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

Abstract

Graphical AbstractHighlights d HDAC4 is an active enzyme d HDAC4 deacetylates myosin heavy chain, PGC-1a, and Hsc70 d HDAC4 inhibition increases myosin heavy chain and PGC-1a protein levels d Maintaining acetylation of myosin heavy chain and Hsc70 prevents atrophy SUMMARY HDAC4, a class IIa histone deacetylase, is upregulated in skeletal muscle in response to denervationinduced 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-1a), 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-1a directly interacts with class IIa HDACs; selective inhibitors increased PGC-1a 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. Cell Reports 29, 749-763, October 15, 2019 ª 2019 The Author(s). 749 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).(D) Densitometry of Immunoreactive bands in (C). The ratio of MyHC IIb to sarcomeric actin was determined. Relative mean fold change (versus CON of HDAC4 iRKO mice) ± SEM was calculated and plotted. #### p < 0.0001 comparing control legs (CONs) to denervated legs (DENs) of WT mice. ***p < 0.01 comparing linked groups using two-way ANOVA and Sidak's post hoc test. (E) MYH gene expression in GAS muscles from CONs and DENs of female WT and HDAC4 iRKO mice. Geometric mean of TBP and VPS26A levels was used to normalize RNA amount added. The relative mean fold change (versus CON of flox À/À Cremice) ± SEM is plotted.(C) Venn diagram of genes regulated in DENs of HDAC4 iRKO mice or WT mice treated with NVS-HD1, both compared to WT mice treated with VEH. (D) Gene expression changes in GAS muscles from CONs and DENs of 8-month-old mice treated with NVS-HD1 5-days post denervation. Geometric mean of TBP, B2M, and VPS26A levels was used to normalize RNA amount added. Relative mean fold change (versus CONs of VEH-treated mice) ± SEM is plotted.

Role of Histone Deacetylases in Skeletal Muscle Physiology and Systemic Energy Homeostasis: Implications for Metabolic Diseases and Therapy

“…The leaving HDAC5 releases its repressive effect on Baf60c and enhancing insulin-independent AKT activation (Meng et al, 2017). Using specific inhibitor of class IIa HDAC activity, myosin heavy chain, PGC-1α, and heat-shock cognate (HSC70) are confirmed to be one of the substrates of HDAC4 in denervation-induced atrophy muscle in comparison with acetylated protein enrichment with untreated group (Luo et al, 2019). Taken together, Class IIa HDACs play critical roles in exercise capacity, remodeling, and nutrient sensing of skeletal muscles (Figure 3).…”

Signaling Pathways That Control Muscle Mass

“…HDAC4 also mediates induction of growth arrest and DNA damage-inducible 45α (Gadd45a), a small myonuclear protein that is required for denervation-induced muscle atrophy. A recent study, which aimed at uncovering additional HDAC4 substrates in skeletal muscle, identified myosin heavy chain, PGC-1α, and heat shock cognate 71 kDa protein (Hsc70) to all be regulated by HDAC4 [ 163 ]. Thus, HDAC4 is an important regulator of muscle trophism in denervation and NMJ disorders, but more research is required to better understand its signaling network and mechanism of action within skeletal muscle.…”

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

“…This suggests that TIP60 acts as a mediator, linking HIF-1α to HIF-1α target genes. In human cells, the 18 deacetylases are divided into four classes [ 131 ]. The class II is divided into two subclasses, IIa (HDAC4, HDAC5, HDAC7 and HDAC9) and IIb (HDAC6 and HDAC10), among which HDAC4, HDAC5 and HDAC6 are thought to be related to the regulation of HIF functional activity [ 2 , 131 , 132 ].…”

“…In human cells, the 18 deacetylases are divided into four classes [ 131 ]. The class II is divided into two subclasses, IIa (HDAC4, HDAC5, HDAC7 and HDAC9) and IIb (HDAC6 and HDAC10), among which HDAC4, HDAC5 and HDAC6 are thought to be related to the regulation of HIF functional activity [ 2 , 131 , 132 ]. Within VHL-positive cancer cell lines, HDAC4 inhibition by shRNA increases HIF-1α protein acetylation levels, while HDAC4 overexpression decreases HIF-1α acetylation levels [ 133 ].…”