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Letters to Nature

Nature 418, 797-801 (15 August 2002) | doi:10.1038/nature00904; Received 19 April 2002; Accepted 29 May 2002

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

Jiandie Lin1, Hai Wu2, Paul T. Tarr1, Chen-Yu Zhang3, Zhidan Wu1, Olivier Boss3, Laura F. Michael1, Pere Puigserver1, Eiji Isotani4, Eric N. Olson2, Bradford B. Lowell3, Rhonda Bassel-Duby5 & Bruce M. Spiegelman1

  1. Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
  2. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
  3. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
  4. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
  5. Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA

Correspondence to: Bruce M. Spiegelman1 Correspondence and requests for materials should be addressed to B.M.S. (e-mail: Email: bruce_spiegelman@dfci.harvard.edu).

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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) fibres1. We have previously identified a transcriptional co-activator, peroxisome-proliferator-activated receptor-gamma co-activator-1 (PGC-1alpha), which is expressed in several tissues including brown fat and skeletal muscle, and that activates mitochondrial biogenesis and oxidative metabolism2, 3, 4. We show here that PGC-1alpha is expressed preferentially in muscle enriched in type I fibres. When PGC-1alpha 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-1alpha 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-1alpha 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-1alpha is a principal factor regulating muscle fibre type determination.