The transcriptional coactivator PGC-1α is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis

High-capacity mitochondrial ATP production is essential for normal function of the adult heart, and evidence is emerging that mitochondrial derangements occur in common myocardial diseases. Previous overexpression studies have shown that the inducible transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1 alpha is capable of activating postnatal cardiac myocyte mitochondrial biogenesis. Recently, we generated mice deficient in PGC-1 alpha (PGC-1 alpha(-/-) mice), which survive with modestly blunted postnatal cardiac growth. To determine if PGC-1 alpha is essential for normal cardiac energy metabolic capacity, mitochondrial function experiments were performed on saponin-permeabilized myocardial fibers from PGC-1 alpha(-/-) mice. These experiments demonstrated reduced maximal (state 3) palmitoyl-L- carnitine respiration and increased maximal (state 3) pyruvate respiration in PGC-1 alpha(-/)-mice compared with PGC-1 alpha(-/-) controls. ATP synthesis rates obtained during maximal (state 3) respiration in permeabilized myocardial fibers were reduced for PGC-1 alpha(-/-) mice, whereas ATP produced per oxygen consumed (ATP/ O), a measure of metabolic efficiency, was decreased by 58% for PGC-1 alpha(-/-) fibers. Ex vivo isolated working heart experiments demonstrated that PGC-1 alpha(-/-) mice exhibited lower cardiac power, reduced palmitate oxidation, and increased reliance on glucose oxidation, with the latter likely a compensatory response. C-13 NMR revealed that hearts from PGC-1 alpha(-/-) mice exhibited a limited capacity to recruit triglyceride as a source for lipid oxidation during beta-adrenergic challenge. Consistent with reduced mitochondrial fatty acid oxidative enzyme gene expression, the total triglyceride content was greater in hearts of PGC-1 alpha(-/-) mice relative to PGC-1 alpha(-/-) following a fast. Overall, these results demonstrate that PGC-1 alpha is essential for the maintenance of maximal, efficient cardiac mitochondrial fatty acid oxidation, ATP synthesis, and myocardial lipid homeostasis.