A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type

TLDR

Slow- and fast-twitch skeletal muscle fibers express distinct gene programs regulated by motor neuron activity, with slow fibers exhibiting higher intracellular calcium levels, yet the calcium‑mediated signaling that links nerve activity to gene expression remains unclear. Transcriptional activation of slow‑fiber‑specific genes is mediated by a combinatorial mechanism involving NFAT and MEF2 family proteins. Calcineurin signaling regulates slow‑fiber gene expression, where its activation upregulates slow‑fiber promoters and its inhibition induces slow‑to‑fast fiber transformation, establishing a pathway that links motor nerve activity to muscle fiber specialization.

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.