Cardiac muscle cells typically express three myosin isoforms, designated as V1 (high ATPase), V2, and V3 (low ATPase). The pattern of this expression is thought to regulate the intrinsic functional properties of the heart in a wide range of species. Although thyroid hormone (T3) is known to be the chief """"""""up"""""""" regulator of V1 expression, recent findings suggest that high carbohydrate provision can also serve as an """"""""up"""""""" regulator independent of T3 under certain conditions. Since the dependency of carbohydrate as a major energy source appears to be greater in rodents exercised by swimming as opposed to running, factors associated with carbohydrate metabolism in the heart may be critical in accounting for the higher degree of """"""""up"""""""" regulation of V1 expression that occurs in response to training by the former as compared to the latter. The goal of this proposal is to test the hypothesis that the pattern of cardiac isoform expression in response to exercise training is regulated in accordance with the relative degree that carbohydrates contribute to the total energy requirement of the heart during exercise. To test this hypothesis, a series of experiments are proposed using animal models with either """"""""up"""""""" or """"""""down"""""""" regulated cardiac myosin expression in which the utilization potential of carbohydrate by the heart during exercise will be either increased or decreased. This will be accomplished by dietary manipulation coupled with pharmacologic blockers impacting on processes associated with either carbohydrate mobilization or metabolism. Measurements on appropriate nontrained and trained groups of the various manipulated models will focus on cardiac myosin ATPase and isoform expression in the context of the animal's thyroid status and steady state resting and exercise cardiac metabolic patterns. These experiments will thus integrate the important variable of substrate energy provision with the exercise stimulus in expanding our understanding of cardiac myosin isoform regulation.
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