title: Determination of rate constants for turnover of myosin isoforms in rat myocardium: implications for in vivo contractile kinetics.
abstract: The ventricles of small mammals express mostly alpha-myosin heavy chain (alpha-MHC), a fast isoform, whereas the ventricles of large mammals, including humans, express approximately 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 (f(app)) and detachment (g(app)) for myosins composed of 100% alpha-MHC 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 (k(tr)) in solutions of varying Ca(2+) concentrations. The rate of ATP utilization was approximately 2.5-fold higher in preparations expressing 100% alpha-MHC compared with those expressing only beta-MHC, whereas k(tr) was 2-fold faster in the alpha-MHC myocardium. From these variables, we calculated f(app) to be approximately threefold higher for alpha-MHC than beta-MHC and g(app) to be twofold higher in alpha-MHC. Mathematical modeling of isometric twitches predicted that small increases in alpha-MHC significantly increased the rate of force development. These results suggest that low-level expression of alpha-MHC has significant effects on contraction kinetics.
authors.affiliation: Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53711, USA. locher@physiology.wisc.edu
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Locher
authors.forename: Maria V
authors.initials: MV
authors.lastname: Razumova
authors.forename: Julian E
authors.initials: JE
authors.lastname: Stelzer
authors.forename: Holly S
authors.initials: HS
authors.lastname: Norman
authors.forename: Jitandrakumar R
authors.initials: JR
authors.lastname: Patel
authors.forename: Richard L
authors.initials: RL
authors.lastname: Moss
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D005260:Female; D007536:Isomerism; D007537:Isometric Contraction / Q000502:physiology; D007700:Kinetics; D015233:Models, Statistical; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology; D009210:Myofibrils / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism* / Q000502:physiology*; D009218:Myosins / Q000378:metabolism* / Q000502:physiology*; D011773:Pyruvates / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013965:Thyroidectomy
chemical_list: D011773:Pyruvates; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D018995:Myosin Heavy Chains; D009218:Myosins