Effects of low-level α-myosin heavy chain expression on contractile kinetics in porcine myocardium.

Locher MR, Razumova MV, Stelzer JE, Norman HS, Moss RL. Effects of low-level alpha-myosin heavy chain expression on contractile kinetics in porcine myocardium. Am J Physiol Heart Circ Physiol 300: H869-H878, 2011. First published January 7, 2011; doi:10.1152/ajpheart.00452.2010.-Myosin heavy chain (MHC) isoforms are principal determinants of work capacity in mammalian ventricular myocardium. The ventricles of large mammals including humans normally express similar to 10% alpha-MHC on a predominantly beta-MHC background, while in failing human ventricles alpha-MHC is virtually eliminated, suggesting that low-level alpha-MHC expression in normal myocardium can accelerate the kinetics of contraction and augment systolic function. To test this hypothesis in a model similar to human myocardium we determined composite rate constants of cross-bridge attachment (f(app)) and detachment (g(app)) in porcine myocardium expressing either 100% alpha-MHC or 100% beta-MHC in order to predict the MHC isoform-specific effect on twitch kinetics. Right atrial (similar to 100% alpha-MHC) and left ventricular (similar to 100% beta-MHC) tissue was used to measure myosin ATPase activity, isometric force, and the rate constant of force redevelopment (k(tr)) in solutions of varying Ca2+ concentration. The rate of ATP utilization and k(tr) were approximately ninefold higher in atrial compared with ventricular myocardium, while tension cost was approximately eightfold greater in atrial myocardium. From these values, we calculated f(app) to be similar to 10-fold higher in alpha- compared with beta-MHC, while g(app) was 8-fold higher in alpha-MHC. Mathematical modeling of an isometric twitch using these rate constants predicts that the expression of 10% alpha-MHC increases the maximal rate of rise of force (dF/dt(max)) by 92% compared with 0% alpha-MHC. These results suggest that low-level expression of alpha-MHC significantly accelerates myocardial twitch kinetics, thereby enhancing systolic function in large mammalian myocardium.