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

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) fibres1. 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 metabolism2,3,4. 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.

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Figure 1: Analysis of gene expression in wild-type (WT) and transgenic (Tg) muscle.
Figure 2: Morphological, histological and functional properties of skeletal muscles of the MCK–PGC-1α transgenic mouse (strain 31).
Figure 3: Co-activation of the calcineurin signalling pathway by PGC-1α.

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Acknowledgements

We thank R. Sanders Williams and A. Buonanno for providing reporter constructs, and J. Lawitts for generating transgenic mice. This work was supported by grants from the NIH to B.M.S, B.B.L and E.N.O. J.L. was supported by a postdoctoral fellowship from the American Heart Association.

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Correspondence to Bruce M. Spiegelman.

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Lin, J., Wu, H., Tarr, P. et al. Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418, 797–801 (2002). https://doi.org/10.1038/nature00904

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