title: 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 Ca(2+) sensitivity of force (pCa(50)) 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 degrees 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 k(tr) and the pCa(50) 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 muM NEM-S1 elicited similar increases in pCa(50,) 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.
authors.affiliation: Department of Physiology, University of Wisconsin School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706, USA. stelzer@physiology.wisc.edu
authors.forename: Julian E
authors.initials: JE
authors.lastname: Stelzer
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Fitzsimons
authors.forename: Richard L
authors.initials: RL
authors.lastname: Moss
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D002118:Calcium / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D015879:Myosin Subfragments / Q000378:metabolism; D009218:Myosins / Q000378:metabolism*; D011485:Protein Binding; D000099163:Myosin Binding Protein C
chemical_list: D000199:Actins; D002118:Calcium; D002352:Carrier Proteins; D015879:Myosin Subfragments; D009218:Myosins; D000099163:Myosin Binding Protein C