title: The transcriptional coactivator PGC-1alpha is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis.
abstract: 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)-1alpha is capable of activating postnatal cardiac myocyte mitochondrial biogenesis. Recently, we generated mice deficient in PGC-1alpha (PGC-1alpha(-/-) mice), which survive with modestly blunted postnatal cardiac growth. To determine if PGC-1alpha is essential for normal cardiac energy metabolic capacity, mitochondrial function experiments were performed on saponin-permeabilized myocardial fibers from PGC-1alpha(-/-) mice. These experiments demonstrated reduced maximal (state 3) palmitoyl-l-carnitine respiration and increased maximal (state 3) pyruvate respiration in PGC-1alpha(-/-) mice compared with PGC-1alpha(+/+) controls. ATP synthesis rates obtained during maximal (state 3) respiration in permeabilized myocardial fibers were reduced for PGC-1alpha(-/-) mice, whereas ATP produced per oxygen consumed (ATP/O), a measure of metabolic efficiency, was decreased by 58% for PGC-1alpha(-/-) fibers. Ex vivo isolated working heart experiments demonstrated that PGC-1alpha(-/-) mice exhibited lower cardiac power, reduced palmitate oxidation, and increased reliance on glucose oxidation, with the latter likely a compensatory response. (13)C NMR revealed that hearts from PGC-1alpha(-/-) 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-1alpha(-/-) mice relative to PGC-1alpha(+/+) following a fast. Overall, these results demonstrate that PGC-1alpha is essential for the maintenance of maximal, efficient cardiac mitochondrial fatty acid oxidation, ATP synthesis, and myocardial lipid homeostasis.
authors.affiliation: Center for Cardiovascular Research, Washington Univ. School of Medicine, St. Louis, MO 63110, USA. jlehman@wustl.edu
authors.forename: John J
authors.initials: JJ
authors.lastname: Lehman
authors.forename: Sihem
authors.initials: S
authors.lastname: Boudina
authors.forename: Natasha Hausler
authors.initials: NH
authors.lastname: Banke
authors.forename: Nandakumar
authors.initials: N
authors.lastname: Sambandam
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Young
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Leone
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gross
authors.forename: E Douglas
authors.initials: ED
authors.lastname: Lewandowski
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D010172:Palmitoylcarnitine / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D019289:Pyruvic Acid / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; D010172:Palmitoylcarnitine; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D005947:Glucose; D007545:Isoproterenol