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

Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21866-71. doi: 10.1073/pnas.1016089107. Epub 2010 Nov 24.


The coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α) coordinates a broad set of transcriptional programs that regulate the response of skeletal muscle to exercise. However, the complete transcriptional network controlled by PGC-1α 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-1α in cultured skeletal muscle cells. This analysis identified hypoxia-inducible factor 2 α (HIF2α) as a major PGC-1α target in skeletal muscle that is positively regulated by both exercise and β-adrenergic signaling. This transcriptional regulation of HIF2α is completely dependent on the PGC-1α/ERRα complex and is further modulated by the action of SIRT1. Transcriptional profiling of HIF2α target genes in primary myotubes suggested an unexpected role for HIF2α in the regulation of muscle fiber types, specifically enhancing the expression of a slow twitch gene program. The PGC-1α-mediated switch to slow, oxidative fibers in vitro is dependent on HIF2α, and mice with a muscle-specific knockout of HIF2α increase the expression of genes and proteins characteristic of a fast-twitch fiber-type switch. These data indicate that HIF2α acts downstream of PGC-1α as a key regulator of a muscle fiber-type program and the adaptive response to exercise.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cells, Cultured
  • ERRalpha Estrogen-Related Receptor
  • Exercise / physiology
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mice, Knockout
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle Fibers, Skeletal / microbiology*
  • Muscle Fibers, Skeletal / physiology*
  • Nitriles / pharmacology
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Thiazoles / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic


  • Basic Helix-Loop-Helix Transcription Factors
  • Nitriles
  • Receptors, Estrogen
  • Thiazoles
  • Transcription Factors
  • XCT790
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • endothelial PAS domain-containing protein 1
  • Sirt1 protein, mouse
  • Sirtuin 1