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Molecular and Cellular Biology, December 2005, p. 10684-10694, Vol. 25, No. 24
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.24.10684-10694.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

PGC-1{alpha} Coactivates PDK4 Gene Expression via the Orphan Nuclear Receptor ERR{alpha}: a Mechanism for Transcriptional Control of Muscle Glucose Metabolism

Adam R. Wende,1,2 Janice M. Huss,1,2 Paul J. Schaeffer,1,2 Vincent Giguère,5 and Daniel P. Kelly1,2,3,4*

Center for Cardiovascular Research,1 Departments of Medicine,2 Molecular Biology and Pharmacology,3 Pediatrics, Washington University School of Medicine, St. Louis, Missouri,4 Molecular Oncology, McGill University Health Centre, Montreal, Quebec, Canada5

Received 18 May 2005/ Returned for modification 7 July 2005/ Accepted 21 September 2005

The transcriptional coactivator PGC-1{alpha} is a key regulator of energy metabolism, yet little is known about its role in control of substrate selection. We found that physiological stimuli known to induce PGC-1{alpha} expression in skeletal muscle coordinately upregulate the expression of pyruvate dehydrogenase kinase 4 (PDK4), a negative regulator of glucose oxidation. Forced expression of PGC-1{alpha} in C2C12 myotubes induced PDK4 mRNA and protein expression. PGC-1{alpha}-mediated activation of PDK4 expression was shown to occur at the transcriptional level and was mapped to a putative nuclear receptor binding site. Gel shift assays demonstrated that the PGC-1{alpha}-responsive element bound the estrogen-related receptor {alpha} (ERR{alpha}), a recently identified component of the PGC-1{alpha} signaling pathway. In addition, PGC-1{alpha} was shown to activate ERR{alpha} expression. Chromatin immunoprecipitation assays confirmed that PGC-1{alpha} and ERR{alpha} occupied the mPDK4 promoter in C2C12 myotubes. Additionally, transfection studies using ERR{alpha}-null primary fibroblasts demonstrated that ERR{alpha} is required for PGC-1{alpha}-mediated activation of the mPDK4 promoter. As predicted by the effects of PGC-1{alpha} on PDK4 gene transcription, overexpression of PGC-1{alpha} in C2C12 myotubes decreased glucose oxidation rates. These results identify the PDK4 gene as a new PGC-1{alpha}/ERR{alpha} target and suggest a mechanism whereby PGC-1{alpha} exerts reciprocal inhibitory influences on glucose catabolism while increasing alternate mitochondrial oxidative pathways in skeletal muscle.

* Corresponding author. Mailing address: Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO 63110. Phone: (314) 362-8908. Fax: (314) 362-0186. E-mail: dkelly{at}im.wustl.edu.

Molecular and Cellular Biology, December 2005, p. 10684-10694, Vol. 25, No. 24
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.24.10684-10694.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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