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Modulation of Skeletal Muscle Contraction by Myosin Phosphorylation

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ABSTRACT

The striated muscle sarcomere is a highly organized and complex enzymatic and structural organelle. Evolutionary pressures have played a vital role in determining the structure‐function relationship of each protein within the sarcomere. A key part of this multimeric assembly is the light chain‐binding domain (LCBD) of the myosin II motor molecule. This elongated “beam” functions as a biological lever, amplifying small interdomain movements within the myosin head into piconewton forces and nanometer displacements against the thin filament during the cross‐bridge cycle. The LCBD contains two subunits known as the essential and regulatory myosin light chains (ELC and RLC, respectively). Isoformic differences in these respective species provide molecular diversity and, in addition, sites for phosphorylation of serine residues, a highly conserved feature of striated muscle systems. Work on permeabilized skeletal fibers and thick filament systems shows that the skeletal myosin light chain kinase catalyzed phosphorylation of the RLC alters the “interacting head motif” of myosin motor heads on the thick filament surface, with myriad consequences for muscle biology. At rest, structure‐function changes may upregulate actomyosin ATPase activity of phosphorylated cross‐bridges. During activation, these same changes may increase the Ca2+ sensitivity of force development to enhance force, work, and power output, outcomes known as “potentiation.” Thus, although other mechanisms may contribute, RLC phosphorylation may represent a form of thick filament activation that provides a “molecular memory” of contraction. The clinical significance of these RLC phosphorylation mediated alterations to contractile performance of various striated muscle systems are just beginning to be understood. © 2017 American Physiological Society. Compr Physiol 7:171‐212, 2017.

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Figure 1. Figure 1. Paradigm dependence for force potentiation of mouse fast muscle. Example of paradigm and contraction type dependence for potentiation of mouse EDL muscle (in vitro 25°C). (A) Original force records showing isometric (solid line) and concentric (dashed line) twitch forces obtained before (left) and after (right) a potentiating stimulus in WT (top) and skMLCK−/− (bottom) muscles. For both genotypes, the potentiating atimulus consisted of four brief volleys of 100 Hz in a 10‐s time window with the muscle at optimal length; peak tetanic force declined by ∼8% from the first to the last tetanus in both genotypes. In WT muscles, this protocol typically elevates RLC phosphorylation from ∼0.10 to 0.55 mol phos per mol RLC (); in skMLCK−/− muscles this protocol does not change RLC phosphorylation form resting values (). Isometric and concentric twitch forces were increased by ∼20% and 40%, respectively, in the WT muscles. In the skMLCK−/− muscle, isometric twitch force was not increased although concentric twitch force was increased ∼10%. (B) Original force records showing gradual increase in both isometric (solid line) and concentric (dashed line) twitch force during 15 s of 15‐Hz stimulation in WT (top) and skMLCK−/− (bottom) muscles. The first and last twitches of each experiment are shown at right. In the WT muscle, isometric and concentric twitch forces were as increased to ∼20% and 50% of initial levels, respectively. In the skMLCK−/− muscle, isometric twitch force was not increased but concentric twitch force was increased by ∼15%. In this protocol, RLC phosphorylation is typically elevated from ∼0.10 to 0.50 mol phos per mol RLC while in skMLCK−/− muscles this protocol does not change RLC phosphorylation from resting values (unpublished observation). In both A and B muscles, shortened at 0.45 Vmax to obtain concentric twitches; both isometric and conctric twitches were elicted near Lo. In each panel, post CS twitch amplitude is normalized to initial unpotentiated value.
Figure 2. Figure 2. Cartoon depicting structure of sarcomeric myosin. Schematic representation of the myosin II (sarcomeric) protein of vertebrate striated muscle. Cartoon shows how the hexamer molecule is constructed of two MyHC monomers (∼240 kDa), which dimerize along the length of the elongated tail domain (shown in gray) toward the COOH terminus but which separate toward the NH3 terminus to form twin globular head domains. In addition, each head contains a dumbbell‐shaped regulatory (RLC) and ELC (∼20 kDa each) protein subunit (shown in purple and yellow, respectively) bound to the LCBD. The approximate location of the nucleotide binding site on the head is shown (black dot), while the actin binding site is formed by the cleft between the upper and lower subdomains of the head (shown in blue). Digestion by papain or trypsin cleaves the MyHC into heavy (HMM) and light (LMM) meromyosin fragments where the HMM consists of both the S‐1 (blue) domain and the N‐terminus portion of the S‐2 (gray) domain. Note that individual domains are not shown to scale and relative positions are highly idealized. Separation of individual monomers near the N‐terminus of the S‐2 region may allow more flexibility of S‐1 head position than shown. Text at bottom depicts how S‐1 and S‐2 domains constitute LMM and HMM components, respectively, of the MyHC. Myosin dimensions: tail, ∼150 nm; head, ∼16.5 nm in length. For atomic details of myosin S‐1 or RLC structure, see Refs. .
Figure 3. Figure 3. Regulatory cascade for skeletal myosin RLC phosphorylation. Schematic pathway for the calcium (Ca2+) and CaM‐derived activation of skMLCK and myosin RLC phosphorylation in vertebrate striated muscle. During activity, rapid increases in free myoplasmic Ca2+ (top left) drives a reaction cascade that parallels Ca2+ binding to TnC. Saturation of Ca2+‐binding sites on CaM produces a four Ca2+‐CaM pcomplex that is capable of binding to the inactive form of skMLCK. In skeletal muscle, formation of and diffusion of the four Ca2+‐CaM complex is very rapid and not rate limiting. The slower rate of formation of the four Ca2+‐CaM‐skMLCK complex produces an active pool of skMLCK enzyme that catalyzes a phosphotransferase reaction in which the high energy nucleotide molecule ATP donates a phosphoryl group to a serine reside on the RLC. The reverse reaction is catalyzed by MLCP and is unregulated. The thickness of the vertical arrows depicts the 40‐ to 50‐fold greater catalytic rate of skMLCKa (down) versus MLCP (up). During inactivity, Ca2+ sequestration (bottom left) causes the active holoenzyme and Ca2+‐CaM complexes to dissolve. Note that when [Ca2+]i declines Ca2+ first dissociates from the skMLCK bound fraction of Ca2+‐CaM pool, thus allowing CaM to dissociate from skMLCK. The thickness of the horizontal arrows depicts the much greater rate of skMLCK activation (right) versus inactivation (left) during activity and inactivity, respectively. Differences in the rates of skMLCKi → skMLCKa and skMLCKa catalytic activity versus skMLCKi ← skMLCKa and MLCP activity account for the “molecular memomry” of myosin phosphorylation. Note that differences in expression of skMLCK to MLCP in fast ([skMLCK] > [MLCP]) and slow ([skMLCK] < [MLCP]) skeletal muscle fibers also contribute to regulation of RLC phosphorylation (). Regulatory scheme based on Refs. .
Figure 4. Figure 4. Kinetics of force, myoplasmic Ca2+, skMLCK activity and RLC phosphorylation. Kinetic model describing the time course of change in force (black line), peak myoplasmic Ca2+ concentration (solid red line), skMLCK activity (blue line), MLCP active (green line), and RLC phosphorylation (purple line) as a result of 2 s of high‐frequency (100‐150 Hz) tetanic stimulation. Also shown is the proposed change in resting myoplasmic Ca2+ (dotted red line) as a result of stimulation. Due to the rapid time course for RLC phosphorylation during and the relatively slow time course for RLC dephosphorylation following stimulation, RLC phosphorylation is proposed to act as a “molecular memory” of muscle activity by increasing the Ca2+ sensitivity of the contractile element of fast twitch skeletal muscle. During lower‐frequency stimulation, skMLCK activity and RLC phosphorylation occur on a slower time scale but occur rapidly enough to cause staircase potentiation (not shown). The contribution of stimulus‐induced changes to resting myoplasmic Ca2+ is illustrated as relatively minor for PTP; this mechanism may be more prevalent during staircase potentiation. Figure redrawn, from Ref. and modified, according to Ref. . Note that skMLCK catalytic activity is slower than is formation of the active skMLCK holoenzyme by Ca2+‐CaM binding (not shown). Note that all parameters are expressed relative to the maximal response for the time window depicted, not absolute levels.
Figure 5. Figure 5. Influence of RLC phosphorylation on arthropod thick filaments. (A) Three‐dimensional reconstruction of tarantula thick filament segment showing four helical tracks of myosin S‐1 heads. One myosin interacting‐heads motif is highlighted in yellow. Densities of interaction between heads are labelled as “a,” “b,” and “c.” In this configuration, individual myosin heads are less likely to be able to interact with actin, turnover ATP, and/or produce force. Disruption of this motif by phosphorylation may represent a type of thick filament activation that promotes force and ATPase activity. Vertical calibration bar represents 14.5 nm. Reprinted from Alamo et al. 2008 with permission (). (B) Cartoon showing how progressive phosphorylation of the RLC (i.e., nonphosphorylated‐monophosphorylated‐diphosphorylated) influences the distribution of “free” and “blocked” myosin heads. In rested state (a), constitutive monophosphorylation of the free head RLC (yellow dot) is sufficient to produce a population of free heads that “sway” (double arrow) between close contact with their unphosphorylated and “blocked” dimeric partner head and weak contact with the thin filament. Because of their mobility, these heads bind readily to actin during rapid Ca2+ activation of the contractile apparatus (i.e., during a twitch) (b). In (c), activation of skMLCK and diphosphorylation of free heads or monophosphorylation of blocked heads increases the fraction of heads able to bind to actin. In this model, the greater the phosphorylation of the RLC by skMLCK, the greater the potentiation, either by biasing the probability that a free head will bind to actin or by allowing the skMLCK enzyme to access and phosphorylate the RLC of the blocked head. Although withdrawal of Ca2+ by SERCA pumping and reduction of [Ca2+]myo causes relaxation (d) the slow dephosphorylation of the RLC produces a “molecular memory” at the level of the RLC that will produce PTP when the muscle is reactivated (e). Note that the extent to which this scheme applies to mammalian thick filaments is not known. Colour Key: free and swaying heads are shown in light and dark blue, respectively; blocked heads are shown in green; phosphorylation sites on RLC are shown in yellow and red (Ser35 and Ser45, respectively). Monophosphorylation is produced by phosphorylation of either Ser35 or Ser45, while diphosphorylation requires both sites to be phosphorylated. Reprinted from Brito et al. (2015) with permission (). The reader is referred to original papers for more details of the interacting head motif or the molecular mechanism of this thick filament activation by phosphorylation.
Figure 6. Figure 6. Theoretical relationship between Ca2+ sensitivity and isometric twitch force. Theoretical relationship between skMLCK catalyzed RLC phosphorylation mediated increases in Ca2+ sensitivity and isometric twitch force in permeabilized skeletal muscle fibers and intact rodent skeletal muscle, respectively. Main graph: representative force‐pCa relationship of permeabilized fibers where red line is without RLC phosphorylation and blue line is with RLC phosphorylation. In the highly phosphorylated state (>0.70 mol phos mol RLC), the force‐pCa relationship is shifted to the left relative to unphosphrylated state () without effect on maximal Ca2+ activated force (Fmax). Top left panel insert: example traces from EDL muscle (in vitro, 25°C) showing how presence of skMLCK enzyme and stimulation induced elevations in RLC phosphorylation is associated with PTP of isometric twitch force (before stimulation, thick line; after stimulation, thin line). Bottom right panel insert: example traces from skMLCK−/− mouse EDL muscle (in vitro, 25°C) showing how the absence of skMLCK enzyme and absence of stimulation induced RLC phosphorylation is associated with posttetanic depression of force rather than PTP (before stimulation, thick line; after stimulation, thin line). Note that changes to twitch time course (i.e., decreased half‐relaxation time) are roughly similar for both genotypes and thus apparently independent of RLC phosphorylation and PTP per se. Repetitive low frequency stimulation leading to staircase potentiation may produce increases in isometric twitch force amplitude that approach that displayed by WT muscles, indicating the presence of a RLC phosphorylation‐independent mechanism.
Figure 7. Figure 7. Summary of RLC phosphorylation effects on permeabilized fibers. Flow chart depicting theoretical cascade of events during Ca2+ activation of permeabilized skeletal muscle fibers. Distinction is made between suboptimal and optimal Ca2+ activation. Cascade based on results from mammalian muscle fibers at low temperatures. The influence of RLC phosphorylation on αFS is assumed to be due to an increase in fapp without change to gapp. Other mechanisms such as temperature, ionic strength, or Ca2+ binding to cation sites on the RLC are not considered in this model. Abbreviations: fraction of cycling cross‐bridges in force‐generating state (αFS); AM ATPase; loaded shortening velocity (VL); rate constant for steady‐state tension development (ktr or kREDEV); rate of relaxation from steady state (RFR); unloaded shortening velocity as determined by the slack test (Vu).
Figure 8. Figure 8. Influence of potentiation on force‐frequency relation of mouse skeletal muscle. Illustration of the influence of PTP on the force frequency responses of WT mouse EDL muscle (in vitro, 25°C) when measured at the peak of potentiation typically observed 10 to 20 s after a tetanic CS. (A) Isometric force‐frequency responses at optimal length in the unpotentiated (red) and potentiated (blue) state. Unpotentiated and potentiated forces (F) are normalized to peak force (Fo) in the unpotentiated state. The relatively small portion of the activation frequency domain for isometric PTP relative to the frequency stimulus range for fast muscle in vivo is indicated at top. Note that when isometric contractions are very brief (i.e., <100 ms in duration) the relative effect of PTP on the peak force that is attained is much greater. (B) Concentric force‐frequency responses in the unpotentiated (red) and potentiated (blue) state. To construct this model a shortening velocity of 0.35 Vmax was used for both unpotentiated and potentiated conditions; faster and slower speeds of shortening will shift the potentiated curve upward and downward, respectively, relative to the unpoentiateed curve (based on Refs. and ). Unpotentiated and potentiated forces (F) are normalized to peak force (Fo) in the unpotentiated state. The congruence between the activation frequency domains for concentric PTP relative to the frequency stimulus range for fast muscle in vivo is indicated at top. Comparison of panels A and B reveals that the influence of PTP is much greater for concentric than for isometric contractions both in terms of the magnitude of increase and the stimulus frequency range over which potentiation is evident.
Figure 9. Figure 9. Influence of potentiation on force‐velocity relation of mouse skeletal muscle. Illustration of the influence of PTP on the force‐velocity responses of WT mouse EDL muscle (in vitro, 25°C) when measured at the peak of potentiation typically observed 10 s after a tetanic CS. Note that, because the influence of potentiation on concentric force is greatest at moderate shortening speeds and smallest at slow and fast shortening speeds, the potentiated force‐velocity curve is less concave than the unpotentiated force‐velocity curve. Curves represent situations in which muscles are stimulated at high frequency to produce maximal responses in both unpotentiated and potentiated state. Vertical arrow denotes effect on potentiated curve relative to unpotentiated curve if stimulus frequency is increased or decreased (down and up, respectively). Curves are hand drawn.
Figure 10. Figure 10. Effect of genotype on concentric force potentiation of mouse muscle. Hypothetical model for concentric force potentiation of EDL muscles from WT and skMLCK−/− mice (in vitro, 25°). (A) The effect of mouse genotype on the time dependence of concentric force potentiation. Responses shown are for moderate frequency contractions (i.e., 45 Hz).and a moderate speed of shortening (i.e., 0.35 Vmax). Note that although WT muscle (blue line) responses are always greater, skMLCK−/− muscle (red line) also displays a significant potentiation that cannot be attributed to RLC phosphorylation. The vertical arrows represent the difference in potentiation between genotypes hypothesized to be due to RLC phosphorylation (i.e., WT – skMLCK−/− responses). Use of lower or higher‐frequency stimulation will shift both curves up or down the y‐axis, respectively. Potentiation calculated as post‐CS response at select times divided by pre‐CS value and should be considered represent situation for either peak or mean force. Based on unpublished data. (B) The effect of mouse genotype on the stimulus frequency dependence of concentric force potentiation. Values represent the peak of potentiation as captured 10 to 20 s after a tetanic CS. Note that although WT responses are always greater (blue line), it is apparent that skMLCK−/− muscles also display a potentiation at all frequencies that cannot be attributed to RLC phosphorylation. The vertical arrows represent the difference in potentiation hypothized to be solely due to RLC phosphorylation (i.e., WT – skMLCK−/− responses). Curves are based on a shortening speed of 0.35 Vmax and assume maximal potentiation as determined 10 to 20 s after a tetanic CS. Potentiation calculated as post‐CS response divided by pre‐CS value and represent either peak or mean force or work/power. Based on Ref. and unpublished data.
Figure 11. Figure 11. Summary of RLC phosphorylation influence on intact rodent muscle. Flow chart depicting theoretical cascade of events leading to myosin RLC phosphorylation and PTP or staircase potentiation in fast twitch rodent skeletal muscle. The proposed influence of RLC phosphorylation on muscle force, work, and power is illustrated for twitch and tetanic (Pt and Po, respectively) as well as during isometric and dynamic contractions. The possible influence of estrogen on skMLCK activity and upregulating RLC phosphorylation is included. Potentiation due to alternate mechanisms is not considered (dotted lines). Abbreviatons: force‐time integral (FTI); rate of isometric force development (RFD); rate of isometric force relaxation (RFR); isometric twitch (Pt), submaximal force (<Po); peak isometric force (Po); and high‐energy phosphate turnover (HEPT). Economy refers to ratio between HEPT and FTI during isometric contractions while efficiency refers to ratio between HEPT and work performed during concentric contractions. Displacement refers to the magnitude of shortening during isotonic type contractions. Vmax refers to maximum shortening velocity as determined by extrapolation to zero load while Vu refers to unloaded shortening velocity as detrmined by the slack test. The proposed fiber type dependence of myosin RLC phosphorylation mediated potentiation demonstrated in skMLCK overexprssors () is recognized by the bifurcation of the flow chart and the dotted arrow pointing toward type IIa and IIa fibers. Dotted lines depict speculative link between estrogen signaling and skMLCK activity (). Dashed lines depict speculative link between skMLCK catalyzed RLC phosphorylation, the SRX and resting muscle thermogenesis ().
Figure 12. Figure 12. Summary of RLC phosphorylation influence on human skeletal muscle. Flow chart depicting theoretical cascade of events leading to myosin RLC phosphorylation postactivation potentiation (PAP) (staircase or PTP) in human skeletal muscle. A theoretical distinction is made between evoked and voluntary condition contractions as well as between isometric and ballistic contraction types. Studies showing that the magnitude of PAP of evoked contractions tend to be smaller in magnitude than for voluntary contractions is recognized and accounted for by the presence of signals arising in the periphery that act as a negative feedback signal to upper centers to dampen PAP (dashed lines). Dotted lines depict speculative link between reductions in estrogen levels and reductions in phosphorylation of fast and slow RLC isoforms noted in older women relative to either young women or age matched males (). The potential influence of resting RLC phosphorylation levels on muscle thermogenesis, via redistribution of cross‐bridges from SRX to CRX, is included (dotted lines). Ballistic contractions refer to isokinetic contractions at fast (>180°/s) or slow (<180°/s) speeds of shortening. Abbreviations: evoked twitch (Pt); evoked submaximal force (Pt‐Po); evoked peak force (Po); rate of isometric force development (RFD); maximal voluntary contraction (MVC); submaximal voluntary contraction (SVC); and motor unit discharge rate (MUDR). Due to technical limitations, the influence of PAP on MUDR during ballistic contractions has not been determined. Neither metabolic factors inhibiting or alternate mechanisms for PAP are considered in this flowchart (although they may well exist).


Figure 1. Paradigm dependence for force potentiation of mouse fast muscle. Example of paradigm and contraction type dependence for potentiation of mouse EDL muscle (in vitro 25°C). (A) Original force records showing isometric (solid line) and concentric (dashed line) twitch forces obtained before (left) and after (right) a potentiating stimulus in WT (top) and skMLCK−/− (bottom) muscles. For both genotypes, the potentiating atimulus consisted of four brief volleys of 100 Hz in a 10‐s time window with the muscle at optimal length; peak tetanic force declined by ∼8% from the first to the last tetanus in both genotypes. In WT muscles, this protocol typically elevates RLC phosphorylation from ∼0.10 to 0.55 mol phos per mol RLC (); in skMLCK−/− muscles this protocol does not change RLC phosphorylation form resting values (). Isometric and concentric twitch forces were increased by ∼20% and 40%, respectively, in the WT muscles. In the skMLCK−/− muscle, isometric twitch force was not increased although concentric twitch force was increased ∼10%. (B) Original force records showing gradual increase in both isometric (solid line) and concentric (dashed line) twitch force during 15 s of 15‐Hz stimulation in WT (top) and skMLCK−/− (bottom) muscles. The first and last twitches of each experiment are shown at right. In the WT muscle, isometric and concentric twitch forces were as increased to ∼20% and 50% of initial levels, respectively. In the skMLCK−/− muscle, isometric twitch force was not increased but concentric twitch force was increased by ∼15%. In this protocol, RLC phosphorylation is typically elevated from ∼0.10 to 0.50 mol phos per mol RLC while in skMLCK−/− muscles this protocol does not change RLC phosphorylation from resting values (unpublished observation). In both A and B muscles, shortened at 0.45 Vmax to obtain concentric twitches; both isometric and conctric twitches were elicted near Lo. In each panel, post CS twitch amplitude is normalized to initial unpotentiated value.


Figure 2. Cartoon depicting structure of sarcomeric myosin. Schematic representation of the myosin II (sarcomeric) protein of vertebrate striated muscle. Cartoon shows how the hexamer molecule is constructed of two MyHC monomers (∼240 kDa), which dimerize along the length of the elongated tail domain (shown in gray) toward the COOH terminus but which separate toward the NH3 terminus to form twin globular head domains. In addition, each head contains a dumbbell‐shaped regulatory (RLC) and ELC (∼20 kDa each) protein subunit (shown in purple and yellow, respectively) bound to the LCBD. The approximate location of the nucleotide binding site on the head is shown (black dot), while the actin binding site is formed by the cleft between the upper and lower subdomains of the head (shown in blue). Digestion by papain or trypsin cleaves the MyHC into heavy (HMM) and light (LMM) meromyosin fragments where the HMM consists of both the S‐1 (blue) domain and the N‐terminus portion of the S‐2 (gray) domain. Note that individual domains are not shown to scale and relative positions are highly idealized. Separation of individual monomers near the N‐terminus of the S‐2 region may allow more flexibility of S‐1 head position than shown. Text at bottom depicts how S‐1 and S‐2 domains constitute LMM and HMM components, respectively, of the MyHC. Myosin dimensions: tail, ∼150 nm; head, ∼16.5 nm in length. For atomic details of myosin S‐1 or RLC structure, see Refs. .


Figure 3. Regulatory cascade for skeletal myosin RLC phosphorylation. Schematic pathway for the calcium (Ca2+) and CaM‐derived activation of skMLCK and myosin RLC phosphorylation in vertebrate striated muscle. During activity, rapid increases in free myoplasmic Ca2+ (top left) drives a reaction cascade that parallels Ca2+ binding to TnC. Saturation of Ca2+‐binding sites on CaM produces a four Ca2+‐CaM pcomplex that is capable of binding to the inactive form of skMLCK. In skeletal muscle, formation of and diffusion of the four Ca2+‐CaM complex is very rapid and not rate limiting. The slower rate of formation of the four Ca2+‐CaM‐skMLCK complex produces an active pool of skMLCK enzyme that catalyzes a phosphotransferase reaction in which the high energy nucleotide molecule ATP donates a phosphoryl group to a serine reside on the RLC. The reverse reaction is catalyzed by MLCP and is unregulated. The thickness of the vertical arrows depicts the 40‐ to 50‐fold greater catalytic rate of skMLCKa (down) versus MLCP (up). During inactivity, Ca2+ sequestration (bottom left) causes the active holoenzyme and Ca2+‐CaM complexes to dissolve. Note that when [Ca2+]i declines Ca2+ first dissociates from the skMLCK bound fraction of Ca2+‐CaM pool, thus allowing CaM to dissociate from skMLCK. The thickness of the horizontal arrows depicts the much greater rate of skMLCK activation (right) versus inactivation (left) during activity and inactivity, respectively. Differences in the rates of skMLCKi → skMLCKa and skMLCKa catalytic activity versus skMLCKi ← skMLCKa and MLCP activity account for the “molecular memomry” of myosin phosphorylation. Note that differences in expression of skMLCK to MLCP in fast ([skMLCK] > [MLCP]) and slow ([skMLCK] < [MLCP]) skeletal muscle fibers also contribute to regulation of RLC phosphorylation (). Regulatory scheme based on Refs. .


Figure 4. Kinetics of force, myoplasmic Ca2+, skMLCK activity and RLC phosphorylation. Kinetic model describing the time course of change in force (black line), peak myoplasmic Ca2+ concentration (solid red line), skMLCK activity (blue line), MLCP active (green line), and RLC phosphorylation (purple line) as a result of 2 s of high‐frequency (100‐150 Hz) tetanic stimulation. Also shown is the proposed change in resting myoplasmic Ca2+ (dotted red line) as a result of stimulation. Due to the rapid time course for RLC phosphorylation during and the relatively slow time course for RLC dephosphorylation following stimulation, RLC phosphorylation is proposed to act as a “molecular memory” of muscle activity by increasing the Ca2+ sensitivity of the contractile element of fast twitch skeletal muscle. During lower‐frequency stimulation, skMLCK activity and RLC phosphorylation occur on a slower time scale but occur rapidly enough to cause staircase potentiation (not shown). The contribution of stimulus‐induced changes to resting myoplasmic Ca2+ is illustrated as relatively minor for PTP; this mechanism may be more prevalent during staircase potentiation. Figure redrawn, from Ref. and modified, according to Ref. . Note that skMLCK catalytic activity is slower than is formation of the active skMLCK holoenzyme by Ca2+‐CaM binding (not shown). Note that all parameters are expressed relative to the maximal response for the time window depicted, not absolute levels.


Figure 5. Influence of RLC phosphorylation on arthropod thick filaments. (A) Three‐dimensional reconstruction of tarantula thick filament segment showing four helical tracks of myosin S‐1 heads. One myosin interacting‐heads motif is highlighted in yellow. Densities of interaction between heads are labelled as “a,” “b,” and “c.” In this configuration, individual myosin heads are less likely to be able to interact with actin, turnover ATP, and/or produce force. Disruption of this motif by phosphorylation may represent a type of thick filament activation that promotes force and ATPase activity. Vertical calibration bar represents 14.5 nm. Reprinted from Alamo et al. 2008 with permission (). (B) Cartoon showing how progressive phosphorylation of the RLC (i.e., nonphosphorylated‐monophosphorylated‐diphosphorylated) influences the distribution of “free” and “blocked” myosin heads. In rested state (a), constitutive monophosphorylation of the free head RLC (yellow dot) is sufficient to produce a population of free heads that “sway” (double arrow) between close contact with their unphosphorylated and “blocked” dimeric partner head and weak contact with the thin filament. Because of their mobility, these heads bind readily to actin during rapid Ca2+ activation of the contractile apparatus (i.e., during a twitch) (b). In (c), activation of skMLCK and diphosphorylation of free heads or monophosphorylation of blocked heads increases the fraction of heads able to bind to actin. In this model, the greater the phosphorylation of the RLC by skMLCK, the greater the potentiation, either by biasing the probability that a free head will bind to actin or by allowing the skMLCK enzyme to access and phosphorylate the RLC of the blocked head. Although withdrawal of Ca2+ by SERCA pumping and reduction of [Ca2+]myo causes relaxation (d) the slow dephosphorylation of the RLC produces a “molecular memory” at the level of the RLC that will produce PTP when the muscle is reactivated (e). Note that the extent to which this scheme applies to mammalian thick filaments is not known. Colour Key: free and swaying heads are shown in light and dark blue, respectively; blocked heads are shown in green; phosphorylation sites on RLC are shown in yellow and red (Ser35 and Ser45, respectively). Monophosphorylation is produced by phosphorylation of either Ser35 or Ser45, while diphosphorylation requires both sites to be phosphorylated. Reprinted from Brito et al. (2015) with permission (). The reader is referred to original papers for more details of the interacting head motif or the molecular mechanism of this thick filament activation by phosphorylation.


Figure 6. Theoretical relationship between Ca2+ sensitivity and isometric twitch force. Theoretical relationship between skMLCK catalyzed RLC phosphorylation mediated increases in Ca2+ sensitivity and isometric twitch force in permeabilized skeletal muscle fibers and intact rodent skeletal muscle, respectively. Main graph: representative force‐pCa relationship of permeabilized fibers where red line is without RLC phosphorylation and blue line is with RLC phosphorylation. In the highly phosphorylated state (>0.70 mol phos mol RLC), the force‐pCa relationship is shifted to the left relative to unphosphrylated state () without effect on maximal Ca2+ activated force (Fmax). Top left panel insert: example traces from EDL muscle (in vitro, 25°C) showing how presence of skMLCK enzyme and stimulation induced elevations in RLC phosphorylation is associated with PTP of isometric twitch force (before stimulation, thick line; after stimulation, thin line). Bottom right panel insert: example traces from skMLCK−/− mouse EDL muscle (in vitro, 25°C) showing how the absence of skMLCK enzyme and absence of stimulation induced RLC phosphorylation is associated with posttetanic depression of force rather than PTP (before stimulation, thick line; after stimulation, thin line). Note that changes to twitch time course (i.e., decreased half‐relaxation time) are roughly similar for both genotypes and thus apparently independent of RLC phosphorylation and PTP per se. Repetitive low frequency stimulation leading to staircase potentiation may produce increases in isometric twitch force amplitude that approach that displayed by WT muscles, indicating the presence of a RLC phosphorylation‐independent mechanism.


Figure 7. Summary of RLC phosphorylation effects on permeabilized fibers. Flow chart depicting theoretical cascade of events during Ca2+ activation of permeabilized skeletal muscle fibers. Distinction is made between suboptimal and optimal Ca2+ activation. Cascade based on results from mammalian muscle fibers at low temperatures. The influence of RLC phosphorylation on αFS is assumed to be due to an increase in fapp without change to gapp. Other mechanisms such as temperature, ionic strength, or Ca2+ binding to cation sites on the RLC are not considered in this model. Abbreviations: fraction of cycling cross‐bridges in force‐generating state (αFS); AM ATPase; loaded shortening velocity (VL); rate constant for steady‐state tension development (ktr or kREDEV); rate of relaxation from steady state (RFR); unloaded shortening velocity as determined by the slack test (Vu).


Figure 8. Influence of potentiation on force‐frequency relation of mouse skeletal muscle. Illustration of the influence of PTP on the force frequency responses of WT mouse EDL muscle (in vitro, 25°C) when measured at the peak of potentiation typically observed 10 to 20 s after a tetanic CS. (A) Isometric force‐frequency responses at optimal length in the unpotentiated (red) and potentiated (blue) state. Unpotentiated and potentiated forces (F) are normalized to peak force (Fo) in the unpotentiated state. The relatively small portion of the activation frequency domain for isometric PTP relative to the frequency stimulus range for fast muscle in vivo is indicated at top. Note that when isometric contractions are very brief (i.e., <100 ms in duration) the relative effect of PTP on the peak force that is attained is much greater. (B) Concentric force‐frequency responses in the unpotentiated (red) and potentiated (blue) state. To construct this model a shortening velocity of 0.35 Vmax was used for both unpotentiated and potentiated conditions; faster and slower speeds of shortening will shift the potentiated curve upward and downward, respectively, relative to the unpoentiateed curve (based on Refs. and ). Unpotentiated and potentiated forces (F) are normalized to peak force (Fo) in the unpotentiated state. The congruence between the activation frequency domains for concentric PTP relative to the frequency stimulus range for fast muscle in vivo is indicated at top. Comparison of panels A and B reveals that the influence of PTP is much greater for concentric than for isometric contractions both in terms of the magnitude of increase and the stimulus frequency range over which potentiation is evident.


Figure 9. Influence of potentiation on force‐velocity relation of mouse skeletal muscle. Illustration of the influence of PTP on the force‐velocity responses of WT mouse EDL muscle (in vitro, 25°C) when measured at the peak of potentiation typically observed 10 s after a tetanic CS. Note that, because the influence of potentiation on concentric force is greatest at moderate shortening speeds and smallest at slow and fast shortening speeds, the potentiated force‐velocity curve is less concave than the unpotentiated force‐velocity curve. Curves represent situations in which muscles are stimulated at high frequency to produce maximal responses in both unpotentiated and potentiated state. Vertical arrow denotes effect on potentiated curve relative to unpotentiated curve if stimulus frequency is increased or decreased (down and up, respectively). Curves are hand drawn.


Figure 10. Effect of genotype on concentric force potentiation of mouse muscle. Hypothetical model for concentric force potentiation of EDL muscles from WT and skMLCK−/− mice (in vitro, 25°). (A) The effect of mouse genotype on the time dependence of concentric force potentiation. Responses shown are for moderate frequency contractions (i.e., 45 Hz).and a moderate speed of shortening (i.e., 0.35 Vmax). Note that although WT muscle (blue line) responses are always greater, skMLCK−/− muscle (red line) also displays a significant potentiation that cannot be attributed to RLC phosphorylation. The vertical arrows represent the difference in potentiation between genotypes hypothesized to be due to RLC phosphorylation (i.e., WT – skMLCK−/− responses). Use of lower or higher‐frequency stimulation will shift both curves up or down the y‐axis, respectively. Potentiation calculated as post‐CS response at select times divided by pre‐CS value and should be considered represent situation for either peak or mean force. Based on unpublished data. (B) The effect of mouse genotype on the stimulus frequency dependence of concentric force potentiation. Values represent the peak of potentiation as captured 10 to 20 s after a tetanic CS. Note that although WT responses are always greater (blue line), it is apparent that skMLCK−/− muscles also display a potentiation at all frequencies that cannot be attributed to RLC phosphorylation. The vertical arrows represent the difference in potentiation hypothized to be solely due to RLC phosphorylation (i.e., WT – skMLCK−/− responses). Curves are based on a shortening speed of 0.35 Vmax and assume maximal potentiation as determined 10 to 20 s after a tetanic CS. Potentiation calculated as post‐CS response divided by pre‐CS value and represent either peak or mean force or work/power. Based on Ref. and unpublished data.


Figure 11. Summary of RLC phosphorylation influence on intact rodent muscle. Flow chart depicting theoretical cascade of events leading to myosin RLC phosphorylation and PTP or staircase potentiation in fast twitch rodent skeletal muscle. The proposed influence of RLC phosphorylation on muscle force, work, and power is illustrated for twitch and tetanic (Pt and Po, respectively) as well as during isometric and dynamic contractions. The possible influence of estrogen on skMLCK activity and upregulating RLC phosphorylation is included. Potentiation due to alternate mechanisms is not considered (dotted lines). Abbreviatons: force‐time integral (FTI); rate of isometric force development (RFD); rate of isometric force relaxation (RFR); isometric twitch (Pt), submaximal force (<Po); peak isometric force (Po); and high‐energy phosphate turnover (HEPT). Economy refers to ratio between HEPT and FTI during isometric contractions while efficiency refers to ratio between HEPT and work performed during concentric contractions. Displacement refers to the magnitude of shortening during isotonic type contractions. Vmax refers to maximum shortening velocity as determined by extrapolation to zero load while Vu refers to unloaded shortening velocity as detrmined by the slack test. The proposed fiber type dependence of myosin RLC phosphorylation mediated potentiation demonstrated in skMLCK overexprssors () is recognized by the bifurcation of the flow chart and the dotted arrow pointing toward type IIa and IIa fibers. Dotted lines depict speculative link between estrogen signaling and skMLCK activity (). Dashed lines depict speculative link between skMLCK catalyzed RLC phosphorylation, the SRX and resting muscle thermogenesis ().


Figure 12. Summary of RLC phosphorylation influence on human skeletal muscle. Flow chart depicting theoretical cascade of events leading to myosin RLC phosphorylation postactivation potentiation (PAP) (staircase or PTP) in human skeletal muscle. A theoretical distinction is made between evoked and voluntary condition contractions as well as between isometric and ballistic contraction types. Studies showing that the magnitude of PAP of evoked contractions tend to be smaller in magnitude than for voluntary contractions is recognized and accounted for by the presence of signals arising in the periphery that act as a negative feedback signal to upper centers to dampen PAP (dashed lines). Dotted lines depict speculative link between reductions in estrogen levels and reductions in phosphorylation of fast and slow RLC isoforms noted in older women relative to either young women or age matched males (). The potential influence of resting RLC phosphorylation levels on muscle thermogenesis, via redistribution of cross‐bridges from SRX to CRX, is included (dotted lines). Ballistic contractions refer to isokinetic contractions at fast (>180°/s) or slow (<180°/s) speeds of shortening. Abbreviations: evoked twitch (Pt); evoked submaximal force (Pt‐Po); evoked peak force (Po); rate of isometric force development (RFD); maximal voluntary contraction (MVC); submaximal voluntary contraction (SVC); and motor unit discharge rate (MUDR). Due to technical limitations, the influence of PAP on MUDR during ballistic contractions has not been determined. Neither metabolic factors inhibiting or alternate mechanisms for PAP are considered in this flowchart (although they may well exist).
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Rene Vandenboom. Modulation of Skeletal Muscle Contraction by Myosin Phosphorylation. Compr Physiol 2016, 7: 171-212. doi: 10.1002/cphy.c150044