A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type.

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Chin, ER; Olson, EN; Richardson, JA; Yang, Q; Humphries, C; Shelton, JM; Wu, H; Zhu, W; Bassel-Duby, R; Williams, RS

Published Date

  • August 15, 1998

Published In

Volume / Issue

  • 12 / 16

Start / End Page

  • 2499 - 2509

PubMed ID

  • 9716403

International Standard Serial Number (ISSN)

  • 0890-9369

Language

  • eng

Conference Location

  • United States