PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types

Kyle A. Rasbach, Rana K Gupta, Jorge L. Ruas, Jun Wu, Elnaz Naseri, Jennifer L. Estall, Bruce M. Spiegelman

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Abstract

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 hypoxiainducible 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 HIF2αtarget 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 musclefiber-type program and the adaptive response to exercise.

Original languageEnglish (US)
Pages (from-to)21866-21871
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number50
DOIs
StatePublished - Dec 14 2010

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Skeletal Muscle Fibers
Skeletal Muscle
Muscles
Gene Regulatory Networks
Adrenergic Agents
Muscle Cells
Genes
Transcription Factors
Proteins

ASJC Scopus subject areas

  • General

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PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types. / Rasbach, Kyle A.; Gupta, Rana K; Ruas, Jorge L.; Wu, Jun; Naseri, Elnaz; Estall, Jennifer L.; Spiegelman, Bruce M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 50, 14.12.2010, p. 21866-21871.

Research output: Contribution to journalArticle

Rasbach, Kyle A. ; Gupta, Rana K ; Ruas, Jorge L. ; Wu, Jun ; Naseri, Elnaz ; Estall, Jennifer L. ; Spiegelman, Bruce M. / PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 50. pp. 21866-21871.
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