A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type

ER Chin, EN Olson, JA Richardson… - Genes & …, 1998 - genesdev.cshlp.org
ER Chin, EN Olson, JA Richardson, Q Yang, C Humphries, JM Shelton, H Wu, W Zhu…
Genes & development, 1998genesdev.cshlp.org
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 …
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.
genesdev.cshlp.org