Lysine deacetylases (KDACs) regulate PKCõ phosphorylation in response to muscle atrophy.

Post-translational modifications (PTMs) such as acetylation and phosphorylation have been implicated in contractile dysfunction and muscle wasting. Indeed, lysine deacetylase (KDAC) inhibitors attenuate muscle atrophy and delay muscle damage in response to nutrient deprivation, in models of metabolic dysfunction and genetic models of muscle disease (e.g. muscle dystrophy). Historically, lysine acetylation was studied in the regulation of gene transcription, where for instance HDACs remove acetyl groups on lysine residues of histone proteins to suppress gene expression. However, recent evidence demonstrates that non-histone proteins are acetylated; functioning in protein stability, intracellular signaling, mitochondrial function and muscle contraction. Using C2C12 myotubes stimulated with dexamethasone (Dex) as a model of muscle atrophy, we report that KDAC inhibition using Trichostatin A (TSA) restored myotube size and attenuated Dex-induced atrophy genes, Murf1 and Atrogin-1. Despite our current understanding for lysine acetylation in muscle physiology; a role for KDACs in the regulation of muscle signal transduction remains a 'black box.' We report that protein kinase C delta (PKCδ) phosphorylation decreased at threonine 505 (T505) and serine 643 (S643), residues important for PKCδ activity, in myotubes in response to muscle atrophy. Interestingly, PKCδ phosphorylation was restored in myotubes treated with a pan-HDAC inhibitor (TSA) or a class I selective HDAC inhibitor (Apicidin) targeting HDAC1, -2, and -3 in response to Dex. Moreover, we observed that Dex induced skeletal muscle atrophy rapidly in mice, with weight loss noted by day 3 post Dex and muscle weight loss noted by day 7. Similar to our findings in C2C12 myotubes, Dex attenuated phosphorylation of PKCδ at S643, while KDAC inhibition restored or increased PKCδ phosphorylation at both T505 and S643 in the tibialis anterior. These findings suggest that KDACs act as endogenous regulators of skeletal muscle atrophy through the regulation of PKCδ phosphorylation. Consistent with this hypothesis, we report that KDAC inhibition could not restore myotube size in response to Dex in the presence of a PKCδ inhibitor or when overexpressing a dominant negative PKCδ. Combined, these suggest a non-canonical role for KDACs in the regulation of muscle physiology outside of its role in chromatin condensation and gene regulation.