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J. Biol. Chem., Vol. 280, Issue 39, 33588-33598, September 30, 2005
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Peroxisome Proliferator-activated Receptor-
Co-activator 1
-mediated Metabolic Remodeling of Skeletal Myocytes Mimics Exercise Training and Reverses Lipid-induced Mitochondrial Inefficiency*
1
From the
Departments of Medicine and Pharmacology & Cancer Biology, and the Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina 27710, the Department of Medicine, Duke University, Durham, North Carolina 27710, and the ¶Department of Physiology, Brody Medical School, East Carolina University, Greenville, North Carolina 27834
Peroxisome proliferator-activated receptor-
co-activator 1
(PGC1) is a promiscuous co-activator that plays a key role in regulating mitochondrial biogenesis and fuel homeostasis. Emergent evidence links decreased skeletal muscle PGC1 activity and coincident impairments in mitochondrial performance to the development of insulin resistance in humans. Here we used rodent models to demonstrate that muscle mitochondrial efficiency is compromised by diet-induced obesity and is subsequently rescued by exercise training. Chronic high fat feeding caused accelerated rates of incomplete fatty acid oxidation and accumulation of 
-oxidative intermediates. The capacity of muscle mitochondria to fully oxidize a heavy influx of fatty acid depended on factors such as fiber type and exercise training and was positively correlated with expression levels of PGC1. Likewise, an efficient lipid-induced substrate switch in cultured myocytes depended on adenovirus-mediated increases in PGC1 expression. Our results supported a novel paradigm in which a high lipid supply, occurring under conditions of low PGC1, provokes a disconnect between mitochondrial -oxidation and tricarboxylic acid cycle activity. Conversely, the metabolic remodeling that occurred in response to PGC1 overexpression favored a shift from incomplete to complete -oxidation. We proposed that PGC1 enables muscle mitochondria to better cope with a high lipid load, possibly reflecting a fundamental metabolic benefit of exercise training.
Received for publication, July 13, 2005 , and in revised form, July 29, 2005.
* This work was supported by National Institutes of Health Grants DK-56112 (to D. M. M.) and P01 DK58398 (to C. B. N.), the American Diabetes Association (to D. M. M.), and GlaxoSmithKline. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: 4321 Medical Park Dr., Ste. 200, Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC 27704. Tel.: 919-479-2328; Fax: 919-477-0632; E-mail: muoio{at}duke.edu.
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