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Originally published as Biophys J. BioFAST on March 2, 2006.
doi:10.1529/biophysj.105.078147
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Biophysical Journal 90:4119-4127 (2006)
© 2006 The Biophysical Society

Ablation of Myosin-Binding Protein-C Accelerates Force Development in Mouse Myocardium

Julian E. Stelzer, Daniel P. Fitzsimons and Richard L. Moss

Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706

Correspondence: Address reprint requests to Julian E. Stelzer, Dept. of Physiology, University of Wisconsin School of Medicine, 1300 University Ave., Madison, WI 53706. Tel.: 608-262-0694; Fax: 608-265-5512; E-mail: stelzer{at}physiology.wisc.edu.

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.




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