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

¹ University of Wisconsin-Madison

^* To whom correspondence should be addressed. E-mail: stelzer{at}physiology.wisc.edu.

Submitted on November 18, 2005
Revised on January 6, 2006
Accepted on 14 February 2006

	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 (k_tr) 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, non-force-generating analog of myosin subfragment-1 (NEM-S1). In the absence of NEM-S1, maximal force and k_tr and the pCa₅₀ of isometric force did not differ between WT and cMyBP-C^-/- myocardium; however, ablation of cMyBP-C accelerated k_tr 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 k_tr at submaximal forces and thereby markedly reduce the activation-dependence of k_tr 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.

Key Words: NEM-S1, cardiac muscle, cooperativity, cross-bridge kinetics, rate of force development

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