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Myofilaments: Movers and Rulers of the Sarcomere

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ABSTRACT

Striated cardiac and skeletal muscles play very different roles in the body, but they are similar at the molecular level. In particular, contraction, regardless of the type of muscle, is a precise and complex process involving the integral protein myofilaments and their associated regulatory components. The smallest functional unit of muscle contraction is the sarcomere. Within the sarcomere can be found a sophisticated ensemble of proteins associated with the thick filaments (myosin, myosin binding protein‐C, titin, and obscurin) and thin myofilaments (actin, troponin, tropomyosin, nebulin, and nebulette). These parallel thick and thin filaments slide across one another, pulling the two ends of the sarcomere together to regulate contraction. More specifically, the regulation of both timing and force of contraction is accomplished through an intricate network of intra‐ and interfilament interactions belonging to each myofilament. This review introduces the sarcomere proteins involved in striated muscle contraction and places greater emphasis on the more recently identified and less well‐characterized myofilaments: cardiac myosin binding protein‐C, titin, nebulin, and obscurin. © 2017 American Physiological Society. Compr Physiol 7:675‐692, 2017.

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Figure 1. Figure 1. Structure of sarcomere and myofilament proteins. (A) Actin and myosin overlap at the C‐zone in the A‐band where 7 to 9 MyBP‐C stripes interact with both filaments. Myosin and MyBP‐C are arranged in a ratio of ∼ 3:1. Titin spans from Z‐disk to M‐line. (B) Titin containing N2B and PEVK regions in I‐band anchors in Z‐disk via T‐cap and α‐actinin, and it also interacts with actin. (C) C‐terminal (C8‐C10) cMyBP‐C binds to meromyosin and titin, but N‐terminal C0 to M regions associate with actin and myosin head.
Figure 2. Figure 2. Schematic diagram of MyBP‐C isoforms. All three isoforms, cardiac, slow skeletal, and fast skeletal, contain a proline/alanine (P/A)‐rich region, seven immunoglobulin‐like domains (Ig), M‐domain, and three fibronectin 3 (Fn3) domains. Top: cardiac isoform of MyBP‐C has an additional C0 Ig domain at the N‐terminus and 28 residual inserts in C5 (brown vertical line). In addition, five phosphorylation sites (red vertical line) can be observed, one in the P/A region and four in M‐domain. The linker (thick purple band) between C4 and C5 is conserved between cMyBP‐C and ssMyBP‐C. Middle: fast skeletal MyBP‐C isoform is the smallest, and no phosphorylation site has been reported. Bottom: slow skeletal isoform of MyBP‐C has four phosphorylation sites, three in the P/A region and one in the M‐region.
Figure 3. Figure 3. Domain structure in I‐band region of two adult titin isoforms. Titin is a giant myofilament protein consisting of mostly Ig tandem repeats (orange), but also unique regions specific to each isoform (81). Both isoforms consist of proximal poly‐Ig repeats, a variably spliced region, followed by distal poly‐Ig repeats. Isoform differences are notably distinct within the variable region. Top: N2B notably contains an N2B unique sequence, N2B‐U. Bottom: N2BA consists of a PEVK element within its variable region.
Figure 4. Figure 4. Schematic illustration of nebulin (top, >600 kDa) and nebulette (bottom, 107 kDa) structures. Nebulin spans the entire length of thin filament and has a central core region. This central sequence consists of 8 nebulin repeats, 22 nebulin super‐repeats, and an additional 23 nebulin repeats. Nebulette, the cardiac counterpart of nebulin, is much shorter and lacks nebulin super‐repeats.
Figure 5. Figure 5. Domain patterns of obscurin A and B. Both isoforms are homologous, consisting of Ig tandem repeats, Fn3 and IQ domains. The C‐terminal domains of obscurin isoforms are more variable with, for example, additional protein kinase domains and Ig domains.


Figure 1. Structure of sarcomere and myofilament proteins. (A) Actin and myosin overlap at the C‐zone in the A‐band where 7 to 9 MyBP‐C stripes interact with both filaments. Myosin and MyBP‐C are arranged in a ratio of ∼ 3:1. Titin spans from Z‐disk to M‐line. (B) Titin containing N2B and PEVK regions in I‐band anchors in Z‐disk via T‐cap and α‐actinin, and it also interacts with actin. (C) C‐terminal (C8‐C10) cMyBP‐C binds to meromyosin and titin, but N‐terminal C0 to M regions associate with actin and myosin head.


Figure 2. Schematic diagram of MyBP‐C isoforms. All three isoforms, cardiac, slow skeletal, and fast skeletal, contain a proline/alanine (P/A)‐rich region, seven immunoglobulin‐like domains (Ig), M‐domain, and three fibronectin 3 (Fn3) domains. Top: cardiac isoform of MyBP‐C has an additional C0 Ig domain at the N‐terminus and 28 residual inserts in C5 (brown vertical line). In addition, five phosphorylation sites (red vertical line) can be observed, one in the P/A region and four in M‐domain. The linker (thick purple band) between C4 and C5 is conserved between cMyBP‐C and ssMyBP‐C. Middle: fast skeletal MyBP‐C isoform is the smallest, and no phosphorylation site has been reported. Bottom: slow skeletal isoform of MyBP‐C has four phosphorylation sites, three in the P/A region and one in the M‐region.


Figure 3. Domain structure in I‐band region of two adult titin isoforms. Titin is a giant myofilament protein consisting of mostly Ig tandem repeats (orange), but also unique regions specific to each isoform (81). Both isoforms consist of proximal poly‐Ig repeats, a variably spliced region, followed by distal poly‐Ig repeats. Isoform differences are notably distinct within the variable region. Top: N2B notably contains an N2B unique sequence, N2B‐U. Bottom: N2BA consists of a PEVK element within its variable region.


Figure 4. Schematic illustration of nebulin (top, >600 kDa) and nebulette (bottom, 107 kDa) structures. Nebulin spans the entire length of thin filament and has a central core region. This central sequence consists of 8 nebulin repeats, 22 nebulin super‐repeats, and an additional 23 nebulin repeats. Nebulette, the cardiac counterpart of nebulin, is much shorter and lacks nebulin super‐repeats.


Figure 5. Domain patterns of obscurin A and B. Both isoforms are homologous, consisting of Ig tandem repeats, Fn3 and IQ domains. The C‐terminal domains of obscurin isoforms are more variable with, for example, additional protein kinase domains and Ig domains.
References
 1. Ackermann MA , Kerr JP , King B , C WW , Kontrogianni‐Konstantopoulos A . The phosphorylation profile of myosin binding protein‐C slow is dynamically regulated in slow‐twitch muscles in health and disease. Sci Rep 5: 12637, 2015.
 2. 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.
 3. 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.
 4. 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.
 5. Ahmed SH , Lindsey ML . Titin phosphorylation: Myocardial passive stiffness regulated by the intracellular giant. Circ Res 105: 611‐613, 2009.
 6. Ait‐Mou Y , Hsu K , Farman GP , Kumar M , Greaser ML , Irving TC , de Tombe PP . Titin strain contributes to the Frank‐Starling law of the heart by structural rearrangements of both thin‐ and thick‐filament proteins. Proc Natl Acad Sci U S A 113: 2306‐2311, 2016.
 7. Alves ML , Dias FA , Gaffin RD , Simon JN , Montminy EM , Biesiadecki BJ , Hinken AC , Warren CM , Utter MS , Davis RT, III , Sadayappan S , Robbins J , Wieczorek DF , Solaro RJ , Wolska BM . Desensitization of myofilaments to Ca2+ as a therapeutic target for hypertrophic cardiomyopathy with mutations in thin filament proteins. Circ Cardiovasc Genet 7: 132‐143, 2014.
 8. Anderson BR , Bogomolovas J , Labeit S , Granzier H . The effects of PKCalpha phosphorylation on the extensibility of titin's PEVK element. J Struct Biol 170: 270‐277, 2010.
 9. 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.
 10. Babuin L , Jaffe AS . Troponin: The biomarker of choice for the detection of cardiac injury. CMAJ 173: 1191‐1202, 2005.
 11. 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.
 12. Bailey K . Tropomyosin: A new asymmetric protein component of muscle. Nature 157: 368, 1946.
 13. 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.
 14. Bang ML , Li X , Littlefield R , Bremner S , Thor A , Knowlton KU , Lieber RL , Chen J . Nebulin‐deficient mice exhibit shorter thin filament lengths and reduced contractile function in skeletal muscle. J Cell Biol 173: 905‐916, 2006.
 15. 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.
 16. 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.
 17. 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.
 18. Bennett V , Chen L . Ankyrins and cellular targeting of diverse membrane proteins to physiological sites. Curr Opin Cell Biol 13: 61‐67, 2001.
 19. Bers DM. Cardiac excitation‐contraction coupling. Nature 415: 198‐205, 2002.
 20. Bertz M , Wilmanns M , Rief M . The titin‐telethonin complex is a directed, superstable molecular bond in the muscle Z‐disk. Proc Natl Acad Sci U S A 106: 13307‐133310, 2009.
 21. 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.
 22. Biesiadecki BJ , Chong SM , Nosek TM , Jin JP . Troponin T core structure and the regulatory NH2‐terminal variable region. Biochemistry 46: 1368‐1379, 2007.
 23. Bonne G , Carrier L , Richard P , Hainque B , Schwartz K . Familial hypertrophic cardiomyopathy: From mutations to functional defects. Circ Res 83: 580‐593, 1998.
 24. Bonzo JR , Norris AA , Esham M , Moncman CL . The nebulette repeat domain is necessary for proper maintenance of tropomyosin with the cardiac sarcomere. Exp Cell Res 314: 3519‐3530, 2008.
 25. 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.
 26. 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.
 27. 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.
 28. 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.
 29. 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.
 30. Brault V , Reedy MC , Sauder U , Kammerer RA , Aebi U , Schoenenberger C . Substitution of flight muscle‐specific actin by human (beta)‐cytoplasmic actin in the indirect flight muscle of Drosophila. J Cell Sci 112(Pt 21): 3627‐3639, 1999.
 31. Brault V , Sauder U , Reedy MC , Aebi U , Schoenenberger CA . Differential epitope tagging of actin in transformed Drosophila produces distinct effects on myofibril assembly and function of the indirect flight muscle. Mol Biol Cell 10: 135‐149, 1999.
 32. Carrier L , Hengstenberg C , Beckmann JS , Guicheney P , Dufour C , Bercovici J , Dausse E , Berebbi‐Bertrand I , Wisnewsky C , Pulvenis D , et al. Mapping of a novel gene for familial hypertrophic cardiomyopathy to chromosome 11. Nat Genet 4: 311‐313, 1993.
 33. Carrier L , Mearini G , Stathopoulou K , Cuello F . Cardiac myosin‐binding protein C (MYBPC3) in cardiac pathophysiology. Gene 573: 188‐197, 2015.
 34. Castillo A , Nowak R , Littlefield KP , Fowler VM , Littlefield RS . A nebulin ruler does not dictate thin filament lengths. Biophys J 96: 1856‐1865, 2009.
 35. Cazorla O , Freiburg A , Helmes M , Centner T , McNabb M , Wu Y , Trombitas K , Labeit S , Granzier H . Differential expression of cardiac titin isoforms and modulation of cellular stiffness. Circ Res 86: 59‐67, 2000.
 36. 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.
 37. Chung CS , Methawasin M , Nelson OL , Radke MH , Hidalgo CG , Gotthardt M , Granzier HL . Titin based viscosity in ventricular physiology: An integrative investigation of PEVK‐actin interactions. J Mol Cell Cardiol 51: 428‐434, 2011.
 38. Clark KA , McElhinny AS , Beckerle MC , Gregorio CC . Striated muscle cytoarchitecture: An intricate web of form and function. Annu Rev Cell Dev Biol 18: 637‐706, 2002.
 39. Colegrave M , Peckham M . Structural implications of beta‐cardiac myosin heavy chain mutations in human disease. Anat Rec (Hoboken) 297: 1670‐1680, 2014.
 40. Colson BA , Thompson AR , Espinoza‐Fonseca LM , Thomas DD . Site‐directed spectroscopy of cardiac myosin‐binding protein C reveals effects of phosphorylation on protein structural dynamics. Proc Natl Acad Sci U S A 113:3233‐3238, 2016.
 41. 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.
 42. Craig R , Offer G . The location of C‐protein in rabbit skeletal muscle. Proc R Soc Lond B Biol Sci 192: 451‐461, 1976.
 43. Cunha SR , Mohler PJ . Cardiac ankyrins: Essential components for development and maintenance of excitable membrane domains in heart. Cardiovasc Res 71: 22‐29, 2006.
 44. Cunha SR , Mohler PJ . Obscurin targets ankyrin‐B and protein phosphatase 2A to the cardiac M‐line. J Biol Chem 283: 31968‐31980, 2008.
 45. de Tombe PP , Mateja RD , Tachampa K , Ait Mou Y , Farman GP , Irving TC . Myofilament length dependent activation. J Mol Cell Cardiol 48: 851‐858, 2010.
 46. Dennis JE , Shimizu T , Reinach FC , Fischman DA . Localization of C‐protein isoforms in chicken skeletal muscle: Ultrastructural detection using monoclonal antibodies. J Cell Biol 98: 1514‐1522, 1984.
 47. Dhoot GK , Hales MC , Grail BM , Perry SV . The isoforms of C protein and their distribution in mammalian skeletal muscle. J Muscle Res Cell Motil 6: 487‐505, 1985.
 48. Dhoot GK , Perry SV . Expression of slow skeletal myosin binding C‐protein in normal adult mammalian heart. J Muscle Res Cell Motil 26: 143‐148, 2005.
 49. Dominguez R , Freyzon Y , Trybus KM , Cohen C . Crystal structure of a vertebrate smooth muscle myosin motor domain and its complex with the essential light chain: Visualization of the pre‐power stroke state. Cell 94: 559‐571, 1998.
 50. Ebashi S , Endo M . Calcium ion and muscle contraction. Prog Biophys Mol Biol 18: 123‐183, 1968.
 51. Ebashi S , Kodama A . A new protein factor promoting aggregation of tropomyosin. J Biochem 58: 107‐108, 1965.
 52. Egelman EH , Orlova A . New insights into actin filament dynamics. Curr Opin Struct Biol 5: 172‐180, 1995.
 53. Engelhardt VALMN. Myosin and adenosinetriphosphatase. Nature 144: 668‐669, 1939.
 54. Fabiato A. Calcium‐induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 245: C1‐C14, 1983.
 55. Fill M , Copello JA . Ryanodine receptor calcium release channels. Physiol Rev 82: 893‐922, 2002.
 56. 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.
 57. 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.
 58. Foth BJ , Goedecke MC , Soldati D . New insights into myosin evolution and classification. Proc Natl Acad Sci U S A 103: 3681‐3686, 2006.
 59. Fraser ID , Marston SB . In vitro motility analysis of actin‐tropomyosin regulation by troponin and calcium. The thin filament is switched as a single cooperative unit. J Biol Chem 270: 7836‐7841, 1995.
 60. 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.
 61. Friedland G. Discovery of the function of the heart and circulation of blood. Cardiovasc J Afr 20: 160, 2009.
 62. 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.
 63. 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.
 64. 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.
 65. 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.
 66. Gautel M , Goulding D , Bullard B , Weber K , Furst DO . The central Z‐disk region of titin is assembled from a novel repeat in variable copy numbers. J Cell Sci 109(Pt 11): 2747‐2754, 1996.
 67. 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.
 68. 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.
 69. Geisterfer‐Lowrance AA , Kass S , Tanigawa G , Vosberg HP , McKenna W , Seidman CE , Seidman JG . A molecular basis for familial hypertrophic cardiomyopathy: A beta cardiac myosin heavy chain gene missense mutation. Cell 62: 999‐1006, 1990.
 70. 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.
 71. Gomes AV , Potter JD , Szczesna‐Cordary D . The role of troponins in muscle contraction. IUBMB Life 54: 323‐333, 2002.
 72. Granzier H , Radke M , Royal J , Wu Y , Irving TC , Gotthardt M , Labeit S . Functional genomics of chicken, mouse, and human titin supports splice diversity as an important mechanism for regulating biomechanics of striated muscle. Am J Physiol Regul Integr Comp Physiol 293: R557‐R567, 2007.
 73. Granzier HL , Labeit S . The giant protein titin: A major player in myocardial mechanics, signaling, and disease. Circ Res 94: 284‐295, 2004.
 74. Greaser ML , Gergely J . Reconstitution of troponin activity from three protein components. J Biol Chem 246: 4226‐4233, 1971.
 75. Greaser ML , Krzesinski PR , Warren CM , Kirkpatrick B , Campbell KS , Moss RL . Developmental changes in rat cardiac titin/connectin: Transitions in normal animals and in mutants with a delayed pattern of isoform transition. J Muscle Res Cell Motil 26: 325‐332, 2005.
 76. Gregorio CC , Trombitas K , Centner T , Kolmerer B , Stier G , Kunke K , Suzuki K , Obermayr F , Herrmann B , Granzier H , Sorimachi H , Labeit S . The NH2 terminus of titin spans the Z‐disc: Its interaction with a novel 19‐kD ligand (T‐cap) is required for sarcomeric integrity. J Cell Biol 143: 1013‐1027, 1998.
 77. 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.
 78. 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.
 79. Guo W , Schafer S , Greaser ML , Radke MH , Liss M , Govindarajan T , Maatz H , Schulz H , Li S , Parrish AM , Dauksaite V , Vakeel P , Klaassen S , Gerull B , Thierfelder L , Regitz‐Zagrosek V , Hacker TA , Saupe KW , Dec GW , Ellinor PT , MacRae CA , Spallek B , Fischer R , Perrot A , Ozcelik C , Saar K , Hubner N , Gotthardt M . RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat Med 18: 766‐773, 2012.
 80. 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.
 81. Ha KM , Cleland H , Greensmith A , Chong D , Macgill K , Verhoeven A , Hutson JM . Submucous cleft palate: An often‐missed diagnosis. J Craniofac Surg 24: 878‐885, 2013.
 82. Hamdani N , Krysiak J , Kreusser MM , Neef S , Dos Remedios CG , Maier LS , Kruger M , Backs J , Linke WA . Crucial role for Ca2(+)/calmodulin‐dependent protein kinase‐II in regulating diastolic stress of normal and failing hearts via titin phosphorylation. Circ Res 112: 664‐674, 2013.
 83. 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.
 84. Harvey W. Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus. Am J Obstet Gynecol 121: 1007, 1975
 85. Hashemi SM , Hund TJ , Mohler PJ . Cardiac ankyrins in health and disease. J Mol Cell Cardiol 47: 203‐209, 2009.
 86. Head JG , Houmeida A , Knight PJ , Clarke AR , Trinick J , Brady RL . Stability and folding rates of domains spanning the large A‐band super‐repeat of titin. Biophys J 81: 1570‐1579, 2001.
 87. Heeley DH , Golosinska K , Smillie LB . The effects of troponin T fragments T1 and T2 on the binding of nonpolymerizable tropomyosin to F‐actin in the presence and absence of troponin I and troponin C. J Biol Chem 262: 9971‐9978, 1987.
 88. Helmes M , Trombitas K , Centner T , Kellermayer M , Labeit S , Linke WA , Granzier H . Mechanically driven contour‐length adjustment in rat cardiac titin's unique N2B sequence: Titin is an adjustable spring. Circ Res 84: 1339‐1352, 1999.
 89. 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.
 90. Herron TJ , Rostkova E , Kunst G , Chaturvedi R , Gautel M , Kentish JC . Activation of myocardial contraction by the N‐terminal domains of myosin binding protein‐C. Circ Res 98: 1290‐1298, 2006.
 91. Herzberg O , James MN . Refined crystal structure of troponin C from turkey skeletal muscle at 2.0 A resolution. J Mol Biol 203: 761‐779, 1988.
 92. Hidalgo C , Hudson B , Bogomolovas J , Zhu Y , Anderson B , Greaser M , Labeit S , Granzier H . PKC phosphorylation of titin's PEVK element: A novel and conserved pathway for modulating myocardial stiffness. Circ Res 105: 631‐638, 617 p following 638, 2009.
 93. Hidalgo CG , Chung CS , Saripalli C , Methawasin M , Hutchinson KR , Tsaprailis G , Labeit S , Mattiazzi A , Granzier HL . The multifunctional Ca(2+)/calmodulin‐dependent protein kinase II delta (CaMKIIdelta) phosphorylates cardiac titin's spring elements. J Mol Cell Cardiol 54: 90‐97, 2013.
 94. Hitchcock SE. Cross‐linking of troponin with dimethylimido esters. Biochemistry 14: 5162‐5167, 1975.
 95. Hitchcock SE. Regulation of muscle contraction: Bindings of troponin and its components to actin and tropomyosin. Eur J Biochem 52: 255‐263, 1975.
 96. Hitchcock SE , Lutter LC . Study of troponin with cleavable protein crosslinkers. FEBS Lett 57: 172‐174, 1975.
 97. 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.
 98. Holmes KC , Popp D , Gebhard W , Kabsch W . Atomic model of the actin filament. Nature 347: 44‐49, 1990.
 99. Holtzer H , Marshall JM, Jr. , Finck H . An analysis of myogenesis by the use of fluorescent antimyosin. J Biophys Biochem Cytol 3: 705‐724, 1957.
 100. Hu LY , Kontrogianni‐Konstantopoulos A . The kinase domains of obscurin interact with intercellular adhesion proteins. FASEB J 27: 2001‐2012, 2013.
 101. Huang X , Pi Y , Lee KJ , Henkel AS , Gregg RG , Powers PA , Walker JW . Cardiac troponin I gene knockout: A mouse model of myocardial troponin I deficiency. Circ Res 84: 1‐8, 1999.
 102. Hughes BW , Kusner LL , Kaminski HJ . Molecular architecture of the neuromuscular junction. Muscle Nerve 33: 445‐461, 2006.
 103. Huxley AF , Niedergerke R . Measurement of muscle striations in stretch and contraction. J Physiol 124: 46P‐47P, 1954.
 104. Huxley AF , Niedergerke R . Structural changes in muscle during contraction; interference microscopy of living muscle fibres. Nature 173: 971‐973, 1954.
 105. Huxley H , Hanson J . Changes in the cross‐striations of muscle during contraction and stretch and their structural interpretation. Nature 173: 973‐976, 1954.
 106. Huxley HE. X‐ray analysis and the problem of muscle. P Roy Soc Lond B Bio 141: 59‐62, 1953.
 107. Huxley HE. The double array of filaments in cross‐striated muscle. J Biophys Biochem Cytol 3: 631‐648, 1957.
 108. Jancso A , Graceffa P . Smooth muscle tropomyosin coiled‐coil dimers. Subunit composition, assembly, and end‐to‐end interaction. J Biol Chem 266: 5891‐5897, 1991.
 109. Jideama NM , Crawford BH , Hussain AK , Raynor RL . Dephosphorylation specificities of protein phosphatase for cardiac troponin I, troponin T, and sites within troponin T. Int J Biol Sci 2: 1‐9, 2006.
 110. Jin JP , Chen A , Ogut O , Huang QQ . Conformational modulation of slow skeletal muscle troponin T by an NH(2)‐terminal metal‐binding extension. Am J Physiol Cell Physiol 279: C1067‐C1077, 2000.
 111. Jin JP , Wang K . Cloning, expression, and protein interaction of human nebulin fragments composed of varying numbers of sequence modules. J Biol Chem 266: 21215‐21223, 1991.
 112. Jin JP , Wang K . Nebulin as a giant actin‐binding template protein in skeletal muscle sarcomere. Interaction of actin and cloned human nebulin fragments. FEBS Lett 281: 93‐96, 1991.
 113. Kabsch W , Mannherz HG , Suck D , Pai EF , Holmes KC . Atomic structure of the actin:DNase I complex. Nature 347: 37‐44, 1990.
 114. Kalyva A , Parthenakis FI , Marketou ME , Kontaraki JE , Vardas PE . Biochemical characterisation of Troponin C mutations causing hypertrophic and dilated cardiomyopathies. J Muscle Res Cell Motil 35: 161‐178, 2014.
 115. Kaski JP , Syrris P , Burch M , Tome‐Esteban MT , Fenton M , Christiansen M , Andersen PS , Sebire N , Ashworth M , Deanfield JE , McKenna WJ , Elliott PM . Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes. Heart 94: 1478‐1484, 2008.
 116. Kazmierski ST , Antin PB , Witt CC , Huebner N , McElhinny AS , Labeit S , Gregorio CC . The complete mouse nebulin gene sequence and the identification of cardiac nebulin. J Mol Biol 328: 835‐846, 2003.
 117. Kentish JC , McCloskey DT , Layland J , Palmer S , Leiden JM , Martin AF , Solaro RJ . Phosphorylation of troponin I by protein kinase A accelerates relaxation and crossbridge cycle kinetics in mouse ventricular muscle. Circ Res 88: 1059‐1065, 2001.
 118. Kinbara K , Sorimachi H , Ishiura S , Suzuki K . Muscle‐specific calpain, p94, interacts with the extreme C‐terminal region of connectin, a unique region flanked by two immunoglobulin C2 motifs. Arch Biochem Biophys 342: 99‐107, 1997.
 119. Kinosian HJ , Selden LA , Estes JE , Gershman LC . Actin filament annealing in the presence of ATP and phalloidin. Biochemistry 32: 12353‐12357, 1993.
 120. Kinosian HJ , Selden LA , Estes JE , Gershman LC . Nucleotide binding to actin. Cation dependence of nucleotide dissociation and exchange rates. J Biol Chem 268: 8683‐8691, 1993.
 121. Kleerekoper Q , Howarth JW , Guo X , Solaro RJ , Rosevear PR . Cardiac troponin I induced conformational changes in cardiac troponin C as monitored by NMR using site‐directed spin and isotope labeling. Biochemistry 34: 13343‐13352, 1995.
 122. Knoll R , Buyandelger B , Lab M . The sarcomeric Z‐disc and Z‐discopathies. J Biomed Biotechnol 2011: 569628, 2011.
 123. Kolh P , Windecker S , Alfonso F , Collet JP , Cremer J , Falk V , Filippatos G , Hamm C , Head SJ , Juni P , Kappetein AP , Kastrati A , Knuuti J , Landmesser U , Laufer G , Neumann FJ , Richter DJ , Schauerte P , Sousa Uva M , Stefanini GG , Taggart DP , Torracca L , Valgimigli M , Wijns W , Witkowski A , Zamorano JL , Achenbach S , Baumgartner H , Bax JJ , Bueno H , Dean V , Deaton C , Erol C , Fagard R , Ferrari R , Hasdai D , Hoes AW , Kirchhof P , Lancellotti P , Linhart A , Nihoyannopoulos P , Piepoli MF , Ponikowski P , Sirnes PA , Tamargo JL , Tendera M , Torbicki A , Pepper J , Anyanwu A , Badimon L , Bauersachs J , Baumbach A , Beygui F , Bonaros N , De Carlo M , Dobrev D , Dunning J , Eeckhout E , Gielen S , Luckraz H , Mahrholdt H , Montalescot G , Paparella D , Rastan AJ , Sanmartin M , Sergeant P , Silber S , Tamargo J , ten Berg J , Thiele H , van Geuns RJ , Wagner HO , Wassmann S , Wendler O . 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio‐Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur J Cardio‐Thorac 46: 517‐592, 2014.
 124. 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.
 125. 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.
 126. Koretz JF , Irving TC , Wang K . Filamentous aggregates of native titin and binding of C‐protein and AMP‐deaminase. Arch Biochem Biophys 304: 305‐309, 1993.
 127. Krendel M , Mooseker MS . Myosins: Tails (and heads) of functional diversity. Physiology (Bethesda) 20: 239‐251, 2005.
 128. Krenz M , Robbins J . Impact of beta‐myosin heavy chain expression on cardiac function during stress. J Am Coll Cardiol 44: 2390‐2397, 2004.
 129. Kruger M , Kotter S , Grutzner A , Lang P , Andresen C , Redfield MM , Butt E , dos Remedios CG , Linke WA . Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circ Res 104: 87‐94, 2009.
 130. Kruger M , Linke WA . Protein kinase‐A phosphorylates titin in human heart muscle and reduces myofibrillar passive tension. J Muscle Res Cell Motil 27: 435‐444, 2006.
 131. Kühne W. Untersuchungen über das Protoplasma und die Contractilitat. Leipzig, Engelmann, 1864.
 132. 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.
 133. 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.
 134. Kuster DW , Bawazeer AC , Zaremba R , Goebel M , Boontje NM , van der Velden J . Cardiac myosin binding protein C phosphorylation in cardiac disease. J Muscle Res Cell Motil 33: 43‐52, 2012.
 135. Kuster DW , Govindan S , Springer TI , Martin JL , Finley NL , Sadayappan S . A hypertrophic cardiomyopathy‐associated MYBPC3 mutation common in populations of South Asian descent causes contractile dysfunction. J Biol Chem 290: 5855‐5867, 2015.
 136. 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.
 137. Labeit D , Watanabe K , Witt C , Fujita H , Wu Y , Lahmers S , Funck T , Labeit S , Granzier H . Calcium‐dependent molecular spring elements in the giant protein titin. Proc Natl Acad Sci U S A 100: 13716‐13721, 2003.
 138. Labeit S , Gautel M , Lakey A , Trinick J . Towards a molecular understanding of titin. EMBO J 11: 1711‐1716, 1992.
 139. Labeit S , Gibson T , Lakey A , Leonard K , Zeviani M , Knight P , Wardale J , Trinick J . Evidence that nebulin is a protein‐ruler in muscle thin filaments. FEBS Lett 282: 313‐316, 1991.
 140. Labeit S , Kolmerer B . The complete primary structure of human nebulin and its correlation to muscle structure. J Mol Biol 248: 308‐315, 1995.
 141. Labeit S , Kolmerer B . Titins: Giant proteins in charge of muscle ultrastructure and elasticity. Science 270: 293‐296, 1995.
 142. Labeit S , Lahmers S , Burkart C , Fong C , McNabb M , Witt S , Witt C , Labeit D , Granzier H . Expression of distinct classes of titin isoforms in striated and smooth muscles by alternative splicing, and their conserved interaction with filamins. J Mol Biol 362: 664‐681, 2006.
 143. Lahmers S , Wu Y , Call DR , Labeit S , Granzier H . Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium. Circ Res 94: 505‐513, 2004.
 144. 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.
 145. 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.
 146. 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.
 147. Lee EH , Gao M , Pinotsis N , Wilmanns M , Schulten K . Mechanical strength of the titin Z1Z2‐telethonin complex. Structure 14: 497‐509, 2006.
 148. Lehrer SS , Qian YD , Hvidt S . Assembly of the native heterodimer of Rana esculenta tropomyosin by chain exchange. Science 246: 926‐928, 1989.
 149. 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.
 150. Linke WA. Titin elasticity in the context of the sarcomere: Force and extensibility measurements on single myofibrils. Adv Exp Med Biol 481: 179‐202; discussion 203‐176, 2000.
 151. Linke WA , Ivemeyer M , Labeit S , Hinssen H , Ruegg JC , Gautel M . Actin‐titin interaction in cardiac myofibrils: Probing a physiological role. Biophys J 73: 905‐919, 1997.
 152. Linke WA , Rudy DE , Centner T , Gautel M , Witt C , Labeit S , Gregorio CC . I‐band titin in cardiac muscle is a three‐element molecular spring and is critical for maintaining thin filament structure. J Cell Biol 146: 631‐644, 1999.
 153. Lompre AM , Nadal‐Ginard B , Mahdavi V . Expression of the cardiac ventricular alpha‐ and beta‐myosin heavy chain genes is developmentally and hormonally regulated. J Biol Chem 259: 6437‐6446, 1984.
 154. Lorenz M , Poole KJ , Popp D , Rosenbaum G , Holmes KC . An atomic model of the unregulated thin filament obtained by X‐ray fiber diffraction on oriented actin‐tropomyosin gels. J Mol Biol 246: 108‐119, 1995.
 155. Luther PK , Craig R . Modulation of striated muscle contraction by binding of myosin binding protein C to actin. Bioarchitecture 1: 277‐283, 2011.
 156. Luther PK , Winkler H , Taylor K , Zoghbi ME , Craig R , Padron R , Squire JM , Liu J . Direct visualization of myosin‐binding protein C bridging myosin and actin filaments in intact muscle. Proc Natl Acad Sci U S A 108: 11423‐11428, 2011.
 157. Mahdavi V , Chambers AP , Nadal‐Ginard B . Cardiac alpha‐ and beta‐myosin heavy chain genes are organized in tandem. Proc Natl Acad Sci U S A 81: 2626‐2630, 1984.
 158. Mahdavi V , Lompre AM , Chambers AP , Nadal‐Ginard B . Cardiac myosin heavy chain isozymic transitions during development and under pathological conditions are regulated at the level of mRNA availability. Eur Heart J 5(Suppl F): 181‐191, 1984.
 159. 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.
 160. 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.
 161. Maruyama K . Connectin, an elastic protein from myofibrils. J Biochem 80: 405‐407, 1976.
 162. 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.
 163. Maruyama K , Matsubara S , Natori R , Nonomura Y , Kimura S . Connectin, an elastic protein of muscle. Characterization and function. J Biochem 82: 317‐337, 1977.
 164. Mastrototaro G , Liang X , Li X , Carullo P , Piroddi N , Tesi C , Gu Y , Dalton ND , Peterson KL , Poggesi C , Sheikh F , Chen J , Bang ML . Nebulette knockout mice have normal cardiac function, but show Z‐line widening and up‐regulation of cardiac stress markers. Cardiovasc Res 107: 216‐225, 2015.
 165. Mateja RD , Greaser ML , de Tombe PP . Impact of titin isoform on length dependent activation and cross‐bridge cycling kinetics in rat skeletal muscle. Biochim Biophys Acta 1833: 804‐811, 2013.
 166. Matsumoto Y , Hayashi T , Inagaki N , Takahashi M , Hiroi S , Nakamura T , Arimura T , Nakamura K , Ashizawa N , Yasunami M , Ohe T , Yano K , Kimura A . Functional analysis of titin/connectin N2‐B mutations found in cardiomyopathy. J Muslce Res Cell Motil 26: 367‐374, 2005.
 167. 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.
 168. 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.
 169. McElhinny AS , Schwach C , Valichnac M , Mount‐Patrick S , Gregorio CC . Nebulin regulates the assembly and lengths of the thin filaments in striated muscle. J Cell Biol 170: 947‐957, 2005.
 170. McKillop DF , Geeves MA . Regulation of the interaction between actin and myosin subfragment 1: Evidence for three states of the thin filament. Biophys J 65: 693‐701, 1993.
 171. McLachlan AD , Stewart M . Tropomyosin coiled‐coil interactions: Evidence for an unstaggered structure. J Mol Biol 98: 293‐304, 1975.
 172. McLaughlin PJ , Gooch JT , Mannherz HG , Weeds AG . Structure of gelsolin segment 1‐actin complex and the mechanism of filament severing. Nature 364: 685‐692, 1993.
 173. Michele DE , Metzger JM . Physiological consequences of tropomyosin mutations associated with cardiac and skeletal myopathies. J Mol Med (Berl) 78: 543‐553, 2000.
 174. Millevoi S , Trombitas K , Kolmerer B , Kostin S , Schaper J , Pelin K , Granzier H , Labeit S . Characterization of nebulette and nebulin and emerging concepts of their roles for vertebrate Z‐discs. J Mol Biol 282: 111‐123, 1998.
 175. Milligan RA. Protein‐protein interactions in the rigor actomyosin complex. Proc Natl Acad Sci U S A 93: 21‐26, 1996.
 176. Milligan RA , Whittaker M , Safer D . Molecular structure of F‐actin and location of surface binding sites. Nature 348: 217‐221, 1990.
 177. 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.
 178. 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.
 179. Mogensen J , Hey T , Lambrecht S . A systematic review of phenotypic features associated with cardiac troponin I mutations in hereditary cardiomyopathies. Can J Cardiol 31: 1377‐1385, 2015.
 180. 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.
 181. Molkentin JD , Jobe SM , Markham BE . Alpha‐myosin heavy chain gene regulation: Delineation and characterization of the cardiac muscle‐specific enhancer and muscle‐specific promoter. J Mol Cell Cardiol 28: 1211‐1225, 1996.
 182. Moncman CL , Wang K . Nebulette: A 107 kD nebulin‐like protein in cardiac muscle. Cell Motil Cytoskeleton 32: 205‐225, 1995.
 183. Moncman CL , Wang K . Targeted disruption of nebulette protein expression alters cardiac myofibril assembly and function. Exp Cell Res 273: 204‐218, 2002.
 184. Moore JR , Leinwand L , Warshaw DM . Understanding cardiomyopathy phenotypes based on the functional impact of mutations in the myosin motor. Circ Res 111: 375‐385, 2012.
 185. 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.
 186. Morgan JE , Partridge TA . Muscle satellite cells. Int J Biochem Cell Biol 35: 1151‐1156, 2003.
 187. Morris EP , Lehrer SS . Troponin‐tropomyosin interactions. Fluorescence studies of the binding of troponin, troponin T, and chymotryptic troponin T fragments to specifically labeled tropomyosin. Biochemistry 23: 2214‐2220, 1984.
 188. Mues A , van der Ven PF , Young P , Furst DO , Gautel M . Two immunoglobulin‐like domains of the Z‐disc portion of titin interact in a conformation‐dependent way with telethonin. FEBS Lett 428: 111‐114, 1998.
 189. 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.
 190. Muthuchamy M , Grupp IL , Grupp G , O'Toole BA , Kier AB , Boivin GP , Neumann J , Wieczorek DF . Molecular and physiological effects of overexpressing striated muscle beta‐tropomyosin in the adult murine heart. J Biol Chem 270: 30593‐30603, 1995.
 191. Nadal‐Ginard B , Mahdavi V . Molecular basis of cardiac performance. Plasticity of the myocardium generated through protein isoform switches. J Clin Invest 84: 1693‐1700, 1989.
 192. 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.
 193. Neagoe C , Kulke M , del Monte F , Gwathmey JK , de Tombe PP , Hajjar RJ , Linke WA . Titin isoform switch in ischemic human heart disease. Circulation 106: 1333‐1341, 2002.
 194. Noland TA, Jr. , Kuo JF . Protein kinase C phosphorylation of cardiac troponin I or troponin T inhibits Ca2(+)‐stimulated actomyosin MgATPase activity. J Biol Chem 266: 4974‐4978, 1991.
 195. Noland TA, Jr. , Kuo JF . Protein kinase C phosphorylation of cardiac troponin T decreases Ca(2+)‐dependent actomyosin MgATPase activity and troponin T binding to tropomyosin‐F‐actin complex. Biochem J 288(Pt 1): 123‐129, 1992.
 196. Nyland LR , Palmer BM , Chen Z , Maughan DW , Seidman CE , Seidman JG , Kreplak L , Vigoreaux JO . Cardiac myosin binding protein‐C is essential for thick‐filament stability and flexural rigidity. Biochem J 96: 3273‐3280, 2009.
 197. O'Brien PJ , Smith DE , Knechtel TJ , Marchak MA , Pruimboom‐Brees I , Brees DJ , Spratt DP , Archer FJ , Butler P , Potter AN , Provost JP , Richard J , Snyder PA , Reagan WJ . Cardiac troponin I is a sensitive, specific biomarker of cardiac injury in laboratory animals. Lab Anim 40: 153‐171, 2006.
 198. 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.
 199. 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.
 200. Ohtsuki I , Maruyama K , Ebashi S . Regulatory and cytoskeletal proteins of vertebrate skeletal muscle. Adv Protein Chem 38: 1‐67, 1986.
 201. 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.
 202. Okazaki K , Holtzer H . Myogenesis: Fusion, myosin synthesis, and the mitotic cycle. Proc Natl Acad Sci U S A 56: 1484‐1490, 1966.
 203. Opitz CA , Leake MC , Makarenko I , Benes V , Linke WA . Developmentally regulated switching of titin size alters myofibrillar stiffness in the perinatal heart. Circ Res 94: 967‐975, 2004.
 204. Orlova A , Egelman EH . Structural dynamics of F‐actin: I. Changes in the C terminus. J Mol Biol 245: 582‐597, 1995.
 205. Orlova A , Prochniewicz E , Egelman EH . Structural dynamics of F‐actin: II. Cooperativity in structural transitions. J Mol Biol 245: 598‐607, 1995.
 206. Pacchiarotti I , Bond DJ , Baldessarini RJ , Nolen WA , Grunze H , Licht RW , Post RM , Berk M , Goodwin GM , Sachs GS , Tondo L , Findling RL , Youngstrom EA , Tohen M , Undurraga J , Gonzalez‐Pinto A , Goldberg JF , Yildiz A , Altshuler LL , Calabrese JR , Mitchell PB , Thase ME , Koukopoulos A , Colom F , Frye MA , Malhi GS , Fountoulakis KN , Vazquez G , Perlis RH , Ketter TA , Cassidy F , Akiskal H , Azorin JM , Valenti M , Mazzei DH , Lafer B , Kato T , Mazzarini L , Martinez‐Aran A , Parker G , Souery D , Ozerdem A , McElroy SL , Girardi P , Bauer M , Yatham LN , Zarate CA , Nierenberg AA , Birmaher B , Kanba S , El‐Mallakh RS , Serretti A , Rihmer Z , Young AH , Kotzalidis GD , MacQueen GM , Bowden CL , Ghaemi SN , Lopez‐Jaramillo C , Rybakowski J , Ha K , Perugi G , Kasper S , Amsterdam JD , Hirschfeld RM , Kapczinski F , Vieta E . The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry 170: 1249‐1262, 2013.
 207. Pappas CT , Bhattacharya N , Cooper JA , Gregorio CC . Nebulin interacts with CapZ and regulates thin filament architecture within the Z‐disc. Mol Biol Cell 19: 1837‐1847, 2008.
 208. Pappas CT , Bliss KT , Zieseniss A , Gregorio CC . The Nebulin family: An actin support group. Trends Cell Biol 21: 29‐37, 2011.
 209. Pappas CT , Krieg PA , Gregorio CC . Nebulin regulates actin filament lengths by a stabilization mechanism. J Cell Biol 189: 859‐870, 2010.
 210. Pearlstone JR , Smillie LB . Binding of troponin‐T fragments to several types of tropomyosin. Sensitivity to Ca2+ in the presence of troponin‐C. J Biol Chem 257: 10587‐10592, 1982.
 211. Peng J , Raddatz K , Labeit S , Granzier H , Gotthardt M . Muscle atrophy in titin M‐line deficient mice. J Muscle Res Cell Motil 26: 381‐388, 2005.
 212. Perry NA , Vitolo MI , Martin SS , Kontrogianni‐Konstantopoulos A . Loss of the obscurin‐RhoGEF downregulates RhoA signaling and increases microtentacle formation and attachment of breast epithelial cells. Oncotarget 5: 8558‐8568, 2014.
 213. Perry SV. Vertebrate tropomyosin: Distribution, properties and function. J Muscle Res Cell Motil 22: 5‐49, 2001.
 214. Pfuhl M , Gautel M . Structure, interactions and function of the N‐terminus of cardiac myosin binding protein C (MyBP‐C): Who does what, with what, and to whom? J Muscle Res Cell Motil 33: 83‐94, 2012.
 215. Pope B , Hoh JF , Weeds A . The ATPase activities of rat cardiac myosin isoenzymes. FEBS Lett 118: 205‐208, 1980.
 216. Potter JD , Gergely J . Troponin, tropomyosin, and actin interactions in the Ca2+ regulation of muscle contraction. Biochemistry 13: 2697‐2703, 1974.
 217. Potter JD , Sheng Z , Pan BS , Zhao J . A direct regulatory role for troponin T and a dual role for troponin C in the Ca2+ regulation of muscle contraction. J Biol Chem 270: 2557‐2562, 1995.
 218. 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.
 219. 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.
 220. Puchner EM , Alexandrovich A , Kho AL , Hensen U , Schafer LV , Brandmeier B , Grater F , Grubmuller H , Gaub HE , Gautel M . Mechanoenzymatics of titin kinase. Proc Natl Acad Sci U S A 105: 13385‐13390, 2008.
 221. Pyle WG , Solaro RJ . At the crossroads of myocardial signaling: The role of Z‐discs in intracellular signaling and cardiac function. Circ Res 94: 296‐305, 2004.
 222. Quiat D , Voelker KA , Pei J , Grishin NV , Grange RW , Bassel‐Duby R , Olson EN . Concerted regulation of myofiber‐specific gene expression and muscle performance by the transcriptional repressor Sox6. Proc Natl Acad Sci U S A 108: 10196‐10201, 2011.
 223. Raeker MO , Bieniek AN , Ryan AS , Tsai HJ , Zahn KM , Russell MW . Targeted deletion of the zebrafish obscurin A RhoGEF domain affects heart, skeletal muscle and brain development. Dev Biol 337: 432‐443, 2010.
 224. 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.
 225. 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.
 226. Raskin A , Lange S , Banares K , Lyon RC , Zieseniss A , Lee LK , Yamazaki KG , Granzier HL , Gregorio CC , McCulloch AD , Omens JH , Sheikh F . A novel mechanism involving four‐and‐a‐half LIM domain protein‐1 and extracellular signal‐regulated kinase‐2 regulates titin phosphorylation and mechanics. J Biol Chem 287: 29273‐29284, 2012.
 227. 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.
 228. Rayment I , Holden HM , Whittaker M , Yohn CB , Lorenz M , Holmes KC , Milligan RA . Structure of the actin‐myosin complex and its implications for muscle contraction. Science 261: 58‐65, 1993.
 229. 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.
 230. Razumova MV , Bezold KL , Tu AY , Regnier M , Harris SP . Contribution of the myosin binding protein C motif to functional effects in permeabilized rat trabeculae. J Gen Physiol 132: 575‐585, 2008.
 231. 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.
 232. Robertson SP , Johnson JD , Holroyde MJ , Kranias EG , Potter JD , Solaro RJ . The effect of troponin I phosphorylation on the Ca2+‐binding properties of the Ca2+‐regulatory site of bovine cardiac troponin. J Biol Chem 257: 260‐263, 1982.
 233. Robinson BF , Epstein SE , Beiser GD , Braunwald E . Control of heart rate by the autonomic nervous system. Studies in man on the interrelation between baroreceptor mechanisms and exercise. Circ Res 19: 400‐411, 1966.
 234. Robinson P , Griffiths PJ , Watkins H , Redwood CS . Dilated and hypertrophic cardiomyopathy mutations in troponin and alpha‐tropomyosin have opposing effects on the calcium affinity of cardiac thin filaments. Circ Res 101: 1266‐1273, 2007.
 235. Rome E , Offer G , Pepe FA . X‐ray diffraction of muscle labelled with antibody to C‐protein. Nat New Biol 244: 152‐154, 1973.
 236. Rosol M , Lehman W , Craig R , Landis C , Butters C , Tobacman LS . Three‐dimensional reconstruction of thin filaments containing mutant tropomyosin. Biophys J 78: 908‐917, 2000.
 237. 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.
 238. Sadayappan S , de Tombe PP . Cardiac myosin binding protein‐C: Redefining its structure and function. Biophys Rev 4: 93‐106, 2012.
 239. Satoh M , Takahashi M , Sakamoto T , Hiroe M , Marumo F , Kimura A . Structural analysis of the titin gene in hypertrophic cardiomyopathy: Identification of a novel disease gene. Biochem Biophys Res Commun 262: 411‐417, 1999.
 240. Satyshur KA , Rao ST , Pyzalska D , Drendel W , Greaser M , Sundaralingam M . Refined structure of chicken skeletal muscle troponin C in the two‐calcium state at 2‐A resolution. J Biol Chem 263: 1628‐1647, 1988.
 241. Schaertl S , Lehrer SS , Geeves MA . Separation and characterization of the two functional regions of troponin involved in muscle thin filament regulation. Biochemistry 34: 15890‐15894, 1995.
 242. Schiaffino S , Reggiani C . Fiber types in mammalian skeletal muscles. Physiol Rev 91: 1447‐1531, 2011.
 243. Schutt CE , Lindberg U , Myslik J , Strauss N . Molecular packing in profilin: Actin crystals and its implications. J Mol Biol 209: 735‐746, 1989.
 244. Severs NJ. The cardiac muscle cell. Bioessays 22: 188‐199, 2000.
 245. Shaffer JF , Harris SP . Species‐specific differences in the Pro‐Ala rich region of cardiac myosin binding protein‐C. J Muscle Res Cell Motil 30: 303‐306, 2009.
 246. Sia SK , Li MX , Spyracopoulos L , Gagne SM , Liu W , Putkey JA , Sykes BD . Structure of cardiac muscle troponin C unexpectedly reveals a closed regulatory domain. J Biol Chem 272: 18216‐18221, 1997.
 247. Spudich JA. The myosin mesa and a possible unifying hypothesis for the molecular basis of human hypertrophic cardiomyopathy. Biochem Soc Trans 43: 64‐72, 2015.
 248. 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.
 249. Starr R , Offer G . The interaction of C‐protein with heavy meromyosin and subfragment‐2. Biochem J 171: 813‐816, 1978.
 250. Straub FB . Actin, II. Stud Inst Med Chem Univ Szeged III: 23‐37, 1943.
 251. 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.
 252. Sutter SB , Raeker MO , Borisov AB , Russell MW . Orthologous relationship of obscurin and Unc‐89: Phylogeny of a novel family of tandem myosin light chain kinases. Dev Genes Evol 214: 352‐359, 2004.
 253. Suzuki T , Palmer BM , James J , Wang Y , Chen Z , VanBuren P , Maughan DW , Robbins J , LeWinter MM . Effects of cardiac myosin isoform variation on myofilament function and crossbridge kinetics in transgenic rabbits. Circ Heart Fail 2: 334‐341, 2009.
 254. Syska H , Wilkinson JM , Grand RJ , Perry SV . The relationship between biological activity and primary structure of troponin I from white skeletal muscle of the rabbit. Biochem J 153: 375‐387, 1976.
 255. Tajsharghi H , Ohlsson M , Palm L , Oldfors A . Myopathies associated with beta‐tropomyosin mutations. Neuromuscul Disord 22: 923‐933, 2012.
 256. Takeda S , Yamashita A , Maeda K , Maeda Y . Structure of the core domain of human cardiac troponin in the Ca(2+)‐saturated form. Nature 424: 35‐41, 2003.
 257. Tanigawa G , Jarcho JA , Kass S , Solomon SD , Vosberg HP , Seidman JG , Seidman CE . A molecular basis for familial hypertrophic cardiomyopathy: An alpha/beta cardiac myosin heavy chain hybrid gene. Cell 62: 991‐998, 1990.
 258. Tardiff JC , Hewett TE , Factor SM , Vikstrom KL , Robbins J , Leinwand LA . Expression of the beta (slow)‐isoform of MHC in the adult mouse heart causes dominant‐negative functional effects. Am J Physiol Heart Circ Physiol 278: H412‐H419, 2000.
 259. Terui T , Sodnomtseren M , Matsuba D , Udaka J , Ishiwata S , Ohtsuki I , Kurihara S , Fukuda N . Troponin and titin coordinately regulate length‐dependent activation in skinned porcine ventricular muscle. J Gen Physiol 131: 275‐283, 2008.
 260. Tian LF , Li HY , Jin BF , Pan X , Man JH , Zhang PJ , Li WH , Liang B , Liu H , Zhao J , Gong WL , Zhou T , Zhang XM . MDM2 interacts with and downregulates a sarcomeric protein, TCAP. Biochem Bioph Res Co 345: 355‐361, 2006.
 261. Tonino P , Pappas CT , Hudson BD , Labeit S , Gregorio CC , Granzier H . Reduced myofibrillar connectivity and increased Z‐disk width in nebulin‐deficient skeletal muscle. J Cell Sci 123: 384‐391, 2010.
 262. Toyoshima YY , Kron SJ , McNally EM , Niebling KR , Toyoshima C , Spudich JA . Myosin subfragment‐1 is sufficient to move actin filaments in vitro. Nature 328: 536‐539, 1987.
 263. Trinick J. Understanding the functions of titin and nebulin. FEBS Lett 307: 44‐48, 1992.
 264. Trinick J. Titin and nebulin: Protein rulers in muscle? Trends Biochem Sci 19: 405‐409, 1994.
 265. Trombitas K , Freiburg A , Centner T , Labeit S , Granzier H . Molecular dissection of N2B cardiac titin's extensibility. Biophys J 77: 3189‐3196, 1999.
 266. Trombitas K , Jin JP , Granzier H . The mechanically active domain of titin in cardiac muscle. Circ Res 77: 856‐861, 1995.
 267. van der Ven PF , Furst DO . Assembly of titin, myomesin and M‐protein into the sarcomeric M band in differentiating human skeletal muscle cells in vitro. Cell Struct Funct 22: 163‐171, 1997.
 268. Vandekerckhove J , Weber K . The complete amino acid sequence of actins from bovine aorta, bovine heart, bovine fast skeletal muscle, and rabbit slow skeletal muscle. A protein‐chemical analysis of muscle actin differentiation. Differentiation 14: 123‐133, 1979.
 269. Vassylyev DG , Takeda S , Wakatsuki S , Maeda K , Maeda Y . Crystal structure of troponin C in complex with troponin I fragment at 2.3‐A resolution. Proc Natl Acad Sci U S A 95: 4847‐4852, 1998.
 270. von der Ecken J , Muller M , Lehman W , Manstein DJ , Penczek PA , Raunser S . Structure of the F‐actin‐tropomyosin complex. Nature 519: 114‐117, 2015.
 271. Vydyanath A , Gurnett CA , Marston S , Luther PK . Axial distribution of myosin binding protein‐C is unaffected by mutations in human cardiac and skeletal muscle. J Muscle Res Cell Motil 33: 61‐74, 2012.
 272. Wang K. Purification of titin and nebulin. Methods Enzymol 85(Pt B): 264‐274, 1982.
 273. Wang K. Titin/connectin and nebulin: Giant protein rulers of muscle structure and function. Adv Biophys 33: 123‐134, 1996.
 274. Wang K , Forbes JG , Jin AJ . Single molecule measurements of titin elasticity. Prog Biophys Mol Biol 77: 1‐44, 2001.
 275. Wang K , Knipfer M , Huang QQ , van Heerden A , Hsu LC , Gutierrez G , Quian XL , Stedman H . Human skeletal muscle nebulin sequence encodes a blueprint for thin filament architecture. Sequence motifs and affinity profiles of tandem repeats and terminal SH3. J Biol Chem 271: 4304‐4314, 1996.
 276. Wang K , McClure J , Tu A . Titin: Major myofibrillar components of striated muscle. Proc Natl Acad Sci U S A 76: 3698‐3702, 1979.
 277. Warren CM , Jordan MC , Roos KP , Krzesinski PR , Greaser ML . Titin isoform expression in normal and hypertensive myocardium. Cardiovasc Res 59: 86‐94, 2003.
 278. 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.
 279. White SP , Cohen C , Phillips GN, Jr. Structure of co‐crystals of tropomyosin and troponin. Nature 325: 826‐828, 1987.
 280. 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.
 281. Witayavanitkul N , Ait Mou Y , Kuster DW , Khairallah RJ , Sarkey J , Govindan S , Chen X , Ge Y , Rajan S , Wieczorek DF , Irving T , Westfall MV , de Tombe PP , Sadayappan S . Myocardial infarction‐induced N‐terminal fragment of cardiac myosin‐binding protein C (cMyBP‐C) impairs myofilament function in human myocardium. J Biol Chem 289: 8818‐8827, 2014.
 282. Witt CC , Burkart C , Labeit D , McNabb M , Wu Y , Granzier H , Labeit S . Nebulin regulates thin filament length, contractility, and Z‐disk structure in vivo. EMBO J 25: 3843‐3855, 2006.
 283. Witt CC , Olivieri N , Centner T , Kolmerer B , Millevoi S , Morell J , Labeit D , Labeit S , Jockusch H , Pastore A . A survey of the primary structure and the interspecies conservation of I‐band titin's elastic elements in vertebrates. J Struct Biol 122: 206‐215, 1998.
 284. 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.
 285. Woods EF. The dissociation of tropomyosin by urea. J Mol Biol 16: 581‐584, 1966.
 286. Woods EF . Molecular weight and subunit structure of tropomyosin B. J Biol Chem 242: 2859‐2871, 1967.
 287. Woolner S , Bement WM . Unconventional myosins acting unconventionally. Trends Cell Biol 19: 245‐252, 2009.
 288. Wu Y , Bell SP , Trombitas K , Witt CC , Labeit S , LeWinter MM , Granzier H . Changes in titin isoform expression in pacing‐induced cardiac failure give rise to increased passive muscle stiffness. Circulation 106: 1384‐1389, 2002.
 289. Yamasaki R , Wu Y , McNabb M , Greaser M , Labeit S , Granzier H . Protein kinase A phosphorylates titin's cardiac‐specific N2B domain and reduces passive tension in rat cardiac myocytes. Circ Res 90: 1181‐1188, 2002.
 290. Yin H , Price F , Rudnicki MA . Satellite cells and the muscle stem cell niche. Physiol Rev 93: 23‐67, 2013.
 291. 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.
 292. Young P , Ferguson C , Banuelos S , Gautel M . Molecular structure of the sarcomeric Z‐disk: Two types of titin interactions lead to an asymmetrical sorting of alpha‐actinin. EMBO J 17: 1614‐1624, 1998.
 293. Zhu C , Yin Z , Ren J , McCormick RJ , Ford SP , Guo W . RBM20 is an essential factor for thyroid hormone‐regulated titin isoform transition. J Mol Cell Biol 7: 88‐90, 2015.
 294. Zot AS , Potter JD . Structural aspects of troponin‐tropomyosin regulation of skeletal muscle contraction. Annu Rev Biophys Biophys Chem 16: 535‐559, 1987.

Teaching Material

Lin BL, Song T, Sadayappan S. Myofilaments: movers and rulers of the sarcomere. Compr Physiol 2017, 7: 675-692. doi: 10.1002/cphy.c160026

 

Didactic Synopsis

Major Teaching Points:

  The sarcomere is the functional unit of muscle contraction at the molecular level.

 

    The sarcomere consists of two sets of myofilaments, which are made up of rope-like proteins, called myofilament-associated proteins.

o             Thick filament-associated proteins include myosin, myosin binding protein-C, titin and obscurin.

o             Thin filament-associated proteins include actin, troponin, tropomyosin, and nebulin.

 

    Some myofilaments physically move to affect muscle contraction.

o             Troponin moves tropomyosin on actin to open a myosin-binding site.

o             Myosin binds actin and pulls the entire thin filament.

o             Myosin-binding protein-C regulates myosin binding to actin.

 

     While other myofilaments are rulers that measure out the filament structure, determining, where filament proteins are located on the filament.

o             Titin is the thick filament ruler.

o             Nebulin is the thin filament ruler.

o             Obscurin offers structural support.

 

     Many myofilaments have both structural and functional roles that are still being studied

 

Didactic Figure 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 functional unit of muscle contraction at the molecular level. The basic structure of the sarcomere consists of parallel arrays of myofilament proteins. Thick and thin filament proteins slide across one another, pulling the ends of the sarcomere closer. The thick filament is primarily made of myosin, while the thin filament consists primarily of actin. The actin filament is decorated with troponin and intertwined with tropomyosin. Contraction initiates with troponin binding calcium, resulting in tropomyosin movement. This movement allows myosin to bind to actin, forming a cross-bridge. Other proteins regulate various aspects of sarcomere structure and contraction.

 

Figure 2. Teaching points: Myosin-binding protein-C (MyBP-C) interacts with both thick and thin filaments. There are two skeletal isoforms and a cardiac isoform, with noticeable differences in the N-terminal regulatory region. MyBP-C is a thick filament regulatory protein that controls the rate of contractility.

 

Figure 3. Teaching points: The domain structure of two adult titin isoforms illustrates the enormity of this giant protein. Titin spans half the sarcomere, from Z-disk to M-line. Titin regulates thick filament protein localization and is therefore known as the “thick filament ruler.”

 

Figure 4. Teaching points: Nebulin (top panel, >600 kDa) and nebulette (bottom panel, 107 kDa) proteins are the predominant skeletal and cardiac isoforms, respectively. Nebulette lacks nebulin super-repeats, and is much shorter. These proteins are known as the “thin filament ruler,” because they contribute to the regulation of thin filament length.

 

Figure 5. Teaching points: This figure illustrates domain structure of obscurin A and B, which are titin-binding signaling proteins that regulate muscle contractility. Of the three known “giant” myofilaments, obscurin is the most recently discovered.

 


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How to Cite

Brian Leei Lin, Taejeong Song, Sakthivel Sadayappan. Myofilaments: Movers and Rulers of the Sarcomere. Compr Physiol 2017, 7: 675-692. doi: 10.1002/cphy.c160026