title: 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.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
authors.forename: Clinton
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
authors.forename: Jonas
authors.initials: J
authors.lastname: Schwan
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, USA. Electronic address: stuart.campbell@yale.edu.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Campbell
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003198:Computer Simulation; D007700:Kinetics; D018345:Mice, Knockout; D008954:Models, Biological; D009200:Myocardial Contraction; D011485:Protein Binding; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C
keywords: Cardiomyopathy; Computational modeling; Myofilament cooperativity; Myosin-binding protein C