PGC-1alpha regulates a HIF2alpha-dependent switch in skeletal muscle fiber types.

ABSTRACT: The coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 ? (PGC-1?) coordinates a broad set of transcriptional programs that regulate the response of skeletal muscle to exercise. However, the complete transcriptional network controlled by PGC-1? has not been described. In this study, we used a qPCR-based screen of all known transcriptional components (Quanttrx) to identify transcription factors that are quantitatively regulated by PGC-1? in cultured skeletal muscle cells. This analysis identified hypoxia-inducible factor 2 ? (HIF2?) as a major PGC-1? target in skeletal muscle that is positively regulated by both exercise and ?-adrenergic signaling. This transcriptional regulation of HIF2? is completely dependent on the PGC-1?/ERR? complex and is further modulated by the action of SIRT1. Transcriptional profiling of HIF2? target genes in primary myotubes suggested an unexpected role for HIF2? in the regulation of muscle fiber types, specifically enhancing the expression of a slow twitch gene program. The PGC-1?-mediated switch to slow, oxidative fibers in vitro is dependent on HIF2?, and mice with a muscle-specific knockout of HIF2? increase the expression of genes and proteins characteristic of a fast-twitch fiber-type switch. These data indicate that HIF2? acts downstream of PGC-1? as a key regulator of a muscle fiber-type program and the adaptive response to exercise.

SUBMITTER: Rasbach KA 

PROVIDER: S-EPMC3003089 | biostudies-other | 2010 Dec

REPOSITORIES: biostudies-other