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

Publication ,  Journal Article
Rasbach, KA; Gupta, RK; Ruas, JL; Wu, J; Naseri, E; Estall, JL; Spiegelman, BM
Published in: Proc Natl Acad Sci U S A
December 14, 2010

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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

December 14, 2010

Volume

107

Issue

50

Start / End Page

21866 / 21871

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Transcription Factors
  • Thiazoles
  • Sirtuin 1
  • Receptors, Estrogen
  • Nitriles
  • Muscle Fibers, Skeletal
  • Mice, Knockout
  • Mice
  • Humans
 

Citation

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Rasbach, K. A., Gupta, R. K., Ruas, J. L., Wu, J., Naseri, E., Estall, J. L., & Spiegelman, B. M. (2010). PGC-1alpha regulates a HIF2alpha-dependent switch in skeletal muscle fiber types. Proc Natl Acad Sci U S A, 107(50), 21866–21871. https://doi.org/10.1073/pnas.1016089107
Rasbach, Kyle A., Rana K. Gupta, Jorge L. Ruas, Jun Wu, Elnaz Naseri, Jennifer L. Estall, and Bruce M. Spiegelman. “PGC-1alpha regulates a HIF2alpha-dependent switch in skeletal muscle fiber types.Proc Natl Acad Sci U S A 107, no. 50 (December 14, 2010): 21866–71. https://doi.org/10.1073/pnas.1016089107.
Rasbach KA, Gupta RK, Ruas JL, Wu J, Naseri E, Estall JL, et al. 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.
Rasbach, Kyle A., et al. “PGC-1alpha regulates a HIF2alpha-dependent switch in skeletal muscle fiber types.Proc Natl Acad Sci U S A, vol. 107, no. 50, Dec. 2010, pp. 21866–71. Pubmed, doi:10.1073/pnas.1016089107.
Rasbach KA, Gupta RK, Ruas JL, Wu J, Naseri E, Estall JL, Spiegelman BM. PGC-1alpha regulates a HIF2alpha-dependent switch in skeletal muscle fiber types. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21866–21871.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

December 14, 2010

Volume

107

Issue

50

Start / End Page

21866 / 21871

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Transcription Factors
  • Thiazoles
  • Sirtuin 1
  • Receptors, Estrogen
  • Nitriles
  • Muscle Fibers, Skeletal
  • Mice, Knockout
  • Mice
  • Humans