HDAC4 Controls Muscle Homeostasis through Deacetylation of Myosin Heavy Chain, PGC-1α, and Hsc70

HDAC4, a class IIa histone deacetylase, is upregulated in skeletal muscle in response to denervation-induced atrophy. When HDAC4 is deleted postnatally, mice are partially protected from denervation. Despite the name “histone” deacetylase, HDAC4 demonstrably deacetylates cytosolic and non-histone nuclear proteins. We developed potent and selective class IIa HDAC inhibitors. Using these tools and genetic knockdown, we identified three previously unidentified substrates of HDAC4: myosin heavy chain, peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1α), and heat shock cognate 71 kDa protein (Hsc70). HDAC4 inhibition almost completely prevented denervation-induced loss of myosin heavy chain isoforms and blocked the action of their E3 ligase, MuRF1. PGC-1α directly interacts with class IIa HDACs; selective inhibitors increased PGC-1α protein in muscles. Hsc70 deacetylation by HDAC4 affects its chaperone activity. Through these endogenous HDAC4 substrates, we identified several muscle metabolic pathways that are regulated by class IIa HDACs, opening up new therapeutic options to treat skeletal muscle disorders and potentially other disease where these specific pathways are affected. [Display omitted] •HDAC4 is an active enzyme•HDAC4 deacetylates myosin heavy chain, PGC-1α, and Hsc70•HDAC4 inhibition increases myosin heavy chain and PGC-1α protein levels•Maintaining acetylation of myosin heavy chain and Hsc70 prevents atrophy Luo et al. use class IIa HDAC inhibitors, along with skeletal-muscle-specific and whole-body inducible HDAC4 knockout mice, to demonstrate HDAC4 deacetylates three previously undescribed substrates: myosin heavy chain, PGC-1α, and Hsc70. Through these substrates, HDAC4 inhibition leads to rescue of muscle atrophy and increased succinate dehydrogenase activity.