The capacity of the ventricles to perform work (i.e., power) is essential for moving blood throughout the circulatory system. Ventricular/myocyte power is determined ultimately by three myofibrillar properties;(i) the amount of force developed, (ii) the rate of force development, and (iii) the rate that myocardium shortens against loads. However, the sub-cellular processes that determine these properties are incompletely understood. The overall purpose of this study is to determine the sub-cellular factors that regulate myocyte power generating capacity. The specific objectives of the proposed studies are designed to determine (1) if PKA-mediated phosphorylation of cardiac troponin I (cTnI) is both necessary and sufficient to dictate sarcomere length dependence of force generation in cardiac myocytes, (2) how titin, MyBP-C, and myosin cross-bridges interact to modulate sarcomere length dependence of power output, and (3) to determine the time-course of changes in sarcomere length dependence of force, rates of force development, loaded shortening, and power output during the progression of heart failure. A rodent model of heart failure will be used to test the hypothesis that myocytes in compensated hearts exhibit greater sarcomere length dependence of force and power output due to a combination of greater expression of the larger N2BA titin isoform and greater PKA- induced myofibrillar protein phosphorylation, but with progression to ventricular failure sarcomere length dependence of force and power is markedly reduced due to reduced PKA- mediated phosphorylation of titin, MyBP-C, and cTnI. These studies are highly significant in their potential to determine the basis for the control of power-generating capacity in healthy myocytes and how these processes are altered with the progression of heart failure.
The goal of this project is to understand the factors that control the power generating capacity of individual cardiac myocytes. The control of myocyte power output dictates the pumping capacity of healthy hearts and dysregulation of these control factors contributes to pathological heart conditions, which afflict nearly 6 million citizens of th United States and is the most common cause of hospitalization of US citizens over 65 years of age.
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