Abstract
Several lines of evidence suggest that the primary effect of hypertrophic cardiomyopathy mutations in human β-cardiac myosin is hypercontractility of the heart, which leads to subsequent hypertrophy, fibrosis, and myofilament disarray. Here, I describe three perspectives on the molecular basis of this hypercontractility. The first is that hypercontractility results from changes in the fundamental parameters of the actin-activated β-cardiac myosin chemo-mechanical ATPase cycle. The second considers that hypercontractility results from an increase in the number of functionally accessible heads in the sarcomere for interaction with actin. The final and third perspective is that load dependence of contractility is affected by cardiomyopathy mutations and small-molecule effectors in a manner that changes the power output of cardiac contraction. Experimental approaches associated with each perspective are described along with concepts of therapeutic approaches that could prove valuable in treating hypertrophic cardiomyopathy.
Highlights
The most common form of inherited heart disease is hypertrophic cardiomyopathy (HCM), which affects more than 1 in 500 individuals [32, 54, 74]
Out of hundreds of known HCM mutations, ~ 35% occur in human β-cardiac myosin, ~ 35% in cardiac myosin-binding protein-C (MyBPC; consisting of 13 domains, C0, PA, C1, M, C2, C3, C4, C5, C6, C7, C8, C9, and C10 [30]), and most of the rest are distributed amongst other sarcomeric proteins, especially in the troponins and tropomyosin [47, 102]
The data from all three perspectives inform on the molecular basis of hypercontractility caused by HCM mutations
Summary
The most common form of inherited heart disease is hypertrophic cardiomyopathy (HCM), which affects more than 1 in 500 individuals [32, 54, 74]. The ensemble force that myosin produces in the sarcomere is Fens = Fint·Na·ts/tc, where Fint is the intrinsic force of the myosin molecule, Na is the number of functionally accessible heads for interaction with actin, and ts/tc is the duty ratio that is determined by the kinetic parameters of the ATPase cycle, where ts is myosin’s strongly bound state time to actin and tc is the total Consistent with this point of view, all three parameters (ATPase activity, velocity, and Fint) increase significantly when human β-cardiac myosins carrying the early-onset HCM mutations D239N and H251N are compared to wildtype (WT) myosin [2]. The unifying hypothesis that the majority of myosin HCM mutations weaken a sequestered state, increasing the number of heads functionally accessible for interacting with actin, causing the hypercontractility seen clinically, is attractive, and experimental evidence is accumulating in favor of it. The mechanistic effects of OM are the same at all OM concentrations, and the effects are a summation of what is expected from varying ratios of OMbound heads and OM-free heads [51]
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