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Dynamic coupling of regulated binding sites and cycling myosin heads in striated muscle.

ABSTRACT: In an activated muscle, binding sites on the thin filament and myosin heads switch frequently between different states. Because the status of the binding sites influences the status of the heads, and vice versa, the binding sites and myosin heads are dynamically coupled. The functional consequences of this coupling were investigated using MyoSim, a new computer model of muscle. MyoSim extends existing models based on Huxley-type distribution techniques by incorporating Ca(2+) activation and cooperative effects. It can also simulate arbitrary cross-bridge schemes set by the researcher. Initial calculations investigated the effects of altering the relative speeds of binding-site and cross-bridge kinetics, and of manipulating cooperative processes. Subsequent tests fitted simulated force records to experimental data recorded using permeabilized myocardial preparations. These calculations suggest that the rate of force development at maximum activation is limited by myosin cycling kinetics, whereas the rate at lower levels of activation is limited by how quickly binding sites become available. Additional tests investigated the behavior of transiently activated cells by driving simulations with experimentally recorded Ca(2+) signals. The unloaded shortening profile of a twitching myocyte could be reproduced using a model with two myosin states, cooperative activation, and strain-dependent kinetics. Collectively, these results demonstrate that dynamic coupling of binding sites and myosin heads is important for contractile function.

SUBMITTER: Campbell KS

PROVIDER: S-EPMC3933939 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Myosin-binding protein C (MyBP-C) is a critical regulator of muscle performance that was first identified through its strong binding interactions with myosin, the force-generating protein of muscle. Almost simultaneously with its discovery, MyBP-C was soon found to bind to actin, the physiological catalyst for myosin's activity. However, the two observations posed an apparent paradox, in part because interactions of MyBP-C with myosin were on the thick filament, whereas MyBP-C interactions with actin were on the thin filament. Despite the intervening decades since these initial discoveries, it is only recently that the dual binding modes of MyBP-C are becoming reconciled in models that place MyBP-C at a central position between actin and myosin, where MyBP-C alternately stabilizes a newly discovered super-relaxed state (SRX) of myosin on thick filaments in resting muscle and then prolongs the "on" state of actin on thin filaments in active muscle. Recognition of these dual, alternating functions of MyBP-C reveals how it is central to the regulation of both muscle contraction and relaxation. The purpose of this Viewpoint is to briefly summarize the roles of MyBP-C in binding to myosin and actin and then to highlight a possible new role for MyBP-C in inducing and damping oscillatory waves of contraction and relaxation. Because the contractile waves bear similarity to cycles of contraction and relaxation in insect flight muscles, which evolved for fast, energetically efficient contraction, the ability of MyBP-C to damp so-called spontaneous oscillatory contractions (SPOCs) has broad implications for previously unrecognized regulatory mechanisms in vertebrate striated muscle. While the molecular mechanisms by which MyBP-C can function as a wave maker or a wave breaker are just beginning to be explored, it is likely that MyBP-C dual interactions with both myosin and actin will continue to be important for understanding the new functions of this enigmatic protein.

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Dynamic coupling of regulated binding sites and cycling myosin heads in striated muscle.

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