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

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.

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@article{Chin1998ACT, title={A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type.}, author={Eva R. Chin and Eric N Olson and James A. Richardson and Q Yang and Caroline Humphries and John M Shelton and H Wu and W Zhu and Rhonda S. Bassel-Duby and R . Sanders Williams}, journal={Genes & development}, year={1998}, volume={12 16}, pages={2499-509} }