 2015.
 514.Sheikh F, Lyon RC, Chen J. Getting the skinny on thick filament regulation in cardiac muscle biology and disease. Trends Cardiovasc Med 24: 133‐141, 2014.
 515.Sheikh F, Ouyang K, Campbell SG, Lyon RC, Chuang J, Fitzsimons D, Tangney J, Hidalgo CG, Chung CS, Cheng H, Dalton ND, Gu Y, Kasahara H, Ghassemian M, Omens JH, Peterson KL, Granzier HL, Moss RL, McCulloch AD, Chen J. Mouse and computational models link Mlc2v dephosphorylation to altered myosin kinetics in early cardiac disease. J Clin Invest 122: 1209‐1221, 2012.
 516.Shriver M, Marimuthu S, Paul C, Geist J, Seale T, Konstantopoulos K, Kontrogianni‐Konstantopoulos A. Giant obscurins regulate the PI3K cascade in breast epithelial cells via direct binding to the PI3K/p85 regulatory subunit. Oncotarget 7: 45414‐45428, 2016.
 517.Shriver M, Stroka KM, Vitolo MI, Martin S, Huso DL, Konstantopoulos K, Kontrogianni‐Konstantopoulos A. Loss of giant obscurins from breast epithelium promotes epithelial‐to‐mesenchymal transition, tumorigenicity and metastasis. Oncogene 34: 4248‐4259, 2015.
 518.Sieck GC, Han YS, Prakash YS, Jones KA. Cross‐bridge cycling kinetics, actomyosin ATPase activity and myosin heavy chain isoforms in skeletal and smooth respiratory muscles. Comp Biochem Physiol B Biochem Mol Biol 119: 435‐450, 1998.
 519.Siedner S, Kruger M, Schroeter M, Metzler D, Roell W, Fleischmann BK, Hescheler J, Pfitzer G, Stehle R. Developmental changes in contractility and sarcomeric proteins from the early embryonic to the adult stage in the mouse heart. J Physiol 548: 493‐505, 2003.
 520.Siegert R, Perrot A, Keller S, Behlke J, Michalewska‐Wludarczyk A, Wycisk A, Tendera M, Morano I, Ozcelik C. A myomesin mutation associated with hypertrophic cardiomyopathy deteriorates dimerisation properties. Biochem Biophys Res Commun 405: 473‐479, 2011.
 521.Silver PJ, Buja LM, Stull JT. Frequency‐dependent myosin light chain phosphorylation in isolated myocardium. J Mol Cell Cardiol 18: 31‐37, 1986.
 522.Simonson TS, Zhang Y, Huff CD, Xing J, Watkins WS, Witherspoon DJ, Woodward SR, Jorde LB. Limited distribution of a cardiomyopathy‐associated variant in India. Ann Hum Genet 74: 184‐188, 2010.
 523.Small TM, Gernert KM, Flaherty DB, Mercer KB, Borodovsky M, Benian GM. Three new isoforms of Caenorhabditis elegans UNC‐89 containing MLCK‐like protein kinase domains. J Mol Biol 342: 91‐108, 2004.
 524.Spencer JA, Eliazer S, Ilaria RL, Richardson JA, Olson EN. Regulation of microtubule dynamics and myogenic differentiation by MURF, a striated muscle RING‐finger protein. J Cell Biol 150: 771‐784, 2000.
 525.Spooner PM, Bonner J, Maricq AV, Benian GM, Norman KR. Large isoforms of UNC‐89 (obscurin) are required for muscle cell architecture and optimal calcium release in Caenorhabditis elegans. PLoS One 7: e40182, 2012.
 526.Spudich JA, Aksel T, Bartholomew SR, Nag S, Kawana M, Yu EC, Sarkar SS, Sung J, Sommese RF, Sutton S, Cho C, Adhikari AS, Taylor R, Liu C, Trivedi D, Ruppel KM. Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human beta‐cardiac myosin. J Exp Biol 219: 161‐167, 2016.
 527.Squire JM. Muscle contraction: Sliding filament history, sarcomere dynamics and the two Huxleys. Glob Cardiol Sci Pract 2016: 11, 2016.
 528.Squire JM, Harford JJ, Edman AC, Sjostrom M. Fine structure of the A‐band in cryo‐sections. III. Crossbridge distribution and the axial structure of the human C‐zone. J Mol Biol 155: 467‐494, 1982.
 529.Squire JM, Luther PK, Knupp C. Structural evidence for the interaction of C‐protein (MyBP‐C) with actin and sequence identification of a possible actin‐binding domain. J Mol Biol 331: 713‐724, 2003.
 530.Squire JM, Paul DM, Morris EP. Myosin and actin filaments in muscle: Structures and interactions. Subcell Biochem 82: 319‐371, 2017.
 531.Starr R, Offer G. Polypeptide chains of intermediate molecular weight in myosin preparations. FEBS Lett 15: 40‐44, 1971.
 532.Stennicke HR, Jurgensmeier JM, Shin H, Deveraux Q, Wolf BB, Yang X, Zhou Q, Ellerby HM, Ellerby LM, Bredesen D, Green DR, Reed JC, Froelich CJ, Salvesen GS. Pro‐caspase‐3 is a major physiologic target of caspase‐8. J Biol Chem 273: 27084‐27090, 1998.
 533.Stewart MA, Franks‐Skiba K, Chen S, Cooke R. Myosin ATP turnover rate is a mechanism involved in thermogenesis in resting skeletal muscle fibers. Proc Natl Acad Sci U S A 107: 430‐435, 2010.
 534.Straub FB. Actin, II. Stud Inst Med Chem Univ Szeged III: 23‐37, 1943.
 535.Strehler EE, Pelloni G, Heizmann CW, Eppenberger HM. M‐protein in chicken cardiac muscle. Exp Cell Res 124: 39‐45, 1979.
 536.Stuart CA, Stone WL, Howell ME, Brannon MF, Hall HK, Gibson AL, Stone MH. Myosin content of individual human muscle fibers isolated by laser capture microdissection. Am J Physiol Cell Physiol 310: C381‐C389, 2016.
 537.Stull JT, Lin PJ, Krueger JK, Trewhella J, Zhi G. Myosin light chain kinase: Functional domains and structural motifs. Acta Physiol Scand 164: 471‐482, 1998.
 538.Subahi SA. Distinguishing cardiac features of a novel form of congenital muscular dystrophy (Salih cmd). Pediatr Cardiol 22: 297‐301, 2001.
 539.Sumandea MP, Pyle WG, Kobayashi T, de Tombe PP, Solaro RJ. Identification of a functionally critical protein kinase C phosphorylation residue of cardiac troponin T. J Biol Chem 278: 35135‐35144, 2003.
 540.Sutoh K. An actin‐binding site on the 20K fragment of myosin subfragment 1. Biochemistry 21: 4800‐4804, 1982.
 541.Sutoh K. Identification of myosin‐binding sites on the actin sequence. Biochemistry 21: 3654‐3661, 1982.
 542.Sweeney HL. Function of the N terminus of the myosin essential light chain of vertebrate striated muscle. Biophys J 68: 112S‐118S; discussion 118S‐119S, 1995.
 543.Szent‐Gyorgyi AG. The early history of the biochemistry of muscle contraction. J Gen Physiol 123: 631‐641, 2004.
 544.Tajsharghi H, Hammans S, Lindberg C, Lossos A, Clarke NF, Mazanti I, Waddell LB, Fellig Y, Foulds N, Katifi H, Webster R, Raheem O, Udd B, Argov Z, Oldfors A. Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations. Eur J Hum Genet 22: 801‐808, 2014.
 545.Tajsharghi H, Oldfors A. Myosinopathies: Pathology and mechanisms. Acta Neuropathol 125: 3‐18, 2013.
 546.Tanaka M, Konishi H, Touhara K, Sakane F, Hirata M, Ono Y, Kikkawa U. Identification of myosin II as a binding protein to the PH domain of protein kinase B. Biochem Biophys Res Commun 255: 169‐174, 1999.
 547.Taniguchi M, Okamoto R, Ito M, Goto I, Fujita S, Konishi K, Mizutani H, Dohi K, Hartshorne DJ, Itoh T. New isoform of cardiac myosin light chain kinase and the role of cardiac myosin phosphorylation in alpha1‐adrenoceptor mediated inotropic response. PLoS One 10: e0141130, 2015.
 548.Taveau M, Bourg N, Sillon G, Roudaut C, Bartoli M, Richard I. Calpain 3 is activated through autolysis within the active site and lyses sarcomeric and sarcolemmal components. Mol Cell Biol 23: 9127‐9135, 2003.
 549.Taylor M, Graw S, Sinagra G, Barnes C, Slavov D, Brun F, Pinamonti B, Salcedo EE, Sauer W, Pyxaras S, Anderson B, Simon B, Bogomolovas J, Labeit S, Granzier H, Mestroni L. Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy‐overlap syndromes. Circulation 124: 876‐885, 2011.
 550.Taylor‐Harris PM, Keating LA, Maggs AM, Phillips GW, Birks EJ, Franklin RC, Yacoub MH, Baines AJ, Pinder JC. Cardiac muscle cell cytoskeletal protein 4.1: Analysis of transcripts and subcellular location—Relevance to membrane integrity, microstructure, and possible role in heart failure. Mamm Genome 16: 137‐151, 2005.
 551.Temple JE, Oehler MC, Wright NT. Chemical shift assignments for the Ig2 domain of human obscurin A. Biomol NMR Assign 10: 63‐65, 2016.
 552.Timson DJ, Trayer HR, Smith KJ, Trayer IP. Size and charge requirements for kinetic modulation and actin binding by alkali 1‐type myosin essential light chains. J Biol Chem 274: 18271‐18277, 1999.
 553.Timson DJ, Trayer HR, Trayer IP. The N‐terminus of A1‐type myosin essential light chains binds actin and modulates myosin motor function. Eur J Biochem 255: 654‐662, 1998.
 554.Tong CW, Stelzer JE, Greaser ML, Powers PA, Moss RL. Acceleration of crossbridge kinetics by protein kinase A phosphorylation of cardiac myosin binding protein C modulates cardiac function. Circ Res 103: 974‐982, 2008.
 555.Tong CW, Wu X, Liu Y, Rosas PC, Sadayappan S, Hudmon A, Muthuchamy M, Powers PA, Valdivia HH, Moss RL. Phosphoregulation of cardiac inotropy via myosin binding protein‐C during increased pacing frequency or beta1‐adrenergic stimulation. Circ Heart Fail 8: 595‐604, 2015.
 556.Tong SW, Elzinga M. The sequence of the NH2‐terminal 204‐residue fragment of the heavy chain of rabbit skeletal muscle myosin. J Biol Chem 258: 13100‐13110, 1983.
 557.Toro C, Olivé M, Dalakas MC, Sivakumar K, Bilbao JM, Tyndel F, Vidal N, Farrero E, Sambuughin N, Goldfarb LG. Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins. BMC Neurol 13: 29, 2013.
 558.Toydemir RM, Rutherford A, Whitby FG, Jorde LB, Carey JC, Bamshad MJ. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman‐Sheldon syndrome and Sheldon‐Hall syndrome. Nat Genet 38: 561‐565, 2006.
 559.Trayer IP, Trayer HR, Levine BA. Evidence that the N‐terminal region of A1‐light chain of myosin interacts directly with the C‐terminal region of actin. A proton magnetic resonance study. Eur J Biochem 164: 259‐266, 1987.
 560.Trinick J, Lowey S. M‐protein from chicken pectoralis muscle: Isolation and characterization. J Mol Biol 113: 343‐368, 1977.
 561.Tskhovrebova L, Trinick J. Properties of titin immunoglobulin and fibronectin‐3 domains. J Biol Chem 279: 46351‐46354, 2004.
 562.Tskhovrebova L, Trinick J. Roles of titin in the structure and elasticity of the sarcomere. J Biomed Biotechnol 2010: 612482, 2010.
 563.Tskhovrebova L, Trinick J. Titin and nebulin in thick and thin filament length regulation. Subcell Biochem 82: 285‐318, 2017.
 564.Udd B, Haravuori H, Kalimo H, Partanen J, Pulkkinen L, Paetau A, Peltonen L, Somer H. Tibial muscular dystrophy—From clinical description to linkage on chromosome 2q31. Neuromuscul Disord 8: 327‐332, 1998.
 565.Udd B, Kääriänen H, Somer H. Muscular dystrophy with separate clinical phenotypes in a large family. Muscle Nerve 14: 1050‐1058, 1991.
 566.Udd B, Partanen J, Halonen P, Falck B, Hakamies L, Heikkilä H, Ingo S, Kalimo H, Kääriäinen H, Laulumaa V. Tibial muscular dystrophy. Late adult‐onset distal myopathy in 66 Finnish patients. Arch Neurol 50: 604‐608, 1993.
 567.Van den Bergh PY, Bouquiaux O, Verellen C, Marchand S, Richard I, Hackman P, Udd B. Tibial muscular dystrophy in a Belgian family. Ann Neurol 54: 248‐251, 2003.
 568.van der Ven PF, Bartsch JW, Gautel M, Jockusch H, Furst DO. A functional knock‐out of titin results in defective myofibril assembly. J Cell Sci 113 (Pt 8): 1405‐1414, 2000.
 569.Van der Ven PF, Ehler E, Perriard JC, Furst DO. Thick filament assembly occurs after the formation of a cytoskeletal scaffold. J Muscle Res Cell Motil 20: 569‐579, 1999.
 570.van Dijk SJ, Bezold KL, Harris SP. Earning stripes: Myosin binding protein‐C interactions with actin. Pflugers Arch 466: 445‐450, 2014.
 571.van Dijk SJ, Dooijes D, dos Remedios C, Michels M, Lamers JM, Winegrad S, Schlossarek S, Carrier L, ten Cate FJ, Stienen GJ, van der Velden J. Cardiac myosin‐binding protein C mutations and hypertrophic cardiomyopathy: Haploinsufficiency, deranged phosphorylation, and cardiomyocyte dysfunction. Circulation 119: 1473‐1483, 2009.
 572.van Spaendonck‐Zwarts KY, Posafalvi A, van den Berg MP, Hilfiker‐Kleiner D, Bollen IA, Sliwa K, Alders M, Almomani R, van Langen IM, van der Meer P, Sinke RJ, van der Velden J, Van Veldhuisen DJ, van Tintelen JP, Jongbloed JD. Titin gene mutations are common in families with both peripartum cardiomyopathy and dilated cardiomyopathy. Eur Heart J 35: 2165‐2173, 2014.
 573.Vandenboom R. Modulation of skeletal muscle contraction by myosin phosphorylation. Compr Physiol 7: 171‐212, 2016.
 574.Vandenboom R, Gittings W, Smith IC, Grange RW, Stull JT. Myosin phosphorylation and force potentiation in skeletal muscle: Evidence from animal models. J Muscle Res Cell Motil 34: 317‐332, 2013.
 575.Vaughan KT, Weber FE, Einheber S, Fischman DA. Molecular cloning of chicken myosin‐binding protein (MyBP) H (86‐kDa protein) reveals extensive homology with MyBP‐C (C‐protein) with conserved immunoglobulin C2 and fibronectin type III motifs. J Biol Chem 268: 3670‐3676, 1993.
 576.Vaughan KT, Weber FE, Ried T, Ward DC, Reinach FC, Fischman DA. Human myosin‐binding protein H (MyBP‐H): Complete primary sequence, genomic organization, and chromosomal localization. Genomics 16: 34‐40, 1993.
 577.Venolia L, Waterston RH. The unc‐45 gene of Caenorhabditis elegans is an essential muscle‐affecting gene with maternal expression. Genetics 126: 345‐353, 1990.
 578.Vignier N, Schlossarek S, Fraysse B, Mearini G, Kramer E, Pointu H, Mougenot N, Guiard J, Reimer R, Hohenberg H, Schwartz K, Vernet M, Eschenhagen T, Carrier L. Nonsense‐mediated mRNA decay and ubiquitin‐proteasome system regulate cardiac myosin‐binding protein C mutant levels in cardiomyopathic mice. Circ Res 105: 239‐248, 2009.
 579.Vivarelli E, Brown WE, Whalen RG, Cossu G. The expression of slow myosin during mammalian somitogenesis and limb bud differentiation. J Cell Biol 107: 2191‐2197, 1988.
 580.Waldmuller S, Sakthivel S, Saadi AV, Selignow C, Rakesh PG, Golubenko M, Joseph PK, Padmakumar R, Richard P, Schwartz K, Tharakan JM, Rajamanickam C, Vosberg HP. Novel deletions in MYH7 and MYBPC3 identified in Indian families with familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 35: 623‐636, 2003.
 581.Walklate J, Ujfalusi Z, Geeves MA. Myosin isoforms and the mechanochemical cross‐bridge cycle. J Exp Biol 219: 168‐174, 2016.
 582.Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM. Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: The ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem J 281 (Pt 1): 21‐40, 1992.
 583.Wang K, McClure J, Tu A. Titin: Major myofibrillar components of striated muscle. Proc Natl Acad Sci U S A 76: 3698‐3702, 1979.
 584.Wang K, Ramirez‐Mitchell R, Palter D. Titin is an extraordinarily long, flexible, and slender myofibrillar protein. Proc Natl Acad Sci U S A 81: 3685‐3689, 1984.
 585.Wang L, Muthu P, Szczesna‐Cordary D, Kawai M. Characterizations of myosin essential light chain's N‐terminal truncation mutant Delta43 in transgenic mouse papillary muscles by using tension transients in response to sinusoidal length alterations. J Muscle Res Cell Motil 34: 93‐105, 2013.
 586.Wang SM, Jeng CJ, Sun MC. Studies on the interaction between titin and myosin. Histol Histopathol 7: 333‐337, 1992.
 587.Wang X, Liu X, Wang S, Luan K. Myofibrillogenesis regulator 1 induces hypertrophy by promoting sarcomere organization in neonatal rat cardiomyocytes. Hypertens Res 35: 597‐603, 2012.
 588.Wang Y, Szczesna‐Cordary D, Craig R, Diaz‐Perez Z, Guzman G, Miller T, Potter JD. Fast skeletal muscle regulatory light chain is required for fast and slow skeletal muscle development. FASEB J 21: 2205‐2214, 2007.
 589.Warkman AS, Whitman SA, Miller MK, Garriock RJ, Schwach CM, Gregorio CC, Krieg PA. Developmental expression and cardiac transcriptional regulation of Myh7b, a third myosin heavy chain in the vertebrate heart. Cytoskeleton (Hoboken) 69: 324‐335, 2012.
 590.Warner A, Xiong G, Qadota H, Rogalski T, Vogl AW, Moerman DG, Benian GM. CPNA‐1, a copine domain protein, is located at integrin adhesion sites and is required for myofilament stability in Caenorhabditis elegans. Mol Biol Cell 24: 601‐616, 2013.
 591.Waters S, Marchbank K, Solomon E, Whitehouse C, Gautel M. Interactions with LC3 and polyubiquitin chains link nbr1 to autophagic protein turnover. FEBS Lett 583: 1846‐1852, 2009.
 592.Waterston RH, Thomson JN, Brenner S. Mutants with altered muscle structure of Caenorhabditis elegans. Dev Biol 77: 271‐302, 1980.
 593.Watkins H, Conner D, Thierfelder L, Jarcho JA, MacRae C, McKenna WJ, Maron BJ, Seidman JG, Seidman CE. Mutations in the cardiac myosin binding protein‐C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nat Genet 11: 434‐437, 1995.
 594.Weber FE, Vaughan KT, Reinach FC, Fischman DA. Complete sequence of human fast‐type and slow‐type muscle myosin‐binding‐protein C (MyBP‐C). Differential expression, conserved domain structure and chromosome assignment. Eur J Biochem 216: 661‐669, 1993.
 595.Webster C, Silberstein L, Hays AP, Blau HM. Fast muscle fibers are preferentially affected in Duchenne muscular dystrophy. Cell 52: 503‐513, 1988.
 596.Weisberg A, Winegrad S. Alteration of myosin cross bridges by phosphorylation of myosin‐binding protein C in cardiac muscle. Proc Natl Acad Sci U S A 93: 8999‐9003, 1996.
 597.Weith AE, Previs MJ, Hoeprich GJ, Previs SB, Gulick J, Robbins J, Warshaw DM. The extent of cardiac myosin binding protein‐C phosphorylation modulates actomyosin function in a graded manner. J Muscle Res Cell Motil 33: 449‐459, 2012.
 598.Wessels A, Vermeulen JL, Viragh S, Kalman F, Lamers WH, Moorman AF. Spatial distribution of “tissue‐specific” antigens in the developing human heart and skeletal muscle. II. An immunohistochemical analysis of myosin heavy chain isoform expression patterns in the embryonic heart. Anat Rec 229: 355‐368, 1991.
 599.Weterman MA, Barth PG, van Spaendonck‐Zwarts KY, Aronica E, Poll‐The BT, Brouwer OF, van Tintelen JP, Qahar Z, Bradley EJ, de Wissel M, Salviati L, Angelini C, van den Heuvel L, Thomasse YE, Backx AP, Nurnberg G, Nurnberg P, Baas F. Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy. Brain 136: 282‐293, 2013.
 600.Whiting A, Wardale J, Trinick J. Does titin regulate the length of muscle thick filaments? J Mol Biol 205: 263‐268, 1989.
 601.Whitten AE, Jeffries CM, Harris SP, Trewhella J. Cardiac myosin‐binding protein C decorates F‐actin: Implications for cardiac function. Proc Natl Acad Sci U S A 105: 18360‐18365, 2008.
 602.Willis CD, Oashi T, Busby B, Mackerell AD, Jr., Bloch RJ. Hydrophobic residues in small ankyrin 1 participate in binding to obscurin. Mol Membr Biol 29: 36‐51, 2012.
 603.Wilson KJ, Qadota H, Mains PE, Benian GM. UNC‐89 (obscurin) binds to MEL‐26, a BTB‐domain protein, and affects the function of MEI‐1 (katanin) in striated muscle of Caenorhabditis elegans. Mol Biol Cell 23: 2623‐2634, 2012.
 604.Winegrad S. Cardiac myosin binding protein C. Circ Res 84: 1117‐1126, 1999.
 605.Witt SH, Granzier H, Witt CC, Labeit S. MURF‐1 and MURF‐2 target a specific subset of myofibrillar proteins redundantly: Towards understanding MURF‐dependent muscle ubiquitination. J Mol Biol 350: 713‐722, 2005.
 606.Wohlgemuth SL, Crawford BD, Pilgrim DB. The myosin co‐chaperone UNC‐45 is required for skeletal and cardiac muscle function in zebrafish. Dev Biol 303: 483‐492, 2007.
 607.Wu HC, Yamankurt G, Luo J, Subramaniam J, Hashmi SS, Hu H, Cunha SR. Identification and characterization of two ankyrin‐B isoforms in mammalian heart. Cardiovasc Res 107: 466‐477, 2015.
 608.Xiao S, Grater F. Molecular basis of the mechanical hierarchy in myomesin dimers for sarcomere integrity. Biophys J 107: 965‐973, 2014.
 609.Xiong G, Qadota H, Mercer KB, McGaha LA, Oberhauser AF, Benian GM. A LIM‐9 (FHL)/SCPL‐1 (SCP) complex interacts with the C‐terminal protein kinase regions of UNC‐89 (obscurin) in Caenorhabditis elegans muscle. J Mol Biol 386: 976‐988, 2009.
 610.Xu J, Li Z, Ren X, Dong M, Li J, Shi X, Zhang Y, Xie W, Sun Z, Liu X, Dai Q. Investigation of pathogenic genes in Chinese sporadic hypertrophic cardiomyopathy patients by whole exome sequencing. Sci Rep 5: 16609, 2015.
 611.Xu Q, Dewey S, Nguyen S, Gomes AV. Malignant and benign mutations in familial cardiomyopathies: Insights into mutations linked to complex cardiovascular phenotypes. J Mol Cell Cardiol 48: 899‐909, 2010.
 612.Yagi N. An x‐ray diffraction study on early structural changes in skeletal muscle contraction. Biophys J 84: 1093‐1102, 2003.
 613.Yamamoto K. The binding of skeletal muscle C‐protein to regulated actin. FEBS Lett 208: 123‐127, 1986.
 614.Yasuda M, Koshida S, Sato N, Obinata T. Complete primary structure of chicken cardiac C‐protein (MyBP‐C) and its expression in developing striated muscles. J Mol Cell Cardiol 27: 2275‐2286, 1995.
 615.Yin Z, Ren J, Guo W. Sarcomeric protein isoform transitions in cardiac muscle: A journey to heart failure. Biochim Biophys Acta 1852: 47‐52, 2015.
 616.Yoskovitz G, Peled Y, Gramlich M, Lahat H, Resnik‐Wolf H, Feinberg MS, Afek A, Pras E, Arad M, Gerull B, Freimark D. A novel titin mutation in adult‐onset familial dilated cardiomyopathy. Am J Cardiol 109: 1644‐1650, 2012.
 617.Young P, Ehler E, Gautel M. Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly. J Cell Biol 154: 123‐136, 2001.
 618.Yu H, Chakravorty S, Song W, Ferenczi MA. Phosphorylation of the regulatory light chain of myosin in striated muscle: Methodological perspectives. Eur Biophys J 45: 779‐805, 2016.
 619.Yuan C, Guo Y, Ravi R, Przyklenk K, Shilkofski N, Diez R, Cole RN, Murphy AM. Myosin binding protein C is differentially phosphorylated upon myocardial stunning in canine and rat hearts—Evidence for novel phosphorylation sites. Proteomics 6: 4176‐4186, 2006.
 620.Yuan CC, Muthu P, Kazmierczak K, Liang J, Huang W, Irving TC, Kanashiro‐Takeuchi RM, Hare JM, Szczesna‐Cordary D. Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice. Proc Natl Acad Sci U S A 112: E4138‐E4146, 2015.
 621.Yue D, Gao M, Zhu W, Luo S, Xi J, Wang B, Li Y, Cai S, Li J, Wang Y, Lu J, Zhao C. New disease allele and de novo mutation indicate mutational vulnerability of titin exon 343 in hereditary myopathy with early respiratory failure. Neuromuscul Disord 25: 172‐176, 2015.
 622.Zammit PS, Kelly RG, Franco D, Brown N, Moorman AF, Buckingham ME. Suppression of atrial myosin gene expression occurs independently in the left and right ventricles of the developing mouse heart. Dev Dyn 217: 75‐85, 2000.
 623.Zheng X, Cartee GD. Insulin‐induced effects on the subcellular localization of AKT1, AKT2 and AS160 in rat skeletal muscle. Sci Rep 6: 39230, 2016.
 624.Zhi G, Ryder JW, Huang J, Ding P, Chen Y, Zhao Y, Kamm KE, Stull JT. Myosin light chain kinase and myosin phosphorylation effect frequency‐dependent potentiation of skeletal muscle contraction. Proc Natl Acad Sci U S A 102: 17519‐17524, 2005.
 625.Zhou Z, Huang W, Liang J, Szczesna‐Cordary D. Molecular and functional effects of a splice site mutation in the MYL2 gene associated with cardioskeletal myopathy and early cardiac death in infants. Front Physiol 7: 240, 2016.
 626.Zoghbi ME, Woodhead JL, Moss RL, Craig R. Three‐dimensional structure of vertebrate cardiac muscle myosin filaments. Proc Natl Acad Sci U S A 105: 2386‐2390, 2008.

Teaching Material

L. Wang, J. Geist, A. Grogan, L.-Y. R. Hu, A. Kontrogianni-Konstantopoulos. Thick Filament Protein Network, Functions, and Disease Association. Compr Physiol. 8: 2018, 631-709.

Didactic Synopsis

Major Teaching Points:

  1. Sarcomeres consist of ordered arrays of thick myosin and thin actin filaments along with accessory proteins.
  2. Myosin, the backbone of thick filaments, slides past actin filaments by hydrolyzing ATP to mediate muscle contraction.
  3. Four other proteins that are bound to thick filaments play structural and regulatory roles.
  4. Myosin binding protein-C binds to myosin and actin filaments contributing to their stabilization and modulating cross-bridge cycling.
  5. Titin binds to myosin and functions as a scaffold, signaling mediator, and mechanosensor.
  6. Myomesin forms antiparallel homodimers, cross-linking myosin, and contributing to the elasticity of thick filaments.
  7. Obscurin wraps around myofilaments over M-bands, contributing to the maintenance and alignment of thick filaments with internal membranes.
  8. The functions of myosin and its accessory proteins are regulated via alternative splicing and posttranslational modifications.
  9. Mutations in the respective genes are causatively linked to the development of skeletal and cardiac myopathies.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: The sarcomere is the smallest contractile unit of the striated muscle cell. One of the most remarkable features of sarcomeres is their austere periodicity created by overlapping arrays of thick myosin (A-band) and thin actin (I-band) filaments. The myosin complex composed of myosin heads and rods alongside regulatory and essential light chains is the backbone of the thick filament. In a single thick filament, the globular motor head domains of myosin face outward while their long rod regions face inward forming a bipolar filament. In addition to myosin, a number of other proteins including MyBP-C, titin, myomesin, and obscurin reside in the thick filament playing important structural and regulatory roles. In the middle of the A- and I-band, there is a vertical line called M-band and Z-disk, respectively.

Figure 2. Teaching points: Sarcomeric myosin is a hexameric motor protein composed of two MyHC, two ELC, and two RLC. Each MyHC contains a globular motor “head” domain that bears ATPase activity, a converter segment connecting the head domain to the lever arm and a “tail” that consists of a coiled-coil α-helical region that homodimerizes to form rods. Upon limited trypsin digestion, MyHC is fragmented into HMM, which contains the head region, the converter segment, the lever arm and the NH2-terminal portion of the α-helical rod domain, and light meromyosin (LMM), which contains the COOH-terminal half of the α-helical rod domain. Further cleavage of HMM by papain leads to generation of S1 and S2, with S1 consisting of the head domain, the converter segment, and the lever arm, and S2 containing the NH2-terminus of the α-helical rod domain.

Figure 3. Teaching points: Myosins form stable or transient interactions with proteins involved in different cell processes. In particular, MyHCs bind to proteins playing key roles in contractility (actin, MyBP-C and MyBP-H), cytoskeletal organization (myomesin, M-protein, titin, and nonerythroid 4.1R), signaling (PKB/Akt2), metabolism (AMPD1), protein folding and stability (HspB2 and Unc45b), proteasomal degradation (MuRFs), and apoptosis (caspase-3). Contrary to MyHC, less is known about the binding partners of ELC and RLC with the exception of their ability to interact with actin and MuRFs, respectively.

Figure 4. Teaching points: Both thin and thick filaments undergo structural alterations to accommodate actomyosin binding and the generation of power stroke. Following the generation of power stroke, the myosin head domain remains attached to actin until a new ATP molecule binds to HMM and induces detachment of the myosin head domain from actin. ATP binding to HMM further exerts a conformational strain to myosin leading to rotation of the converter domain by 65o resulting in ATP hydrolysis that enables a weak initial association of actin and myosin. As HMM alters conformation due to ATP hydrolysis, enhanced actomyosin binding occurs mediated by both stereospecific and electrostatic interactions. Following the release of ADP, the lever arm undergoes a conformational change resulting to generation of power stroke and muscle contraction.

Figure 5. Teaching points: The myosin hexamer undergoes extensive posttranslational modifications in mammals including acetylation, arginylation, phosphorylation, and O-GlcNAcylation that regulate its binding, enzymatic, and contractile properties. Notably, only acetylation and phosphorylation sites have been identified for the human isoforms. These are mainly concentrated in the LMM coiled-coil region of MyHCs, with the exception of MYH7 in which they are present throughout the entire length of the protein. Moreover, acetylation and phosphorylation sites are present in the nonmodular NH2-terminus and the first EF-hand motif of ELCs, while they are scattered across the entire length of RLCs.

Figure 6. Teaching points: Myosins are the most heavily mutated proteins in congenital and somatic cardiac and skeletal myopathies. Hundreds of mutations have been identified along the entire length of MYH7, while mutations described in MYH6 and MYH2 are preferentially localized in the motor domain and the coiled-coil region. On the contrary, MYH3 is primarily mutated within the motor domain and the lever arm. No mutations associated with myopathy have been identified in MYH1, MYH4, and MYH7B to date. In addition to mutations in MyHC, mutations in ELC and RLC also lead to disease development. MYL3 is heavily mutated in both the nonmodular NH2-terminus and the EF-hand, whereas only one mutation has been identified in MYL4 and none in MYL1. Similarly, MYL2 is heavily mutated throughout its entire length, whereas no myopathic mutations have been described in MYL7 and MYLPF.

Figure 7. Teaching points: The MyBP-C family comprises three isoforms including cMyBP-C, sMyBP-C, and fMyBP-C that play key roles in sarcomeric maintenance and cross-bridge cycling. The three isoforms share similar structures consisting of seven (sMyBP-C and fMyBP-C) or eight (cMyBP-C) Ig and three FnIII domains numbered from the NH2-terminus to the COOH-terminus as C1-C10. The cardiac isoform includes an additional Ig domain at its extreme NH2-terminus, referred to as C0. A Pro/Ala rich region and the M-motif flank C1 in all three isoforms. cMyBP-C and fMyBP-C also share a conserved linker region between Ig domains C4 and C5, which is absent from sMyBP-C. In contrast to cMyBP-C and fMyBP-C, sMyBP-C undergoes extensive alternative splicing within the Pro/Ala rich motif, the M-motif, Ig domain C7, and the extreme COOH-terminus, resulting in several sMyBP-C variants that likely play distinct structural and regulatory role in skeletal muscles.

Figure 8. Teaching points: The main binding partners of MyBP-C are actin, myosin, and titin. MyBP-C binds actin and myosin-S1 via its NH2-terminus, and these interactions are highly dynamic and regulated by Ca2+ and phosphorylation. Moreover, MyBP-C binds myosin-LMM and titin via its COOH-terminus, and these interactions are stable. In addition to the three major binding partners discussed above, isoform-specific binding partners have also been identified including obscurin and M-CK that specifically interact with sMyBP-C.

Figure 9. Teaching points: Both cMyBP-C and sMyBP-C are subjected to extensive phosphorylation within their NH2-termini that regulates their ability to modulate the formation of actomyosin cross-bridges. Interestingly, cMyBP-C is heavily phosphorylated in the M-motif, whereas sMyBP-C is primarily phosphorylated in the Pro/Ala rich region and to a lesser extent in the M-motif. In addition to phosphorylation, cMyBP-C undergoes acetylation, citrullination, S-glutathiolation, and S-nitrosylation. Acetylation primarily occurs in the NH2-terminus and Ig domain C7 likely promoting proteolysis of cMyBP-C, while S-glutathiolation takes place in the central region within Ig domains C3-C5 possibly decreasing myofilament Ca2+ sensitivity. The effect of citrullination and S-nitrosylation on the activities and stability of cMyBP-C are still unknown.

Figure 10. Teaching points: More than 500 mutations, including missense, nonsense, splice, frameshift, insertion, deletion, and indel have been described for cMyBP-C (MYBPC3 gene) that are primarily associated with the development of HCM and to a lesser extent with DCM and LVNC. These mutations are widely distributed throughout the entire length of the protein. In addition, missense and nonsense mutations in sMyBP-C (MYBPC1 gene) localizing to the NH2-terminal C1-M-C2 region of the protein have been linked to DA, AMC, and LCCS-4. Lastly, two missense mutations located in the M-motif of fMyBP-C (MYBPC2 gene) may contribute to an unclassified form of DA.

Figure 11. Teaching points: Titin, the largest known protein with a total mass of 3 to 4 MDa, spans an entire half sarcomere. The region of titin that associates with the thick filament represents 2 MDa (A-band) and 200 kDa (M-band) of titin's total mass. The region of titin that spans the A-band is composed entirely of Ig and FnIII domains (A1-170) that are organized into two types of super-repeats. The first super-repeat occurs six times in tandem and is followed by 11 copies of the second super-repeat. Titin's most COOH-terminal segment is anchored to the M-band. The M-band region is composed of an MLCK-like Ser/Thr kinase and 10 Ig domains (M1-10) that are interspersed by unique sequences, referred to as interdomain sequences 1-7 (Is1-7). Unlike the NH2-terminus and middle segment, the structure of titin within the A- and M-band is relatively rigid, inelastic, and constitutively expressed among isoforms with the exception of M-band exon 5.

Figure 12. Teaching points: A number of interacting partners have been identified within the A- and M-band portions of titin. In particular, titin contains binding sites for the sarcomeric proteins myosin, MyBP-C, myomesin, M-protein, obscurin, obsl1 and DRAL/FHL2, the E3 ligases MuRF-1 and -2, the tumor suppressor Bin1, the Ca2+-dependent cysteine preotease calpain-3, and the Ca2+-binding protein calmodulin. Moreover, the adaptor zinc-finger proteins Nbr1 and p62, which are involved in proteasomal degradation and autophagy, respectively, are substrates of TK.

Figure 13. Teaching points: The thick filament portion of titin undergoes phosphorylation within the M-band in the KSP motifs present in Is4 and the P+1 loop of TK, and arginylation throughout the A- and M-band. Although the effects of these modifications are currently elusive, it has been postulated that KSP phosphorylation is developmentally regulated and possibly plays a role in myofibrillogenesis and myocyte differentiation, while arginylation may regulate passive force likely by modifying titin's anchorage to the thick filament.

Figure 14. Teaching points: To date, a total of 175 mutations have been identified in the region of titin spanning the A- and M-band. The majority of these mutations (132) are linked to a variety of cardiomyopathies, including DCM, HCM, and ARVC. The remaining mutations are linked to skeletal muscle disorders including TMD, LGMD2J, EDMD, HMERF, CNM, and multiminicore disease with associated heart disease.

Figure 15. Teaching points: The myomesin family comprises a group of three modular proteins, myomesin, M-protein, and myomesin-3 that reside in the sarcomeric M-band where they cross-link myosin filaments and maintain their proper alignment. The three isoforms have similar architectures, and are composed of 13 domains that include a nonmodular NH2-terminal region, My1, followed by an array of Ig and FnIII domains arranged in the following order: 2Ig (My2-My3)-5FnIII (My4-My8)-5Ig (My9-My13). A developmental splice variant of myomesin, EH-myomesin, contains a unique unstructured 100-amino-acid-long Ser/Pro-rich insertion between FnIII domains My6 and My7. The three isoforms share a 40% to 50% overall homology.

Figure 16. Teaching points: The myomesin isoforms contain multiple Ig and FnIII domains, which serve as binding sites for several proteins residing in the thick filament. Specifically, myomesin contains binding sites for the sarcomeric proteins myosin, titin, obscurin, obsl1, and MR1, the metabolic enzyme M-CK, and the sarcolemmal protein dysferlin. Notably, PKA-mediated phosphorylation of myomesin on Ser618 (shown in green) located in the linker region between My4 and My5 inhibits binding to titin. Similarly, phosphorylation of Ser76 (shown in green) in My1 of M-protein precludes binding to LMM.

Figure 17. Teaching points: A limited number of myopathic mutations have been identified to date in MYOM1, whereas there are no known myopathy-causing mutations for MYOM2 and MYOM3. Two missense mutations have been identified in MYOM1, including Glu247Lys residing in My1 and Val1490Ile located in My12 that have been associated with congenital DCM and HCM, respectively. Moreover, aberrant inclusion of MYOM1 exon 17a encoding a 60 to 100-amino-acid-long insert between FnIII domains My6-My7 of myomesin has been implicated in DM1 skeletal myopathy.

Figure 18. Teaching points: Obscurin is the most recently discovered, and the third member of the family of giant sarcomeric proteins expressed in vertebrate striated muscles, along with titin and nebulin. The prototypical obscurin, referred to as obscurin-A (720 kDa), contains tandem Ig and FnIII domains followed by an array of signaling motifs. In particular, the NH2-terminus and middle of the molecule consist of 59 Ig and 3 FnIII domains, followed by an IQ rich domain, a SH3 domain, a RhoGEF motif, a PH domain, and a 417-amino acids long COOH-terminal nonmodular region. Obscurin-B (870 kDa) is also a giant isoform that shares the same architecture with obscurin-A with the exception of its COOH-terminus that contains two Ser/Thr kinase domains (referred to as Kinase1 and Kinase2) preceded by Ig and Ig/FnIII domains, respectively. Kinase1 and Kinase2 belong to the MLCK subfamily, and can also be expressed as smaller proteins that contain one or both kinase domains, referred to as single (55 kDa, only containing Kinase2) and double (145 kDa, containing partial Kinase1 and full length Kinase2) kinase isoforms.

Figure 19. Teaching points: Similar to titin, obscurin is a modular protein composed of tandem adhesion and signaling domains which provide binding sites for sarcomeric (MyBP-C, titin, and myomesin), membrane-associated (ankyrins, N-cadherin, and the β1 subunit of NKA-β1), and signaling (RhoA, Ran binding protein 9, and calmodulin) proteins. In addition, a number of binding partners have been identified for the invertebrate obscurin, UNC-89, which are highly conserved among species and include sarcomeric (paramyosin) and signaling (RHO-1, SCPL-1, LIM-9, CPNA-1, Ball, and MASK) proteins as well as E3 ligases (MEL-26).

Figure 20. Teaching points: Little is known about the regulation of obscurins via posttranslational modifications. To date, the only known modification that obscurins undergo is phosphorylation. It is worth noting that both kinase domains present in obscurin-B undergo autophosphorylation in vitro, although the exact sites or the functional significance of these events are currently unknown.

Figure 21. Teaching points: The involvement of obscurins in the development of myopathies has only been recently interrogated leading to the identification of 15 mutations which are linked to different forms of cardiomyopathy including HCM (7), DCM (5), and LVNC (3). Notably, it was recently suggested that OBSCN mutations might be more commonly associated with the pathogenesis of LVNC rather than DCM given their high prevalence in a small cohort of LVNC patients (3/10) versus a large(r) cohort of DCM patients (1/325).


Related Articles:

Force Generation and Shortening in Skeletal Muscle
Myofilaments: Movers and Rulers of the Sarcomere
Cellular Basis of Physiological and Pathological Myocardial Growth

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Li Wang, Janelle Geist, Alyssa Grogan, Li‐Yen R. Hu, Aikaterini Kontrogianni‐Konstantopoulos. Thick Filament Protein Network, Functions, and Disease Association. Compr Physiol 2018, 8: 631-709. doi: 10.1002/cphy.c170023