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

ABSTRACT: 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 ?-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.

SUBMITTER: Rasbach KA

PROVIDER: S-EPMC3003089 | biostudies-other | 2010 Dec

REPOSITORIES: biostudies-other

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

Rasbach Kyle A KA Gupta Rana K RK Ruas Jorge L JL Wu Jun J Naseri Elnaz E Estall Jennifer L JL Spiegelman Bruce M BM

Proceedings of the National Academy of Sciences of the United States of America 20101124 50

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. T ...[more]

PMID: 21106753

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Project description:Title: Total Skeletal Muscle PGC-1 Deficiency Uncouples Mitochondrial Derangements from Fiber Type Determination and Insulin Sensitivity Abstract: Evidence is emerging that the PGC-1 coactivators serve a critical role in skeletal muscle metabolism, function, and disease. Mice with total PGC-1 deficiency in skeletal muscle (PGC-1α-/- βf/f/MLC-Cre mice) were generated and characterized. PGC-1α-/-βf/f/MLC-Cre mice exhibit a dramatic reduction in exercise performance compared to single PGC-1α- or PGC-1β-deficient mice and wild-type controls. The exercise phenotype of the PGC-1α-/-βf/f/MLC-Cre mice was associated with a marked diminution in muscle oxidative capacity and mitochondrial structural derangements consistent with fusion/fission and biogenic defects together with rapid depletion of muscle glycogen stores during exercise. Surprisingly, the skeletal muscle fiber type profile of the PGC-1α-/-βf/f/MLCCre mice was not significantly different than the wild-type mice. Moreover, insulin sensitivity and glucose tolerance were also not altered in the PGC-1α-/-βf/f/MLC-Cre mice. Taken together, we conclude that PGC-1 coactivators are necessary for the oxidative and mitochondrial programs of skeletal muscle but are dispensable for fundamental fiber type determination and insulin sensitivity. RNA from PGC-1alpha-/- beta f/f/Mlc1fcre was obtained and gene expression pattern compared with PGC-1alpha -/-, PGC-1beta f/f, and PGC-1beta f/f/Mlc1fCre controls. Results file descriptions: 1. GSE23365_skfloxAKO_PPexcl_genesup_GEO-8-16-2010: This table contains genes that were upregulated ≥2.0 fold in gastrocnemius muscle from PGC-1alpha-/- - mice, PGC-1beta f/f/Mlc1fCre mice and PGC-1alpha-/- - beta f/f/Mlc1fCre mice. All groups are normalized to PGC-1beta f/f mice and values are expressed as mean±SEM. The column “description’ contains the gene name, and the column “ID” contains Agilent probe names. 2. GSE23365_skfloxAKO_PPexcl_genesdown_GEO-8-16-2010 This table contains genes that were downregulated ≤0.7 fold in gastrocnemius muscle from PGC-1alpha-/- - mice, PGC-1beta f/f/Mlc1fCre mice and PGC-1alpha-/- - beta f/f/Mlc1fCre mice. All groups are normalized to PGC-1beta f/f mice and values are expressed as mean±SEM. The column “description’ contains the gene name, and the column “ID” contains Agilent probe names.

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

Publications

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

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