The role of Calcineurin in skeletal muscle differentiation

Abstract

1. Strong evidence suggests that Calcineurin levels are higher in fast muscle fibers compared to slow-twitch in resting skeletal muscles. Activation of the Calcineurin in 4 skeletal muscle myocytes selectively up-regulates slowfiber- specific gene promoters through a mechanism involving the transcription factor NFATcI. The Calcineurin pathway itself was down-regulated when rat skeletal muscles were chronically stimulated at 10 FIz for a period of 3 weeks illustrating adaptation.
2. Skeletal muscles that received chronic stimulation treatment showed a significant increase in mitochondrial content. Histochemical studies detected a change towards the slow phenotype, through the decrease of fast-twitch Type
Bib fiber content in fast skeletal muscles. Metabolic activity was not significantly affected through this period of chronic stimulation.
3. Cyclosporin A was not able to prevent this initial transition towards the slow phenotype, even though 3 weeks of 10 Hz chronic stimulation was insufficient to cause marked changes in the skeletal muscle metabolism. This suggests an incomplete fast-to-slow transformation was elicited by these conditions.
4. Stimulation of L6 myocytes with the calcium ionophore 4-Bromo-A23 187 (I 0 M) a partial fast-to-slow transformation occurred. It is likely that this change was brought about by a number of processes including NFAT
translocation to the nucleus.