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.

Calcineurin signaling in avian cardiovascular development

“…Together, these studies demonstrate that the early differentiation and diversification of cardiac myocytes is not dependent on calcineurin signal transduction. This finding is in contrast to the effects of CsA treatment or loss of CnA isoforms on the differentiation of cultured skeletal muscle myocytes and on the diversification of slow vs. fast skeletal muscle lineages (Abbott et al, 1998;Chin et al, 1998;Delling et al, 2000;Parsons et al, 2003). In general, calcineurin inhibition leads to loss of slow muscle fibers in cultured skeletal myocytes or genetically altered mice.…”

Effect of calcineurin inhibitors on myotoxic activity of crotoxin and Bothrops asper phospholipase A2 myotoxins in vivo and in vitro

“…(b) The heterodimeric nature of CTX might play a role in the calcineurin dependent myotoxic effect; accordingly, subunit A might be somehow involved in calcineurin activation. (c) Since calcineurin is involved in muscle fiber type determination (Chin et al, 1998), our results may reflect the different specificity of these PLA 2 s toward different fiber types. CTX and other neurotoxic PLA 2 myotoxins have preference for type I fibers (Harris et al, 1975;Salvini et al, 2001), whereas types I and II fibers present a similar susceptibility to a viperid Lys-49 myotoxic PLA 2 (Morini et al, 1998).…”

“…This phosphatase has been involved in muscle differentiation (Abbott et al, 1998), fiber type determination (Chin et al, 1998) and hypertrophy (Musaro et al, 1999). Calcineurin binds to and activates nuclear factor of activated T cells (NFAT) (Rao et al, 1997;Crabtree, 1999), which targets the nucleus, dimerizes with other nuclear factors and modulates transcription of target genes (Rao et al, 1997).…”

Mitochondrial biogenesis: Which part of “NO” do we understand?

“…Taking skeletal muscle as an example, there are several fiber-type-specific properties that could conceivably impinge upon NO metabolism. These include fiber-type-specific differences in calcium transients, (19) in the levels of the bioactive NO scavenger myoglobin, (20) and in the relative expression of neuronal NOS versus eNOS. (21) Clarifying the exact nature of the signaling pathway, and potential tissue-specific differences in its various elements, is therefore critical to delineating its mode(s) of action, and assessing how widespread an impact NO has on regulating mitochondrial properties.…”