The overall purpose of this project is to understand the cellular and sub-cellular mechanisms that determine the work capacity of the heart.
The specific aims of this study include determining how physiological factors including sarcomere length, myosin heavy chain (MyHC), titin isoforms, and phosphorylation status of myofibrillar proteins modulate the power output generating capacity of cardiac myocytes. An additional aim addresses how power output and its sarcomere length dependence are modified in two mouse models of dilated cardiomyopathy.
A final aim uses transgenic animals to determine the specific phosphorylation sites that are responsible for PKA and PKC modulation of power output. Myocyte power output is of utmost importance in maintaining the pump capacity of the ventricles and diseases leading to heart failure yield depressed myocyte power output yet the biochemical and biophysical mechanisms underlying these changes are unknown. To investigate potential mechanism regulating power output a skinned myocyte preparation will be used to directly measure myofibrillar power output and how it is modulated by sarcomere length, phosphorylation of myofibrillar proteins, and during the progression of heart failure. Experiments are designed to test the hypothesis that sarcomere length dependence of power output is modulated by passive mechanical properties of the sarcomeric protein titin. Additional experiments will test the central theme that during the progression of heart failure compensated hearts express more (3-MyHC, which is compensatory by enhancing sarcomere length dependence of myocyte power output. However, the subsequent transition to myocardial decompensation that leads to heart failure arises, in part, from depressed length dependence of power resulting from altered titin isoform expression and changes in the phosphorylation status of sarcomeric proteins. These ideas will be directly addressed by examining how altered titin structure/isoforms, modified protein kinase-induced phosphorylation status of myofibrils, and dilated cardiomyopathy affects sarcomere length dependence of myocyte power output. Overall, results from this study should help elucidate the molecular mechanisms that regulate power output in normal myocardium and provide a better understanding of the factors that impair myocyte power output in diseased hearts.
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