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

Jiandie Lin, Hai Wu, Paul T. Tarr, Chen Yu Zhang, Zhidan Wu, Olivier Boss, Laura F. Michael, Pere Puigserver, Elji Isotani, Eric N. Olson, Bradford B. Lowell, Rhonda Bassel-Duby, Bruce M. Spiegelman

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1813 Scopus citations

Abstract

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 coactivator-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.

Original languageEnglish (US)
Pages (from-to)797-801
Number of pages5
JournalNature
Volume418
Issue number6899
DOIs
StatePublished - Aug 15 2002

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    Lin, J., Wu, H., Tarr, P. T., Zhang, C. Y., Wu, Z., Boss, O., Michael, L. F., Puigserver, P., Isotani, E., Olson, E. N., Lowell, B. B., Bassel-Duby, R., & Spiegelman, B. M. (2002). Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature, 418(6899), 797-801. https://doi.org/10.1038/nature00904