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Loaded Shortening, Power Output, and Rate of Force Redevelopment Are Increased With Knockout of Cardiac Myosin Binding Protein-C

From the Department of Medical Pharmacology and Physiology (F.S.K., K.S.M.), University of Missouri, Columbia, Mo; and the Department of Physiology (S.P.H., R.L.M.), University of Wisconsin, Madison, Wis.

Correspondence to Kerry S. McDonald, PhD, One Hospital Dr, MA415 MSB, Columbia, MO 65212. E-mail McDonaldKS{at}missouri.edu

Myosin binding protein-C (MyBP-C) is localized to the thick filaments of striated muscle where it appears to have both structural and regulatory functions. Importantly, mutations in the cardiac MyBP-C gene are associated with familial hypertrophic cardiomyopathy. The purpose of this study was to examine the role that MyBP-C plays in regulating force, power output, and force development rates in cardiac myocytes. Skinned cardiac myocytes from wild-type (WT) and MyBP-C knockout (MyBP-C^-/-) mice were attached between a force transducer and position motor. Force, loaded shortening velocities, and rates of force redevelopment were measured during both maximal and half-maximal Ca²⁺ activations. Isometric force was not different between the two groups with force being 17.0±7.2 and 20.5±3.1 kN/m² in wild-type and MyBP-C^-/- myocytes, respectively. Peak normalized power output was significantly increased by 26% in MyBP-C^-/- myocytes (0.15±0.01 versus 0.19±0.03 P/P_o · ML/sec) during maximal Ca²⁺ activations. Interestingly, peak power output in MyBP-C^-/- myocytes was increased to an even greater extent (46%, 0.09±0.03 versus 0.14±0.02 P/P_o · ML/sec) during half-maximal Ca²⁺ activations. There was also an effect on the rate constant of force redevelopment (k_tr) during half-maximal Ca²⁺ activations, with k_tr being significantly greater in MyBP-C^-/- myocytes (WT=5.8±0.9 s^-1 versus MyBP-C^-/-=7.7±1.7 s^-1). These results suggest that cMyBP-C is an important regulator of myocardial work capacity whereby MyBP-C acts to limit power output.

Key Words: cardiac myocytes • myosin binding protein-C • sarcomere proteins • cardiac contractility • power output

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