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(Circulation Research. 1999;84:862-865.)
© 1999 American Heart Association, Inc.

Editorial

Plasticity in the Dynamics of Myocardial Contraction

Ca²⁺, Crossbridge Kinetics, or Molecular Cooperation

Richard L. Moss

From the Department of Physiology, U.W. Cardiovascular Research Center, University of Wisconsin Medical School, Madison, Wis.

Correspondence to Richard L. Moss, PhD, Department of Physiology, U.W. Cardiovascular Research Center, University of Wisconsin Medical School, Madison, WI 53706. E-mail rlmoss{at}physiology.wisc.edu

Key Words: myocardium • contraction • kinetics • regulation • Ca²⁺

The myocardial twitch exhibits remarkable plasticity in terms of peak developed force and the kinetics of force development and relaxation. In the heart, such plasticity contributes to beat-to-beat adjustments in stroke volume and to changes in cardiac output as a consequence of altered sympathetic tone. There is ample awareness of some of the mechanisms underlying the variability in the cardiac twitch, including the Frank-Starling mechanism¹ and neurohumoral modulation of cardiac contractility.^{2 3} At the same time, the molecular mechanisms by which the twitch is altered are not completely understood, although most investigators would attribute changes in the twitch to a combination of alterations in Ca²⁺ delivery to the myoplasm, Ca²⁺ sensitivity of regulatory proteins, and kinetics of crossbridge interaction with actin. These are interactive variables in the sense that changes in Ca²⁺ delivery or Ca²⁺ sensitivity would be expected to change crossbridge interaction kinetics. Cooperative interactions among contractile and regulatory proteins comprise yet another variable that appears to regulate crossbridge interaction in myocardium, ie, most contemporary models include cooperativity as part of the Ca²⁺ activation process.^{4 5 6} Cooperation does not appear as a single process, but it most likely involves a combination of positive cooperativity in Ca²⁺ binding to the thin filament as well as effects of crossbridges to enhance Ca²⁺ binding, to enhance further crossbridge binding, and to speed the rate of crossbridge binding.⁶ Although cooperative mechanisms such as these might contribute significantly to the cardiac twitch, we do not yet know the degree to which these mechanisms contribute to the twitch or to beat-to-beat variations in the twitch.

In this issue of Circulation Research, an article by Wolska et al⁷ addresses possible roles of the thin-filament protein tropomyosin in regulating the dynamics of the myocardial twitch. This problem has considerable significance in view of the central role of tropomyosin in regulating interactions between myosin and actin, as well as recent reports^{8 9} that point mutations in tropomyosin are linked to some cases of familial hypertrophic cardiomyopathy. Using an impressive combination of transgenic, biochemical, and biophysical approaches, the authors test the idea that muscle-specific expression of tropomyosin (Tm) isoforms might account for differences in contractile performance of cardiac and skeletal muscles. Tm in adult mouse hearts is typically 100% isoform, but in the Wolska et al⁷ study, transgenic mouse hearts overexpressed the skeletal (ß) isoform of Tm,¹⁰ resulting in average ß-Tm levels of 65% and 61% of the totals in two transgenic lines.

Expression of ß-Tm significantly altered the cardiac twitch, which was assessed in paced free-floating myocytes by recording the time courses of myocyte shortening and relengthening. Maximum rates of contraction and relaxation were slowed in transgenic ß-Tm myocytes compared with wild-type, but the total extent of shortening was unaffected by Tm isoform. A potential explanation for altered rates is that crossbridge turnover kinetics (which are determined by crossbridge detachment rate) vary with Tm isoform. In this regard, Wolska et al⁷ show that isometric force is reduced (consistent with increased detachment rate) and maximum myofibrillar ATPase activity is reduced (consistent with decreased detachment rate) in skinned myocardium from ß-Tm transgenic hearts, results that are difficult to reconcile with a simple two-state model of contraction. However, more detailed analysis suggests that the fundamental rate of crossbridge detachment is unaffected by changes in Tm isoform. Both the Ca²⁺ sensitivities of force and ATPase activities were increased in the transgenic myocytes, ie, less Ca²⁺ was required to achieve a particular submaximal force or ATPase activity, but the ratio of ATPase activity to force, or "tension cost," was similar in transgenic and wild-type myocytes. Because the ratio of ATPase activity to force provides an estimate of the rate constant of crossbridge detachment,¹¹ it seems unlikely that the contractile effects of changes in Tm isoforms can be attributed to a change in crossbridge detachment rate.

On the other hand, changes in the force-pCa relationship provide important clues about the mechanism underlying slowed relaxation in transgenic myocytes. The increases in force at each submaximal Ca²⁺ and in the steepness of the force-pCa relationship in ß-Tm transgenic myocytes are consistent with an enhanced cooperative response of thin filaments to strongly bound crossbridges.^{4 5 6 12 13 14} Most models of regulation of contraction that are widely used include positive cooperative processes, particularly the effects of crossbridge binding to recruit additional crossbridges and to increase Ca²⁺ binding to troponin C. Such mechanisms amplify the responsiveness of myofilaments to submaximal levels of Ca²⁺, resulting in a greater force at each [Ca²⁺] and a steeper force-pCa relationship than would be expected if noncooperative binding of Ca²⁺ were the sole determinant of thin-filament activation. In this regard, the results of Wolska et al⁷ suggest that ß-Tm confers a greater cooperative response of the thin filament to strong binding crossbridges. As the authors point out, such a mechanism would be expected to contribute to slowed rates of relaxation, because sustained activation of thin filaments by strongly bound crossbridges would facilitate reattachment of crossbridges that dissociate from actin. This same kind of mechanism would also be expected to slow the rate of force development, at least according to the model of myocardial activation developed by Campbell.⁴ In this model, the rate of activation is slow at low levels of Ca²⁺ due to progressive cooperative recruitment of crossbridges to force-generating states, ie, initial binding induces further binding, and so forth, until force finally reaches a steady value. At high levels of activation, the rate of activation is much faster because of depletion of the pool of unbound crossbridges, ie, the force achieved due to initial binding of crossbridges is close to the final steady-state level. Alternatively, slowed contraction in ß-Tm transgenic myocytes may involve a reduction in the rate of crossbridge attachment or transition to force-generating states, although these possibilities were not pursued by Wolska et al.⁷

Implications for Regulation of the Dynamics of Contraction

The results of Wolska et al ⁷ provide strong evidence in support of the idea that cooperative activation of the thin filament is an important determinant of contraction dynamics in myocardium. Expression of ß-Tm increased the apparent cooperativity of isometric tension development, which the authors inferred from increased steepness of the force-pCa relationship and increased Ca²⁺ sensitivity of force, but slowed the rates of contraction and relaxation of force. There have certainly been many studies suggesting that cooperativity plays an important role in myocardial contraction,⁶ and models such as Campbell's⁴ have provided insights into possible mechanisms by which cooperation would influence the kinetics of contraction. In the Wolska et al⁷ study, the authors have shown that these mechanisms have physiological relevance in living myocytes. Furthermore, in view of recent findings that point mutations in Tm have been linked to some families with familial hypertrophic cardiomyopathy,^{8 9} it may be possible to explain functional abnormalities in the hearts of these individuals on the basis of alterations in thin-filament cooperativity or responsiveness to strong binding crossbridges. These results also raise the possibility that alterations in kinetics observed under conditions such as altered [Ca²⁺], force, or myofibrillar protein phosphorylations might be due to molecular mechanism(s) that involve modulation of the interaction of actin or regulatory proteins with Tm. Much work must still be done to identify and characterize the molecular interactions that mediate the effects of Tm on contraction kinetics.

A question that emerges from the study by Wolska et al ⁷ is the extent to which Tm regulates contraction kinetics in myocardium. Obviously, other proteins play important roles in determining kinetics, but it is not yet known which of these is dominant. Of particular interest in this regard are myosin heavy chains (MHC), because it has been shown that the kinetics of force development and relaxation are slow in myocardium expressing ß-MHC and much faster in myocardium expressing -MHC.¹⁵ Although some of these differences might be explained by differences in thin-filament responsiveness to alternative isoforms of MHC, it is evident from a number of studies that the rate of crossbridge detachment is much slower for ß-MHC than for -MHC.¹⁶ There is also evidence that myosin light chain (MLC) isoforms influence crossbridge interaction kinetics, because velocity of unloaded shortening varies with MLC content in skeletal muscle fibers¹⁶ and in in vitro motility assays.¹⁷ Finally, several investigators have found that myosin interaction kinetics vary with the level of ß-adrenergic stimulation of myocardium, presumably as a result of changes in phosphorylation of troponin I¹⁴ or myosin binding protein C.¹⁸ The fundamental frequency of crossbridge cycling in myocardium increases with ß stimulation,¹⁹ as does the maximum velocity of myocardial shortening.²⁰

Variations in Ca²⁺ concentration per se also influence the strength and speed of myocardial contraction. Several groups^{21 22 23} (but not all²⁴ ) have found that the rate of force development increases 5- to 10-fold as activation is increased from low to maximal levels in skinned myocardium. Such effects may involve direct actions of Ca²⁺ on kinetic transitions in the crossbridge interaction cycle, but this seems unlikely in view of the fact that Ca²⁺ has little²⁵ or no²⁶ effect on the kinetics of the force-generating step in either skeletal or cardiac muscles.²⁷ Instead, these effects of Ca²⁺ appear to be mediated by Ca²⁺-dependent alterations in the number of crossbridges strongly bound to the thin filament. Previous work has shown that increasing the number of strongly bound crossbridges at low levels of Ca²⁺ accelerates the rate of force development in both skeletal²⁸ and cardiac (D.P. Fitzsimons and R.L. Moss, unpublished data, 1999) muscles. Even at threshold levels of Ca²⁺, addition of strongly bound crossbridges accelerated force development to rates typical of maximally activated muscles. In the context of the Campbell⁴ model of activation, such an effect could be explained on the basis of saturation of the effect of strong binding crossbridges to cooperatively activate the thin filament. Considering the study by Wolska et al,⁷ it is possible that Tm isoforms would differentially affect the kinetics of cooperative activation of the thin filament by strongly bound crossbridges and thus contribute to variations in rates of force development in myocytes expressing one or the other Tm isoform. Experiments have yet to be done to directly test this possibility.

Differences in Skeletal and Cardiac Muscle Contraction

Another logical question from the study by Wolska et al⁷ is whether differences in Tm expression can account for differences in mechanical properties of heart and fast-twitch skeletal muscles. Certainly, the greater steepness of the force-pCa relationship in ß-Tm transgenic myocytes is consistent with the greater steepness of such relationships observed in skeletal muscle,⁶ although the Hill coefficient observed in ß-Tm myocytes does not approach the much higher Hill coefficients often reported in skeletal muscle.¹³ Of course, ß-Tm expression in the Wolska et al study was only about 60% of the total, and it may be that there would be greater changes in the Hill coefficient if expression were closer to 100%. Even when this is taken into account, it seems likely that Tm isoform is just one of several determinants of the steepness of the tension-pCa relationship and apparent cooperativity of force development.⁶

Wolska et al⁷ exploited the increased cooperativity of tension development in transgenic myocytes to test the idea that length-dependent changes in Ca²⁺ sensitivity of tension are due to an increased likelihood of crossbridge binding at long lengths, which in turn would be expected to enhance cooperative activation of force.^{29 30 31 32} Generally, cardiac muscle is believed to exhibit a greater sensitivity to changes in length,^{1 32 33} giving rise to the possibility that differences in sensitivity between cardiac and skeletal muscles might be due to differences in Tm isoforms. However, Wolska et al⁷ observed no change in the length dependence of the tension-pCa relationship when ß-Tm was expressed in place of -Tm. This result certainly suggests that Tm isoforms do not alter the length dependence of activation, although the authors have not eliminated the possibility that Tm plays a role in conferring length dependence to myocardial contraction. Also, the increase in apparent cooperativity of force development due to transgenic expression of ß-Tm was insufficient to mimic the greater cooperativity of force development in skeletal muscle, leaving open the question about whether differences in cooperative activation of the thin filament due to mechanisms other than Tm content can account for differences in length dependence of contraction in heart and skeletal muscles.

An obvious difference in the physiological performance of skeletal and cardiac muscles is the nature of the twitch in each kind of muscle: the skeletal twitch tends to be an explosive, all-or-none event, whereas the cardiac twitch is continuously graded on a beat-to-beat basis. Although Tm isoforms could contribute to such a difference, the results of Wolska et al⁷ do not directly address this issue, because the [Ca²⁺]_i transients vary considerably between the two muscles. [Ca²⁺]_i transients in skeletal muscle are sufficient to saturate regulatory sites even during a single twitch, making it likely that cooperative activation plays a relatively minor role in regulating contraction kinetics in this muscle type. In a model such as Campbell's,⁴ crossbridge attachment at high levels of Ca²⁺ is determined primarily by the attachment rate constant, with little or no modulation of rate by cooperative activation. Viewed another way, overall activation of the thin filament is related to the sum of effects of Ca²⁺ bound to troponin C and crossbridges bound to the thin filament.^{34 35} When Ca²⁺ concentration is high, there will be little additional activation of the thin filament because of strong binding bridges. In contrast, the situation in cardiac muscle must account for the fact that Ca²⁺ activation is submaximal in most twitches, ie, the rate of force development will vary on a twitch-to-twitch basis depending on the level of Ca²⁺ activation: at low levels of Ca²⁺, the rate will be slow but would be expected to increase as Ca²⁺ concentration is increased. Thus, low levels of Ca²⁺ activation will be associated with low rates of tension development because of the greater contributions of cooperative effects due to crossbridge binding.^{4 5 6 12 14 35} As pointed out by several investigators,^{6 14} such a mechanism leads to exquisite control of force development and the rate of force development during the cardiac twitch and would be expected to contribute to beat-to-beat variations in myocardial contraction.

In this regard, Wolska et al⁷ have not explained the basis for their observation that the extent of shortening during the twitch is virtually identical in wild-type (-Tm) and transgenic (ß-Tm) myocytes. Assuming that the Ca²⁺ transient is identical in the two cases, this result could be a fortuitous consequence of a slower rate of force development (due to greater cooperativity) and a larger pool of available crossbridges (evident as greater tension at each submaximal Ca²⁺ concentration) in the ß-Tm myocytes, ie, during an identical Ca²⁺ transient, the product of a slower rate of crossbridge attachment times a larger pool of crossbridges might be expected to equal the product of a faster rate of crossbridge attachment times a smaller pool of crossbridges. On the other hand, it is possible that extent of shortening is not a very accurate measure of crossbridge kinetic processes, because the large internal loads that appear to arise when cardiac muscle shortens at low levels of activation would be expected to dramatically slow shortening and the rate of crossbridge cycling.³⁶ If this is the case in the experiments reported by Wolska et al,⁷ it would be difficult to reach definitive conclusions about kinetics from the observation that the extent of shortening is unchanged. Overall, their study suggests that differences in Tm isoform expression contribute to altered twitch kinetics when all other variables (protein background, levels of [Ca²⁺]_i, phosphorylation of myofibrillar proteins) are kept constant, and the mechanism of this effect involves a change in cooperative activation of the thin filament. To determine the degree to which Tm isoforms contribute to differences in the rates of force development and relaxation in heart and skeletal muscles, experiments would have to be done to compare the kinetics of force development in preparations activated to similar submaximal levels. One approach would be to study skinned preparations that are activated to various levels by photorelease of Ca²⁺ from caged Ca²⁺.

Implications for Future Studies of Contractile Dynamics

The article by Wolska et al⁷ has significant practical implications for future studies of the regulation of contraction dynamics in myocardium. Most importantly from their results, there is a need to consider the possibility that alterations in the cooperative activation of cardiac thin filaments may account for changes in contractile dynamics because of experimental perturbations or in diseased myocardium. Recent models of myocardial contraction have included cooperative mechanisms, but the molecular details of cooperativity are likely to be more complex than assumed in these models. Given that the presence of cooperation complicates the analysis of mechanical data, it is also important to recognize that the relationships between contractile dynamics and fundamental rate constants of crossbridges are not always straightforward. In the study presented by Wolska et al, ultimate conclusions about possible effects of Tm isoforms on the rate constant of crossbridge dissociation were opposite to the predictions one would have made strictly on the basis of mechanical data, ie, if the rate of relaxation is slowed, an intuitive prediction is that the rate constant of dissociation is also slowed. However, by making careful measurements of ATPase activity on the same preparations as the mechanical measurements, the authors discovered that the dissociation rate constant was unchanged (at least in terms of a simple two-state model of crossbridge interaction). Only with additional experiments and close inspection of the data were the authors able to discern the possible participation of altered thin-filament cooperativity in the mechanical response.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Moss, R. L. Search for Related Content PubMed PubMed Citation Articles by Moss, R. L. Related Collections Gene regulation Genetically altered mice Smooth muscle proliferation and differentiation