期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：50
页码：21866-21871
DOI：10.1073/pnas.1016089107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 {beta}-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.
