Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres

• Published in: Nature (London) Vol. 418; no. 6899; pp. 797 - 801
• Main Authors: Spiegelman, Bruce M, Lin, Jiandie, Wu, Hai, Tarr, Paul T, Zhang, Chen-Yu, Wu, Zhidan, Boss, Olivier, Michael, Laura F, Puigserver, Pere, Isotani, Eiji, Olson, Eric N, Lowell, Bradford B, Bassel-Duby, Rhonda
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 15-08-2002; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Cell Line; Creatine Kinase - genetics; Creatine Kinase, MM Form; DNA-Binding Proteins - metabolism; Electric Stimulation; Fundamental and applied biological sciences. Psychology; Isoenzymes - genetics; MEF2 Transcription Factors; Mice; Mice, Transgenic; Muscle Fatigue; Muscle Fibers, Slow-Twitch - metabolism; Muscle, Skeletal - growth & development; Muscle, Skeletal - metabolism; Myogenic Regulatory Factors; Myoglobin - analysis; Promoter Regions, Genetic - genetics; Space life sciences; Striated muscle. Tendons; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Transcriptional Activation; Transgenes - genetics; Troponin I - analysis; Vertebrates: osteoarticular system, musculoskeletal system; Myofibril; Nuclear receptor; Transcription; Rodentia; Muscular fiber type I; Transgenic animal; Activation; Gene expression; Muscular fiber type II; Striated muscle; Metabolism; Peroxisome proliferator; Protein; Vertebrata; Mitochondria; Mammalia; Mouse
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature00904

The biochemical basis for the regulation of fibre-type determination in skeletal muscle is not well understood. In addition to the expression of particular myofibrillar proteins, type I (slow-twitch) fibres are much higher in mitochondrial content and are more dependent on oxidative metabolism than type II (fast-twitch) fibres. We have previously identified a transcriptional co-activator, peroxisome-proliferator-activated receptor-γ co-activator-1 (PGC-1α), which is expressed in several tissues including brown fat and skeletal muscle, and that activates mitochondrial biogenesis and oxidative metabolism. We show here that PGC-1α is expressed preferentially in muscle enriched in type I fibres. When PGC-1α is expressed at physiological levels in transgenic mice driven by a muscle creatine kinase (MCK) promoter, a fibre type conversion is observed: muscles normally rich in type II fibres are redder and activate genes of mitochondrial oxidative metabolism. Notably, putative type II muscles from PGC-1α transgenic mice also express proteins characteristic of type I fibres, such as troponin I (slow) and myoglobin, and show a much greater resistance to electrically stimulated fatigue. Using fibre-type-specific promoters, we show in cultured muscle cells that PGC-1α activates transcription in cooperation with Mef2 proteins and serves as a target for calcineurin signalling, which has been implicated in slow fibre gene expression. These data indicate that PGC-1α is a principal factor regulating muscle fibre type determination.