The heart consumes tremendous amounts of energy. Loss of normal energy homeostasis is a hallmark of cardiac failure. The nuclear receptor co-activator PPAR-Gamma Co-activator 1 (PGC1)-alpha is a well-established global regulator of energy homeostasis in numerous tissues; strong evidence suggests that it does so in the heart as well. Evidence also points to modulation of PGC1-alpha in heart failure, coincident with important changes in energy homeostasis. PGC1-beta, a close homologue of PGC1-alpha, has closely overlapping functions and is equally abundant in the heart, yet no definitive demonstration of its role in normal or diseases heart has been made. The precise mechanisms whereby PGC1-alpha and beta act in the heart remain poorly understood. Here, we hypothesize that PGC1-alpha and -beta play essential roles in regulating the heart's ability to meet energy demands. To address this hypothesis, the metabolic and contractile functions of hearts from mice deficient for either PGC1-alpha or beta will be investigated. Genetic expression in these hearts will also be studied in search of better insight into the mechanisms of PGC1-alpha and beta in this tissue. We also hypothesize that down-regulation of PGC1-alpha is a maladaptive response that contributes to the development of heart failure. To address this question, we will determine if preventing down-regulation of PGC1-alpha can prevent heart failure. The ultimate goals of this project are twofold: first, to help decipher the molecular mechanisms that control metabolism and contractile function in normal and diseased hearts; and second, to transition the applicant to an independent career of investigation in cardiac physiology and transcriptional mechanisms using genetic manipulations of mice as a tool.
