title: NFATc1 controls skeletal muscle fiber type and is a negative regulator of MyoD activity.
abstract: Skeletal muscle comprises a heterogeneous population of fibers with important physiological differences. Fast fibers are glycolytic and fatigue rapidly. Slow fibers utilize oxidative metabolism and are fatigue resistant. Muscle diseases such as sarcopenia and atrophy selectively affect fast fibers, but the molecular mechanisms regulating fiber type-specific gene expression remain incompletely understood. Here, we show that the transcription factor NFATc1 controls fiber type composition and is required for fast-to-slow fiber type switching in response to exercise in vivo. Moreover, MyoD is a crucial transcriptional effector of the fast fiber phenotype, and we show that NFATc1 inhibits MyoD-dependent fast fiber gene promoters by physically interacting with the N-terminal activation domain of MyoD and blocking recruitment of the essential transcriptional coactivator p300. These studies establish a molecular mechanism for fiber type switching through direct inhibition of MyoD to control the opposing roles of MyoD and NFATc1 in fast versus slow fiber phenotypes.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517, USA.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Ehlers
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Celona
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517, USA. Electronic address: brian.black@ucsf.edu.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Black
mesh_terms: D000818:Animals; D005260:Female; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D016296:Mutagenesis; D017570:MyoD Protein / Q000737:chemistry / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010805:Physical Conditioning, Animal; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors / Q000737:chemistry / Q000378:metabolism
chemical_list: D064326:MEF2 Transcription Factors; D017570:MyoD Protein; D050778:NFATC Transcription Factors; D020033:Protein Isoforms; D050880:p300-CBP Transcription Factors