HC toxin (a HDAC inhibitor) enhances IRS1–Akt signalling and metabolism in mouse myotubes

Abstract

Exercise enhances numerous signalling pathways and activates substrate metabolism in skeletal muscle. Small molecule compounds that activate these cellular responses have been shown to recapitulate the metabolic benefits of exercise. In this study, a histone deacetylase (HDAC) inhibitor, HC toxin, was investigated as a small molecule compound that activates exercise-induced adaptations. In C2C12 myotubes, HC toxin treatment activated two exercise-stimulated pathways: AMP-activated protein kinase (AMPK) and Akt pathways. HC toxin increased the protein content and phosphorylation of insulin receptor substrate 1 as well as the activation of downstream Akt signalling. The effects of HC toxin on IRS1-Akt signalling were PI3K-dependent as wortmannin abolishes its effects on IRS1 protein accumulation and Akt phosphorylation. HC toxin-induced Akt activation was sufficient to enhance downstream mTOR complex 1 (mTORC1) signalling including p70S6K and S6, which were consistently abolished by PI3K inhibition. Insulin-stimulated glucose uptake, glycolysis, mitochondrial respiration and fatty acid oxidation were also enhanced in HC toxin-treated myotubes. When myotubes were challenged with serum starvation for the induction of atrophy, HC toxin treatment prevented the induction of genes that are involved in autophagy and proteasomal proteolysis. Conversely, IRS1-Akt signalling was not induced by HC toxin in several hepatoma cell lines, providing evidence for a favourable safety profile of this small molecule. These data highlight the potential of HDAC inhibitors as a novel class of small molecules for the induction of exercise-like signalling pathways and metabolism.

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

“…These results are consistent with previous studies on the effect by HDAC inhibition on insulin resistance in different models (54–56), including in the heart of diabetic mice (15, 57, 58). Therefore, reducing insulin resistance may contribute, at certain levels, to the cardioprotection of HDAC3 inhibitor in OVE26 diabetic mouse model although the exact mechanism needs to be further explored in our future work.…”

Antitumor activity and pharmacologic characterization of the depsipeptide analog as a novel histone deacetylase/ phosphatidylinositol 3‐kinase dual inhibitor

“…This result corresponded with previous reports that HDAC inhibitors activate the PI3K/ AKT pathway in a cell-specific manner. (23)(24)(25) In regards to HDAC inhibition, FK-A11 and FK-A3 as well as SAHA promoted acetylation of histone H3 (Fig. 3c, Fig.…”

Exercise and the Skeletal Muscle Epigenome

“…Acute administration of scriptaid to mice increased the expression of exerciseresponsive metabolic genes in skeletal muscle, whereas chronic administration increased exercise performance, whole-body energy expenditure, and lipid oxidation and reduced plasma glucose and lipids (Gaur et al 2016). A number of other studies using various HDAC inhibitors have reported similar enhancements in various aspects of muscle and whole-body metabolism, including insulin sensitivity (Tan et al 2015) and enhanced oxidative capacity (Galmozzi et al 2013). The exact mechanism of action of some of these broad-spectrum HDAC inhibitors remains to be determined, but could include inhibition of HDAC3, the class I HDAC that provides deacetylase activity to the class IIa HDAC corepressor complex (Fischle et al 2002;Hudson et al 2015).…”