HDAC4 regulates muscle fiber type-specific gene expression programs.
Fiber type-specific programs controlled by the transcription factor MEF2 dictate muscle functionality. Here, we show that HDAC4, a potent MEF2 inhibitor, is predominantly localized to the nuclei in fast/glycolytic fibers in contrast to the sarcoplasm in slow/oxidative fibers. The cytoplasmic localization is associated with HDAC4 hyper-phosphorylation in slow/oxidative-fibers. Genetic reprogramming of fast/glycolytic fibers to oxidative fibers by active CaMKII or calcineurin leads to increased HDAC4 phosphorylation, HDAC4 nuclear export, and an increase in markers associated with oxidative fibers. Indeed, HDAC4 represses the MEF2-dependent, PGC-1α-mediated oxidative metabolic gene program. Thus differential phosphorylation and localization of HDAC4 contributes to establishing fiber type-specific transcriptional programs.
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.|Department of Neurology, UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Todd J
TJ
Cohen
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Moon-Chang
MC
Choi
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Meghan
M
Kapur
Department of Medicine, Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA22908, USA.
Vitor A
VA
Lira
Department of Medicine, Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA22908, USA.
Zhen
Z
Yan
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Tso-Pang
TP
Yao
D000818:Animals; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D019076:Transgenes
D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
HDAC4; MEF2; PGC-1α; fiber type