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J. Biol. Chem., Vol. 282, Issue 50, 36642-36651, December 14, 2007

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A Role for the Transcriptional Coactivator PGC-1 in Muscle Refueling^*

Adam R. Wende¹, Paul J. Schaeffer, Glendon J. Parker^¶, Christoph Zechner², Dong-Ho Han³, May M. Chen, Chad R. Hancock, John J. Lehman, Janice M. Huss, Donald A. McClain^¶, John O. Holloszy, and Daniel P. Kelly^||**4

From the Center for Cardiovascular Research, Departments of Medicine, ^||Molecular Biology and Pharmacology, and ^**Pediatrics, Washington University School of Medicine, St. Louis, Missouri, 63110 and the ^¶Veterans Affairs Medical Center and Division of Endocrinology, University of Utah School of Medicine, Salt Lake City, Utah, 84112

The transcriptional coactivator peroxisome proliferator-activated receptor coactivator-1 (PGC-1) has been identified as an inducible regulator of mitochondrial function. Skeletal muscle PGC-1 expression is induced post-exercise. Therefore, we sought to determine its role in the regulation of muscle fuel metabolism. Studies were performed using conditional, muscle-specific, PGC-1 gain-of-function and constitutive, generalized, loss-of-function mice. Forced expression of PGC-1 increased muscle glucose uptake concomitant with augmentation of glycogen stores, a metabolic response similar to post-exercise recovery. Induction of muscle PGC-1 expression prevented muscle glycogen depletion during exercise. Conversely, PGC-1-deficient animals exhibited reduced rates of muscle glycogen repletion post-exercise. PGC-1 was shown to increase muscle glycogen stores via several mechanisms including stimulation of glucose import, suppression of glycolytic flux, and by down-regulation of the expression of glycogen phosphorylase and its activating kinase, phosphorylase kinase . These findings identify PGC-1 as a critical regulator of skeletal muscle fuel stores.

Received for publication, August 21, 2007 , and in revised form, October 9, 2007.

^* This work was supported in part by National Institutes of Health Grant RO1 DK045416 and Diabetes Research and Training Center Grant P60 DK020579. All histologic studies performed in the Digestive Disease Research Core Center at Washington University were supported by National Institutes of Health Grant P30 DK052574. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ Supported by Washington University School of Medicine Cardiovascular Training Grant T32 HL007275.

² Recipient of Deutsche Forschungsgemeinschaft Research Fellowship ZE 796/2-1.

³ Supported by National Institutes of Health Grant RO1 AG000425.

⁴ To whom correspondence should be addressed: Center for Cardiovascular Research, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-8908; Fax: 314-362-0186; E-mail: dkelly{at}im.wustl.edu.

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