A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type

Eva R. Chin, Eric N. Olson, James A. Richardson, Quan Yang, Caroline Humphries, John M. Shelton, Hai Wu, Weiguang Zhu, Rhonda Bassel-Duby, R. Sanders Williams

Research output: Contribution to journalArticle

784 Scopus citations

Abstract

Slow- and fast-twitch myofibers of adult skeletal muscles express unique sets of muscle-specific genes, and these distinctive programs of gene expression are controlled by variations in motor neuron activity. It is well established that, as a consequence of more frequent neural stimulation, slow fibers maintain higher levels of intracellular free calcium than fast fibers, but the mechanisms by which calcium may function as a messenger linking nerve activity to changes in gene expression in skeletal muscle have been unknown. Here, fiber-type-specific gene expression in skeletal muscles is shown to be controlled by a signaling pathway that involves calcineurin, a cyclosporin- sensitive, calcium-regulated serine/threonine phosphatase. Activation of calcineurin in skeletal myocytes selectively up-regulates slow-fiber-specific gene promoters. Conversely, inhibition of calcineurin activity by administration of cyclosporin A to intact animals promotes slow-to-fast fiber transformation. Transcriptional activation of slow-fiber-specific transcription appears to be mediated by a combinatorial mechanism involving proteins of the NFAT and MEF2 families. These results identify a molecular mechanism by which different patterns of motor nerve activity promote selective changes in gene expression to establish the specialized characteristics of slow and fast myofibers.

Original languageEnglish (US)
Pages (from-to)2499-2509
Number of pages11
JournalGenes and Development
Volume12
Issue number16
DOIs
StatePublished - Aug 15 1998

Keywords

  • Cyclosporin A
  • Exercise
  • MEF2
  • Myoglobin
  • Myosin
  • NFAT

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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