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 fibre-types by differentially regulating transcription in a use-dependent manner while retaining the adaptive properties of adult muscles.
Department of Molecular Biosciences, University of Oslo, Oslo, Norway. z.a.rana@imbv.uio.no
Zaheer A
ZA
Rana
Kristian
K
Gundersen
Andres
A
Buonanno
D000328:Adult; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007438:Introns; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D009132:Muscles / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D019210:Troponin I / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D014157:Transcription Factors; D019210:Troponin I