HDAC4 regulates muscle fiber type-specific gene expression programs

Abstract

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 fastlglycolytic fibers in contrast to the sarco-plasm in slowloxidative fibers. The cytoplasmic localization is associated with HDAC4 hyper-phosphorylation in slowloxi-dative-fibers. Genetic reprogramming of fastlglycolytic fibers to oxidative fibers by active CaMKll 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-la-mediated oxidative metabolic gene program. Thus differential phosphorylation and localization of HDAC4 contributes to establishing fiber type-specific transcriptional programs.