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

John J Lehman; Sihem Boudina; Natasha Hausler Banke; Nandakumar Sambandam; Xianlin Han; Deanna M Young; Teresa C Leone; Richard W Gross; E. Douglas Lewandowski; E. Dale Abel; Daniel P Kelly

doi:10.1152/ajpheart.00081.2008

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

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

John J Lehman, Sihem Boudina, Natasha Hausler Banke, Nandakumar Sambandam, Xianlin Han, Deanna M Young, Teresa C Leone, Richard W Gross, E. Douglas Lewandowski, E. Dale Abel, …

American journal of physiology. Heart and circulatory physiology, Vol.295(1), pp.H185-H196

07/2008

DOI: 10.1152/ajpheart.00081.2008

PMCID: PMC2494758

PMID: 18487436

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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-γ coactivator (PGC)-1α is capable of activating postnatal cardiac myocyte mitochondrial biogenesis. Recently, we generated mice deficient in PGC-1α (PGC-1α −/− mice), which survive with modestly blunted postnatal cardiac growth. To determine if PGC-1α is essential for normal cardiac energy metabolic capacity, mitochondrial function experiments were performed on saponin-permeabilized myocardial fibers from PGC-1α −/− mice. These experiments demonstrated reduced maximal (state 3) palmitoyl- l -carnitine respiration and increased maximal (state 3) pyruvate respiration in PGC-1α −/− mice compared with PGC-1α +/+ controls. ATP synthesis rates obtained during maximal (state 3) respiration in permeabilized myocardial fibers were reduced for PGC-1α −/− mice, whereas ATP produced per oxygen consumed (ATP/O), a measure of metabolic efficiency, was decreased by 58% for PGC-1α −/− fibers. Ex vivo isolated working heart experiments demonstrated that PGC-1α −/− 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-1α −/− mice exhibited a limited capacity to recruit triglyceride as a source for lipid oxidation during β-adrenergic challenge. Consistent with reduced mitochondrial fatty acid oxidative enzyme gene expression, the total triglyceride content was greater in hearts of PGC-1α −/− mice relative to PGC-1α +/+ following a fast. Overall, these results demonstrate that PGC-1α is essential for the maintenance of maximal, efficient cardiac mitochondrial fatty acid oxidation, ATP synthesis, and myocardial lipid homeostasis.

nuclear receptors

cardiac energetics

heart failure

peroxisome proliferator-activated receptor-γ coactivator-1α

left ventricular hypertrophy

ATP

Details

Title: Subtitle: The transcriptional coactivator PGC-1α is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis
Creators: John J Lehman - Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
Sihem Boudina - Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
Natasha Hausler Banke - Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
Nandakumar Sambandam - Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
Xianlin Han - Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
Deanna M Young - Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
Teresa C Leone - Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
Richard W Gross - Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
E. Douglas Lewandowski - Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
E. Dale Abel - Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
Daniel P Kelly - Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
Resource Type: Journal article
Publication Details: American journal of physiology. Heart and circulatory physiology, Vol.295(1), pp.H185-H196
DOI: 10.1152/ajpheart.00081.2008
PMID: 18487436
PMCID: PMC2494758
NLM abbreviation: Am J Physiol Heart Circ Physiol
ISSN: 0363-6135
eISSN: 1522-1539
Publisher: American Physiological Society
Language: English
Date published: 07/2008
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024522502771

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