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A. M. Gordon is in the Department of Physiology and Biophysics and M. Regnier is in the Department of Bioengineering, University of Washington, Seattle, WA. E. Homsher is in the Department of Physiology, University of California at Los Angeles, Los Angeles, CA.
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Abstract |
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Introduction |
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 Top Introduction Structural and biochemical basis...Mechanical correlates of the...Ca2+ regulation of contractionDifferences between skeletal and...SummaryReferences |
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At the cellular level, an action potential triggers release of Ca2+ from the sarcoplasmic reticulum, elevating intracellular Ca2+ concentration ([Ca2+]) and rapidly activating skeletal muscle. This electrical activity is initiated and coordinated by the nervous system to activate groups of muscle fibers as a motor unit. Although the force from each motor unit varies somewhat with frequency of nerve stimulation, gradation of force is largely accomplished through controlling the recruitment of motor units. Activation of the heart is also rapid, but in each cardiac contraction all of the heart's cells are activated. Electrical activity is spontaneous in cardiac pacemaker cells, and coordination occurs through the spread of electrical activity from cell to cell by specialized cells and structures, not by direct neural control through motor units. Nevertheless, this electrical activity still triggers Ca2+ release from the sarcoplasmic reticulum, elevating intracellular [Ca2+]. The heart's output is graded instead by controlling contraction frequency and modulating mechanical output of each cell, not the number of activated cells. Contractions are controlled by intrinsic factors such as heart rate and chamber volume (cell length, venous return, the Frank-Starling relationship) and extrinsic factors such as autonomic control of heart rate and intensity of cardiac myocyte activation. Extrinsic control is exerted primarily through phosphorylation of specific regulatory proteins.
Although the sarcomeric structures are the same for both skeletal and cardiac muscle, the contractile protein isoforms are different, giving rise to the different properties. Below, we discuss recent observations that describe how Ca2+ regulates contraction in striated muscle and the basis of the functional differences between heart and skeletal muscle. A detailed review of this topic has appeared recently and should be consulted for supporting evidence and references to the research literature (2).
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Structural and biochemical basis of regulation |
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TopIntroductionStructural and biochemical basis...Mechanical correlates of the...Ca2+ regulation of contractionDifferences between skeletal and...SummaryReferences |
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) [see review by Geeves and Holmes (1)]. This force causes the thin filament to slide over the thick filament and the sarcomere to shorten and develop force against a load the muscle must move. Ca2+ binding to troponin (Tn) on the thin filament initiates the force-generating interaction of myosin and actin, and ATP hydrolysis provides the energy for the molecular changes that drive force generation and muscle shortening (Fig. 3). Regulation by Ca2+ is mediated through changes in the thin filament, although modulation can occur through myosin.
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shows the salient structural features of thin filament regulation. Helically arranged actins form the backbone of the thin filament, with the regulatory proteins tropomyosin (Tm) and Tn attached to actin (A) in a 7:1:1 (A:Tm:Tn) ratio. Tm, a long, flexible molecule, binds to seven actin monomers in the thin filament helix and overlaps the adjacent Tms (Fig. 1B). Tn attaches to two actins in the absence of Ca2+ through its TnI subunit and to Tm through the TnT subunit at the Tm/Tm overlap zone (Fig. 1C). Ca2+ binding to the TnC subunit strengthens the TnC-TnI interaction and detaches TnI from its contacts with actin (Fig. 1C) (2, 9, 10). Recent structural studies (11, 15) show that this Ca2+-mediated detachment of TnI from actin allows Tm to move over the surface of the thin filament. On the actin surface, there are sites for weak (mainly electrostatic) and strong myosin binding (Fig. 2A). Tm either rolls around its axis or slides from a position near the outer edge of the thin filament [where it covers many of the myosin binding sites on actin (Fig. 2B)] to a position allowing increased weak and some strong myosin head binding (Fig. 2C). Tm is a flexible molecule, and its positioning should be considered dynamic; Tm does not occupy a single fixed position in the presence of elevated [Ca2+] but "rocks and rolls" or "slips and slides" back and forth over the actin surface. The Tm positions shown in Fig. 2, B–D should therefore be considered average positions. When myosin cross-bridge is strongly bound to actin, Tm is locally stabilized in a position that makes both weak and strong myosin binding sites available on nearby actin monomers (Fig. 2D). Thus structural data suggests that thin filament activation is achieved by the movement of Tm over the actin surface, which is controlled both by Ca2+ binding to TnC and initial cross-bridge binding to actin to allow additional strong cross-bridge binding. This Tm motion permits force generation and shortening.
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), a second in which cross-bridges can weakly bind to actin [called the "closed" state (Fig. 2C)], and a third in which myosin can strongly bind to actin [called an "open" state (Fig. 2D)]. In the presence of saturating Ca2+, the position of Tm is such that ~20% of the actin sites at any time are in the open state and ~80% are in the closed state (6), corresponding to an average position of Tm, indicated in Fig. 2C. Ca2+ binding to TnC partially activates the thin filament by allowing Tm to move to a position in which a fraction of the cross-bridges can bind strongly and generate force. Because cross-bridges bind strongly, they hold the Tm in a position that exposes strong binding sites on actin for a longer duration and more fully activate the thin filament. Biochemical data suggest that Ca2+ binding and subsequent strong cross-bridge attachment spatially extends activation along the thin filament to 12–14 actins, i.e., beyond the 7 actins covered by a single Tm (5). Thus there is good correspondence between the structural and biochemical states of thin filament activation as defined by Tm position and the ability of cross-bridges to bind either weakly or strongly to actin. This cooperative model of activation by Ca2+ and strongly attached cross-bridges is the basis for the discussion below of regulation in physiological preparations. |
Mechanical correlates of the cross-bridge cycle and its regulation |
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TopIntroductionStructural and biochemical basis...Mechanical correlates of the...Ca2+ regulation of contractionDifferences between skeletal and...SummaryReferences |
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are for fast skeletal muscle myosin; in many cases analogous rates for slow skeletal and cardiac myosin isoforms remain to be determined. Figure 3 shows the cross-bridge cycle in terms of the various reactants and products (A) and the corresponding structural changes (B).
At physiological ATP concentrations (3–5 mM), ATP binding to myosin (step 1) is very rapid and irreversible. The subsequent detachment of actin from the actin-myosin•ATP (A~M•ATP) complex (step 2) is similarly rapid and is caused by an opening between myosin's upper and lower 50-kDa regions (Fig. 3B) like the opening of jaws. A "flexing" or bending of the myosin neck region (Fig. 3B) accompanies step 3, the hydrolytic cleavage of ATP, whose equilibrium constant (K3, defined as k+3/k–3) is only ~10. Following ATP cleavage, myosin again binds weakly to actin at a high rate, but in the absence of Ca2+ Tm sterically blocks access of the myosin head to strong binding sites on actin (Fig. 3B). However, when Ca2+ is bound to TnC, TnI detaches from actin, allowing the Tm/Tn complex to roll or slide over the thin filament surface. This exposes weak binding sites on actin and transiently exposes strong binding sites on actin (Fig. 3B) for binding to the complementary regions in myosin's 50-kDa domain. The greater the [Ca2+], the greater the fraction of time the Tm/Tn complex allows myosin access to strong binding sites on actin. Consequently, the rate of strong cross-bridge attachment, the flux through step 5, is dependent on [Ca2+] and Tm position (i.e., in the simplest case, the value of k+5 is proportional to the fraction of Tn having bound calcium). Strong binding of myosin to actin (Fig. 3B) is associated with movement of the upper and lower 50-kDa subdomains toward each other (or closing the jaws). This movement may allow the neck region of myosin to extend, opening a pathway for inorganic phosphate release from the ATP binding pocket in myosin. Alternatively, closing the jaws might promote inorganic phosphate release from the binding pocket, which then allows the extension of myosin's neck region. In any event, myosin neck extension, step 6, is the power stroke that, in isometric muscle, stretches an elastic element (represented here as the S2 segment) by some 10 nm and produces a force of ~2 pN/cross-bridge (7). In nonisometric conditions, shortening of the neck extension causes the thick and thin filaments to slide past each other. Step 7 is an irreversible isomerization and is strain sensitive; i.e., when the force on the cross-bridge is large as in isometric contractions, k+7 is slow (3–10 s–1) and is the rate-limiting step for the cross-bridge cycle. However, when the strain on the cross-bridge is low, as during rapid shortening, k+7 rises to >500 s–1. Finally, ADP is released from A•Mf•ADP (where f is a cross-bridge exerting force) in the reversible step 8 to form the rigor state, A•Mf. During isometric contractions, the slowness of k+7 causes the population of cross-bridges in the initial force-bearing (A•Mf*•ADP) state to rise and with it force. Cross-bridges attach and exert force constantly during steps 7, 8, and 1 during isometric contraction, and force drops to zero when the cross-bridges detach in step 2. During shortening contractions the filaments slide past each other, the strain on the cross-bridge is reduced, and step 7 occurs more rapidly. This accounts for the Fenn effect (an increased rate of energy liberation above the isometric rate as shortening velocity increases).
The chemomechanical mechanism shown in Fig. 3 implies that during an isometric contraction, a cross-bridge remains strongly attached to actin for a relatively long time (>100 ms/cycle). Strongly bound cross-bridges prevent Tm/Tn from returning to its blocked or closed position, maintaining the thin filament in a "switched on" position (Fig. 3B). In the absence of Ca2+, cross-bridge detachment at the end of the cycle allows Tm/Tn to cover the strong myosin binding sites on actin and deactivate the thin filament (Fig. 3A).
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Ca2+ regulation of contraction |
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TopIntroductionStructural and biochemical basis...Mechanical correlates of the...Ca2+ regulation of contractionDifferences between skeletal and...SummaryReferences |
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Force-pCa relationship.
The force exerted by the muscle in the isometric state depends on the number of strongly attached cross-bridges and the force developed by each cross-bridge. In turn, this depends on the number of actin binding sites open for strong myosin binding. The maximum number of cross-bridges attached during contraction is uncertain [see Gordon et al. (2)]. Structural considerations suggest that no more than four myosin S1 heads can attach per seven-actin unit. During isometric contraction it is likely that only 20–40% of the available cross-bridges attach at one time, meaning ~1–2 myosin S1 heads per 7 actins.
The chemomechanical model of the cross-bridge cycle describes the interaction of one myosin with one actin in the thin filament, yet the sarcomeric structure implies that activation involves many potential myosin interactions with actins along the length of each thin filament (Fig. 1A). Thus activation could involve cooperativity within and between regulatory units (A7TnTm). The model of activation shown in Figs. 1, 2, and 3 implies that there are four mechanisms whereby Ca2+ binding to TnC and subsequent binding of cross-bridges create an allosteric or cooperative increase in cross-bridge binding along the thin filament (see Fig. 4).
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). This effect on the Ca2+ sensitivity of force is moderate, maximally increasing the Hill coefficient (n) to 2. Second, strong binding of cross-bridges in one A7TmTn unit increases the Ca2+ binding in that unit or in n-n units (Fig. 4B). This is small in skeletal muscle under physiological conditions but may be important in cardiac muscle (12). Third, strong binding of cross-bridges in one A7TmTn unit increases strong binding of cross-bridges in that unit and in n-n units (Fig. 4C). This occurs primarily through interactions between Tms along the thin filament (Fig. 4C) linked by head-to-tail connections, but may also occur through interactions between actins (Fig. 4D). This source of cooperativity helps explain the steep relationship between force and [Ca2+] but plays less of a role in regulating the rate of force redevelopment (2).
In the simplest model of activation, the value of k+5 (the rate of strong cross-bridge attachment) increases in proportion to Ca2+ bound to Tn. Cooperative activation mechanisms can modify this controlling step (step 5; Fig. 3) of the chemomechanical cross-bridge cycle. Kinetic analysis of the mechanism in Fig. 3A shows that the number of force-generating cross-bridges is a hyperbolic function of the value of k+5, approaching an asymptote when (k+5/k–5) > 3.
Relative isometric force is given by the following relationship: relative isometric force = 1/[1 + 
ß + (
/k+5)], where = k+1k+7k+8/(k+1k+7 + k+1k+8 + k+7k+8), ß = [1/k+2 + (k–3 + k+4)/k+3k+4 + 1/k+4 + 1/k+6], and = [ + (k–5/k+6)]. This follows from the differential equations describing the cross-bridge cycle and reasonable assumptions about rates and reversibility. See Regnier and Homsher (8) for a discussion of how cross-bridge cycle kinetics affect force and ktr.
If one considers only the control of k+5 by Ca2+ binding to TnC, with no contribution to activation from strongly attached cross-bridges and no other cooperativity, the dependence of force on [Ca2+] can be calculated. Assuming that k+5 is proportional to the fraction of TnC bound to Ca2+, the relationship between the relative force (F/Fmax) and pCa will be given by F/Fmax = 1/{1 + 10[n(pCa–pCa50)]} where pCa50 = –log Kd for Ca2+ binding to TnC (where Kd is the dissociation constant) and n will be ~1. However, the relationship between F/Fmax and pCa measured in a skinned muscle preparation is much steeper (Fig. 4E), with n much greater than 1 (as much as 6) and a pCa50 (termed the Ca2+ sensitivity) of 5–6.5, depending on the preparation. Thus the control of step 5 in the cycle must involve a highly cooperative activation of the thin filament to increase the fraction of cross-bridges that strongly attach. Of the four processes that may contribute to cooperative activation of the thin filament (Fig. 4), the most important is the effect of strongly attached cross-bridges to increase activation of the regulatory unit and neighboring units (Fig. 4C), as shown in Fig. 2D. Functionally this means that strongly attached cross-bridges have the effect of increasing the value of k+5 at any given [Ca2+]. Factors that modify attachment or availability of cross-bridges (such as decreased spacing between thick and thin filaments as sarcomere length increases or movement of myosin heads away from the thick filament backbone following myosin light chain phosphorylation) can increase Ca2+ sensitivity and/or steepness of the force-pCa curve by increasing the effective k+5.
Rate of force redevelopment.
In addition to steady-state force, there is also a steep relationship between [Ca2+] and the rate constant for force development. This is normally measured as ktr after an activated, demembranated muscle preparation has been allowed to shorten (to detach cross-bridges), restretched rapidly to the initial length, and then held isometric while cross-bridges reattach and force redevelops. [Fig. 4F, plotted here as the relationship between ktr and initial isometric force to demonstrate clearly how ktr relates to the number of attached, force-generating cross-bridges (proportional to force); see Gordon et al. (2)]. The best models to date support the idea that Ca2+ binding and activation of the weakly to strongly bound cross-bridge transition (step 5; Fig. 3) can account for the relationship between ktr and force. For skeletal muscle, the force-ktr relationship changes little until F/Fmax > 0.5 but increases rapidly thereafter. This seems to suggest cooperative behavior (Fig. 4E). However, this behavior is explained by the cross-bridge cycle shown in Fig. 3 and Ca2+-dependent control of k+5 without hypothesizing any cooperative behavior. The mechanism given in Fig. 3A predicts that ktr can be approximated as [k+7 + k+6(K5/(K5 + 1)]. As K5 rises from zero at low [Ca2+] to higher values with increasing [Ca2+], [K5/(K5 + 1)] will initially be small (<0.2, at which isometric force is 50% of maximal) and ktr will be dominated by k+7. However, as K5 increases to >0.2, ktr will increase dramatically as k+6[K5/(K5 + 1)] begins to dominate ktr, even though force continues to increase linearly. This behavior is shown experimentally in Fig. 4F. Thus this steep relationship between force and ktr follows directly from the regulation of strong attachment at individual cross-bridges and does not require a cooperativity between regulatory units, as was required to account for the steep steady-state isometric force-pCa relationship (Fig. 4E) in striated muscle.
Force-sarcomere length relationship.
Sarcomere length affects the maximum force and Ca2+ sensitivity of force in skeletal and cardiac muscle. The dependence of maximum tetanic tension in skeletal muscle, particularly the decline at long sarcomere lengths, has been used to support the cross-bridge model of muscle contraction (3), whereas the decline at short sarcomere lengths (the so-called ascending limb) has been less precisely explained. The ascending limb of the length-tension relationship is of great importance in cardiac muscle because it is the sarcomere length range over which the heart normally operates, giving rise to the Frank-Starling relationship.
Of additional importance is the increase in Ca2+ sensitivity seen with increasing sarcomere length in both skeletal and cardiac muscle. This effect is greater in cardiac muscle and contributes to its greater length dependency of activation, enhancing the Frank-Starling relationship. The reduction in Ca2+ sensitivity with decreasing sarcomere length may be most easily explained by increased distance between thick and thin filament (lattice spacing), in effect decreasing k+5. Strongly attached cross-bridges contribute to activation, along with Ca2+ binding, and the probability of these attachments (determined by k+5) at a given [Ca2+] decreases with increasing lattice spacing. The differences in the relative effect of sarcomere length in skeletal and cardiac muscle could result from different dependencies on strongly attached cross-bridges to activate and maintain activation of the thin filament, as discussed below.
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Differences between skeletal and cardiac muscle regulation |
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TopIntroductionStructural and biochemical basis...Mechanical correlates of the...Ca2+ regulation of contractionDifferences between skeletal and...SummaryReferences |
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). The major difference between cardiac and skeletal muscle is modulation of the extent of thin filament activation. Force development must be controlled mainly at the cellular level in cardiac muscle because each cardiac cell is activated on each beat. Thus each cell must be able to undergo the full dynamic range shown by the cardiac output. Contributing to this behavior in cardiac muscle cells are 1) incomplete thin filament activation with each transient increase in intracellular [Ca2+], 2) a less steep force-pCa relationship, 3) a greater change in force achieved during either submaximal or maximal Ca2+ activation with neural or hormonal modulation, and 4) a greater dependence of force on sarcomere length for a given level of Ca2+ activation.
The first of these properties arises in part from the phasic electrical activity of cardiac muscle, but incomplete thin filament activation and the other three important properties probably arise from the different regulatory protein isoforms in the two muscle types. The basic activation mechanisms in cardiac and skeletal muscle are the same, with some minor differences resulting from the properties of individual proteins. The cross-bridge scheme (Fig. 3) is the same (with differences in rate constants still to be determined), and the Ca2+-regulated step is probably the same. As discussed, Tm movement and activation depend on both Ca2+ binding to TnC (with Tn dissociation from actin) and strong binding of myosin to actin, amplified by the cooperativity mechanisms shown in Fig. 4. The direct activating effect of Ca2+ appears to be less in cardiac cells, so that they rely more on strong cross-bridge attachment for activation. In fact, cycling cross-bridge enhancement of Ca2+ binding is observed most prominently in cardiac muscle (12).
The result of greater reliance on cross-bridge attachment for activation in the heart is that factors that modulate strong (and perhaps weak) attachment of cross-bridges can have a greater effect on submaximal and maximal activation. This would include factors such as sarcomere length (discussed above) and modulation of cross-bridge structure through phosphorylation of the myosin regulatory light chain or myosin binding protein C, under either adrenergic or Ca2+ control. Phosphorylation of the myosin regulatory light chain and myosin binding protein C both result in movement of the myosin heads away from the thick filament and toward the thin filament, thus increasing the probability of attachment (13) and enhancing both the force-generating and activating effects of cross-bridges in the heart. This would allow greater modulation of contraction at the cellular level. The molecular properties of the regulatory protein isoforms responsible for these functional differences in skeletal and cardiac muscle regulation are currently under investigation.
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Summary |
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TopIntroductionStructural and biochemical basis...Mechanical correlates of the...Ca2+ regulation of contractionDifferences between skeletal and...SummaryReferences |
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Acknowledgments |
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This work was supported by grants from the National Institutes of Health [NS-08384 (A. M. Gordon), AR-30988 (E. Homsher), and HL-61683 (M. Regnier)].
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TopIntroductionStructural and biochemical basis...Mechanical correlates of the...Ca2+ regulation of contractionDifferences between skeletal and...SummaryReferences |
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