Assuming That Myosin-Binding Protein C Interacts With Both Myosin And Actin Can Explain Its Role In Skinned Fiber Mechanics

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. Which of these interactions is of greatest physiological relevance remains unclear. 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 minimal effect on the rate of force redevelopment (ktr). In contrast, cMyBP-C binding to actin increases myofilament Ca2+ sensitivity and slows ktr at sub-maximal Ca2+ values. This slowing is due to cooperation between cMyBP-C ‘crossbridges’ and traditional myosin crossbridges as they co-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. Assuming 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. A possible advantage of this arrangement is the tuning of cardiac lusitropy independent of contractility through modification of a single protein target. Furthermore, results 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. Our model provides specific hypotheses and mechanistic descriptions to assist ongoing experimental work toward unraveling cMyBP-Cu0027s contribution to inherited cardiomyopathy and phosphoregulation in normal cardiac muscle regulation.