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Am J Physiol Heart Circ Physiol (April 24, 2009). doi:10.1152/ajpheart.00922.2008
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Submitted on August 21, 2008
Revised on March 27, 2009
Accepted on April 14, 2009

DETERMINATION OF RATE CONSTANTS FOR TURNOVER OF MYOSIN ISOFORMS IN RAT MYOCARDIUM: IMPLICATIONS FOR IN VIVO CONTRACTILE KINETICS

Matthew R Locher1*, Maria V. Razumova2, Julian Stelzer3, Holly S. Norman1, Jitandrakumar R Patel1, and Richard L. Moss1

1 University of Wisconsin Medical School
2 University of Washington - Seattle
3 Case Western Reserve University

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

The ventricles of small mammals express mostly {alpha} MHC, a fast isoform, while the ventricles of large mammals including humans express ~10% {alpha} MHC on a predominately {beta} MHC (slow isoform) background. In failing human ventricles the amount of {alpha} MHC is dramatically reduced leading to the hypothesis that even small amounts of {alpha} MHC on a predominately {beta} MHC background confer significantly higher rates of force development in healthy ventricles. To test this hypothesis it is necessary to determine the fundamental rate constants of cross-bridge attachment (fapp) and detachment (gapp) for myosins comprised of 100% {alpha} or {beta} MHC which can then be used to calculate twitch time courses for muscles expressing variable ratios of MHC isoforms. In the present study, rat skinned trabeculae expressing either 100% {alpha} MHC or 100% {beta} MHC were used to measure ATPase activity, isometric force, and the rate constant of force redevelopment (ktr) in solutions of varying [Ca2+]. The rate of ATP utilization was approximately 2.5-fold higher in preparations expressing 100% {alpha} MHC compared to those expressing only {alpha} MHC, while ktr was 2-fold faster in {beta} MHC myocardium. From these variables, we calculated fapp to be approximately 3-fold higher for {alpha} than {beta} MHC, and gapp to be 2-fold higher in {alpha} MHC. Mathematical modeling of isometric twitches predicted that small increases in {alpha} MHC significantly increased the rate of force development (dF/dtmax). These results suggest that low-level expression of {alpha} MHC has significant effects on contraction kinetics.







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