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The ups and downs of gene regulation by electrical activity in skeletal muscles Rana ZA; Gundersen K; Buonanno AJ Muscle Res Cell Motil 2009[Dec]; 30 (7-8): 255-60Adult 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 fibre-types by differentially regulating transcription in a use-dependent manner while retaining the adaptive properties of adult muscles.|*Gene Expression Regulation[MESH]|*Up-Regulation[MESH]|Adult[MESH]|Animals[MESH]|Cell Nucleus/genetics/metabolism[MESH]|Humans[MESH]|Introns[MESH]|Mice[MESH]|Motor Neurons/metabolism[MESH]|Muscle Denervation[MESH]|Muscle, Skeletal/*metabolism/physiology[MESH]|Muscles/metabolism[MESH]|Regulatory Sequences, Nucleic Acid[MESH]|Transcription Factors/*genetics/*metabolism[MESH]|Transcriptional Activation[MESH]|Transfection[MESH]|Troponin I/genetics/metabolism[MESH] |
