A CALCINEURIN-DEPENDENT TRANSCRIPTIONAL PATHWAY CONTROLS SKELETAL-MUSCLE FIBER-TYPE

Slow- and fast-twitch myofibers of adult skeletal muscles express uniq ue sets of muscle-specific genes, and these distinctive programs of ge ne expression are controlled by variations in motor neuron activity. I t is well established that, as a consequence of more frequent neural s timulation, slow fibers maintain higher levels of intracellular free c alcium than fast fibers, but the mechanisms by which calcium may funct ion as a messenger linking nerve activity to changes in gene expressio n in skeletal muscle have been unknown. Here, fiber-type-specific gene expression in skeletal muscles is shown to be controlled by a signali ng 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 pr omoters. Conversely, inhibition of calcineurin activity by administrat ion of cyclosporin A to intact animals promotes slow-to-fast fiber tra nsformation. Transcriptional activation of slow-fiber-specific transcr iption appears to be mediated by a combinatorial mechanism involving p roteins of the NFAT and MEF2 families. These results identify a molecu lar mechanism by which different patterns of motor nerve activity prom ote selective changes in gene expression to establish the specialized characteristics of slow and fast myofibers.