Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway

Hai Wu, Beverly Rothermel, Shane Kanatous, Paul Rosenberg, Francisco J. Naya, John M. Shelton, Kelley A. Hutcheson, J. Michael DiMaio, Eric N. Olson, Rhonda Bassel-Duby, R. Sanders Williams

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Abstract

Gene expression in skeletal muscles of adult vertebrates is altered profoundly by changing patterns of contractile work. Here we observed that the functional activity of MEF2 transcription factors is stimulated by sustained periods of endurance exercise or motor nerve pacing, as assessed by expression in transgenic mice of a MEF2-dependent reporter gene (desMEF2-lacZ). This response is accompanied by transformation of specialized myofiber subtypes, and is blocked either by cyclosporin A, a specific chemical inhibitor of calcineurin, or by forced expression of the endogenous calcineurin inhibitory protein, myocyte-enriched calcineurin interacting protein 1. Calcineurin removes phosphate groups from MEF2, and augments the potency of the transcriptional activation domain of MEF2 fused to a heterologous DNA binding domain. Across a broad range, the enzymatic activity of calcineurin correlates directly with expression of endogenous genes that are transcriptionally activated by muscle contractions. These results delineate a molecular pathway in which calcineurin and MEF2 participate in the adaptive mechanisms by which skeletal myofibers acquire specialized contractile and metabolic properties as a function of changing patterns of muscle contraction.

Original languageEnglish (US)
Pages (from-to)6414-6423
Number of pages10
JournalEMBO Journal
Volume20
Issue number22
DOIs
StatePublished - Nov 15 2001

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Keywords

  • Calcineurin
  • Exercise
  • MEF2
  • Motor neuron
  • Skeletal muscle

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Wu, H., Rothermel, B., Kanatous, S., Rosenberg, P., Naya, F. J., Shelton, J. M., Hutcheson, K. A., DiMaio, J. M., Olson, E. N., Bassel-Duby, R., & Williams, R. S. (2001). Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway. EMBO Journal, 20(22), 6414-6423. https://doi.org/10.1093/emboj/20.22.6414