Ablation of myosin-binding protein-C accelerates force development in mouse myocardium

Abstract

Myosin-binding protein-C (MyBP-C) is a thick filament-associated protein that binds tightly to myosin. Given that cMyBP-C may act to modulate cooperative activation of the thin filament by constraining the availability of myosin cross-bridges for binding to actin, we investigated the role of MyBP-C in the regulation of cardiac muscle contraction. We assessed the Ca2+ sensitivity of force (pCa50) and the activation dependence of the rate of force redevelopment (ktr) in skinned myocardium isolated from wild-type (WT) and cMyBP-C null (cMyBP-C-/-) mice. Mechanical measurements were performed at 22°C in the absence and presence of a strong-binding, nonforce-generating analog of myosin subfragment-1 (NEM-S1). In the absence of NEM-S1, maximal force and ktr and the pCa50 of isometric force did not differ between WT and cMyBP-C-/- myocardium; however, ablation of cMyBP-C-accelerated ktr at each submaximal force. Treatment of WT and cMyBP-C-/- myocardium with 3 μM NEM-S1 elicited similar increases in pCa50, but the effects of NEM-S1 to increase ktr at submaximal forces and thereby markedly reduce the activation dependence of ktr occurred to a greater degree in cMyBP-C-/- myocardium. Together, these results support the idea that cMyBP-C normally acts to constrain the interaction between myosin and actin, which in turn limits steady-state force development and the kinetics of cross-bridge interaction. © 2006 by the Biophysical Society.