| First Author | Rasbach KA | Year | 2010 |
| Journal | Proc Natl Acad Sci U S A | Volume | 107 |
| Issue | 50 | Pages | 21866-71 |
| PubMed ID | 21106753 | Mgi Jnum | J:167144 |
| Mgi Id | MGI:4867337 | Doi | 10.1073/pnas.1016089107 |
| Citation | Rasbach KA, et al. (2010) PGC-1alpha regulates a HIF2alpha-dependent switch in skeletal muscle fiber types. Proc Natl Acad Sci U S A 107(50):21866-71 |
| abstractText | The coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1alpha) coordinates a broad set of transcriptional programs that regulate the response of skeletal muscle to exercise. However, the complete transcriptional network controlled by PGC-1alpha 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-1alpha in cultured skeletal muscle cells. This analysis identified hypoxia-inducible factor 2 alpha (HIF2alpha) as a major PGC-1alpha target in skeletal muscle that is positively regulated by both exercise and beta-adrenergic signaling. This transcriptional regulation of HIF2alpha is completely dependent on the PGC-1alpha/ERRalpha complex and is further modulated by the action of SIRT1. Transcriptional profiling of HIF2alpha target genes in primary myotubes suggested an unexpected role for HIF2alpha in the regulation of muscle fiber types, specifically enhancing the expression of a slow twitch gene program. The PGC-1alpha-mediated switch to slow, oxidative fibers in vitro is dependent on HIF2alpha, and mice with a muscle-specific knockout of HIF2alpha increase the expression of genes and proteins characteristic of a fast-twitch fiber-type switch. These data indicate that HIF2alpha acts downstream of PGC-1alpha as a key regulator of a muscle fiber-type program and the adaptive response to exercise. |
