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Slowing of contractile kinetics by myosin-binding protein C can be explained by its cooperative binding to the thin filament.

ABSTRACT: Cardiac myosin binding protein C (cMyBP-C) is a thick filament-associated protein that participates in the regulation of muscle contraction. Simplified in vitro systems show that cMyBP-C binds not only to myosin, but also to the actin filament. The physiological significance of these separate binding interactions remains unclear, as does the question of whether either interaction is capable of explaining the behavior of intact muscle from which cMyBP-C has been removed. We have used a computational model to explore the characteristic effects of myosin-binding versus actin-binding by cMyBP-C. Simulations suggest that myosin-cMyBP-C interactions reduce peak force and Ca2 + sensitivity of the myofilaments, but have no appreciable effect on the rate of force redevelopment (ktr). In contrast, cMyBP-C binding to actin increases myofilament Ca2 + sensitivity and slows ktrat sub-maximal Ca2 + values. This slowing is due to cooperation between cMyBP-C ‘crossbridges’ and traditional myosin crossbridges as they bind to and activate the actin thin filament. We further observed that an overall recapitulation of skinned myocardial data from wild type and cMyBP-C knockout mice requires the interaction of cMyBP-C with of both of its binding targets in our model. The assumption of significant interactions with both partners was also sufficient to explain published effects of cMyBP-C ablation on twitch kinetics. These modeling results strongly support the view that both binding interactions play critical roles in the physiology of intact muscle. Furthermore, they suggest that the widely observed phenomenon of slowed force development in the presence of cMyBP-C may actually be a manifestation of cooperative binding of this protein to the thin filament.

SUBMITTER: Wang C

PROVIDER: S-EPMC4826328 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Slowing of contractile kinetics by myosin-binding protein C can be explained by its cooperative binding to the thin filament.

Wang Clinton C Schwan Jonas J Campbell Stuart G SG

Journal of molecular and cellular cardiology 20151008

Cardiac myosin binding protein C (cMyBP-C) is a thick filament-associated protein that participates in the regulation of muscle contraction. Simplified in vitro systems show that cMyBP-C binds not only to myosin, but also to the actin filament. The physiological significance of these separate binding interactions remains unclear, as does the question of whether either interaction is capable of explaining the behavior of intact muscle from which cMyBP-C has been removed. We have used a computatio ...[more]

PMID: 26454159

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Project description:Hypertrophic cardiomyopathy (HCM) caused by mutations in cardiac myosin-binding protein-C (cMyBP-C) is a heterogenous disease in which the phenotypic presentation is influenced by genetic, environmental, and developmental factors. Though mouse models have been used extensively to study the contractile effects of cMyBP-C ablation, early postnatal hypertrophic and dilatory remodeling may overshadow primary contractile defects. The use of a murine engineered cardiac tissue (mECT) model of cMyBP-C ablation in the present study permits delineation of the primary contractile kinetic abnormalities in an intact tissue model under mechanical loading conditions in the absence of confounding remodeling events. We generated mechanically integrated mECT using isolated postnatal day 1 mouse cardiac cells from both wild-type (WT) and cMyBP-C-null hearts. After culturing for 1 wk to establish coordinated spontaneous contraction, we measured twitch force and Ca(2+) transients at 37°C during pacing at 6 and 9 Hz, with and without dobutamine. Compared with WT, the cMyBP-C-null mECT demonstrated faster late contraction kinetics and significantly faster early relaxation kinetics with no difference in Ca(2+) transient kinetics. Strikingly, the ability of cMyBP-C-null mECT to increase contractile kinetics in response to adrenergic stimulation and increased pacing frequency were severely impaired. We conclude that cMyBP-C ablation results in constitutively accelerated contractile kinetics with preserved peak force with minimal contractile kinetic reserve. These functional abnormalities precede the development of the hypertrophic phenotype and do not result from alterations in Ca(2+) transient kinetics, suggesting that alterations in contractile velocity may serve as the primary functional trigger for the development of hypertrophy in this model of HCM. Our findings strongly support a mechanism in which cMyBP-C functions as a physiological brake on contraction by positioning myosin heads away from the thin filament, a constraint which is removed upon adrenergic stimulation or cMyBP-C ablation.

Project description:Cells require mechanical forces for their physiological functions. The forces are generated mainly from molecular interactions between actin filaments, cross-linking proteins, and myosin motors in the actin cytoskeleton. To better understand the molecular interactions, many studies employed myosin motility assays with actin filaments propelled by myosin heads fixed on a surface. Various interesting behaviors of actin filaments have been observed in the motility assay experiments. Despite the popularity of the motility assays, there were only a few computational models designed for simulating the motility assay systems. Most of the previous models have limitations which precluded full understanding of molecular origins for behaviors of actin filaments. In this study, we used an agent-based computational model based on Brownian dynamics for simulating the motility assay system. Our model rigorously describes the mechanics, dynamics, and interactions of actin filaments, cross-linking proteins, and molecular motors. Using the model, we first investigated how properties of actin filaments and motors affect gliding motions of actin filaments without volume-exclusion effects as a base study. We found that actin filaments can continuously glide at relative fast speed only when they are sufficiently longer than the average spacing between neighboring motors and that the gliding speed of F-actins shows a biphasic dependence on processivity of motors. Then, we showed that volume-exclusion effects between actin filaments can induce diverse collective movements and alignment of actin filaments, thus creating thick bundles and ring-like structures in the absence of cross-linking proteins. Lastly, we demonstrated that cross-linking proteins can lead to distinct contractile behaviors of actin networks depending on the density and kinetics of the cross-linking proteins. Results from our study show the ability of our model to simulate the motility assay system under various conditions and provide insights into understanding of different behaviors of actin filaments.

Dataset Information

Slowing of contractile kinetics by myosin-binding protein C can be explained by its cooperative binding to the thin filament.

Publications

Slowing of contractile kinetics by myosin-binding protein C can be explained by its cooperative binding to the thin filament.

Similar Datasets

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