Nerve activity-dependent modulation of calcineurin signaling in adult fastand slow skeletal muscle fibers

This study tested the hypothesis that calcineurin signaling is modulated in skeletal muscle cells by fluctuations in nerve-mediated activity. We show that dephosphorylation of NFATc1, MEF2A, and MEF2D transcription factors by calcineurin in all muscle types is dependent on nerve activity and positiv ely correlated with muscle usage under normal weightbearing conditions. Wit h increased nerve-mediated activity, calcineurin dephosphorylation of these targets was found to be potentiated in a way that paralleled the higher mu scle activation profiles associated with functional overload or nerve elect rical stimulation conditions. We also establish that muscle activity must b e sustained above native levels for calcineurin-dependent dephosphorylation of MEF2A and MEF2D to be transduced into an increase in MEF2 transcription al function, suggesting that calcineurin cooperates with other activity-lin ked events to signal via these proteins. Finally, examination of individual fiber responses to overload and nerve electrical stimulation revealed that calcineurin-MEF2 signaling occurs in all fiber types but most readily in f ibers that are normally least active (i.e. those expressing IIx and IIb myo sin heavy chain (MHC)), suggesting that signaling via this phosphatase is a lso dependent upon the activation history of the muscle cell.