PGC-1α coactivates PDK4 gene expression via the orphan nuclear receptor ERRα:: a mechanism for transcriptional control of muscle glucose metabolism

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/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.