The ups and downs of gene regulation by electrical activity in skeletal muscles

Adult skeletal muscles retain an adaptive capacity to switch between slow-and fast-twitch properties that are largely dependent on motoneuron activity. Our studies on the transcriptional regulation of the Troponin I slow (TnIs) and fast (TnIf) genes uncovered a dual mechanism of transcriptional enhancement and repression by a single activity pattern, that promotes the phenotypic differences among myofibers while preserving their adaptive capacity. Using the Tnf Fast Intronic Regulatory Element (FIRE), we initially demonstrated that fast-patterned activity (infrequent, high frequency depolarization) is necessary to up-regulate FIRE-dependent transcription and that its effect differs dramatically from muscle denervation. Hence, the "fast muscle program" is not a default state mimicked simply by denervation or muscle inactivity. Next, we found that slow-patterned activity (tonic, slow frequency stimulation) selectively represses FIRE-dependent transcription while enhancing transcription from the TnIs Slow Upstream Regulatory Element. Unexpectedly, repression of the TnIf FIRE by slow-patterned activity is mediated by an NFAT element that directly binds NFATc1, a transcription factor that translocates to the nucleus selectively by slow-pattern depolarization and has been implicated in the up-regulation of the slow muscle program. Transfection of siRNAs targeting NFATc1 or mutation of the TnIFIRE NFAT site result in the upregulation of FIRE-dependent transcription in slow muscle, but have no effect in fast muscle. These findings demonstrate a novel function of NFAT as a repressor of transcription of fast contractile genes in slow muscles and, more importantly, they illustrate how specific activity patterns can enhance the phenotypic differences among fibretypes by differentially regulating transcription in a use-dependent manner while retaining the adaptive properties of adult muscles.