Transcriptional Co-Activator PGC-1 Alpha Drives the Formation of Slow-Twitch Muscle Fibres

Nature. 2002 Aug 15;418(6899):797-801. doi: 10.1038/nature00904.

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-gamma co-activator-1 (PGC-1 alpha), 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-1 alpha is expressed preferentially in muscle enriched in type I fibres. When PGC-1 alpha 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-1 alpha 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-1 alpha 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-1 alpha is a principal factor regulating muscle fibre type determination.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Creatine Kinase / genetics
  • Creatine Kinase, MM Form
  • DNA-Binding Proteins / metabolism
  • Electric Stimulation
  • 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
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transcriptional Activation*
  • Transgenes / genetics
  • Troponin I / analysis

Substances

  • DNA-Binding Proteins
  • Isoenzymes
  • MEF2 Transcription Factors
  • Myogenic Regulatory Factors
  • Myoglobin
  • Transcription Factors
  • Troponin I
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • Creatine Kinase
  • Creatine Kinase, MM Form