The histone deacetylase SIRT6 blocks myostatin expression and development of muscle atrophy

Abstract

Muscle wasting, also known as cachexia, is associated with many chronic diseases, which worsens prognosis of primary illness leading to enhanced mortality. Molecular basis of this metabolic syndrome is not yet completely understood. SIRT6 is a chromatin-bound member of the sirtuin family, implicated in regulating many cellular processes, ranging from metabolism, DNA repair to aging. SIRT6 knockout (SIRT6-KO) mice display loss of muscle, fat and bone density, typical characteristics of cachexia. Here we report that SIRT6 depletion in cardiac as well as skeletal muscle cells promotes myostatin (Mstn) expression. We also observed upregulation of other factors implicated in muscle atrophy, such as angiotensin-II, activin and Acvr2b, in SIRT6 depleted cells. SIRT6-KO mice showed degenerated skeletal muscle phenotype with significant fibrosis, an effect consistent with increased levels of Mstn. Additionally, we observed that in an in vivo model of cancer cachexia, Mstn expression coupled with downregulation of SIRT6. Furthermore, SIRT6 overexpression downregulated the cytokine (TNFα-IFNγ)-induced Mstn expression in C2C12 cells, and promoted myogenesis. From the ChIP assay, we found that SIRT6 controls Mstn expression by attenuating NF-κB binding to the Mstn promoter. Together, these data suggest a novel role for SIRT6 in maintaining muscle mass by controlling expression of atrophic factors like Mstn and activin.

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

“…Our data showed that Ex‐4 treatment activates both PKA and AKT signalling pathways and inhibits phosphorylated NF‐κB protein expression. Activated AKT signalling can directly suppress the phosphorylated protein level of NF‐κB in C2C12 myotubes, which may in turn reduce the binding of NF‐κB to promoter regions of MSTN . As expected, Ex‐4 treatment decreased MSTN protein expression and Ex‐9 or GLP‐1R knockdown inhibited this effect, suggesting that the GLP‐1R‐mediated signalling pathway might be involved in regulation of MSTN expression.…”

A high‐fat diet reverses metabolic disorders and premature aging by modulating insulin and IGF1 signaling in SIRT6 knockout mice

“…The high‐fat diet significantly reversed these atrophy features (Figure and Figure ). It was reported recently that SIRT6 can block myostatin expression and the development of muscle atrophy (Samant et al, ). The high‐fat diet efficiently attenuated the overexpression of myostatin caused by the SIRT6 deficiency (Figure f).…”

“…SIRT6 deficiency in mice causes a severe metabolic disorder, which leads to multi‐organ atrophy, premature aging features, and death within 1 month. Recently, it was reported that SIRT6 can block myostatin expression and SIRT6 deficiency‐induced muscle atrophy (Samant et al, ). In our experiments, the high‐fat diet effectively reversed the SIRT6 KO‐induced shortening of the lifespan, multi‐organ atrophy, premature aging, and metabolic abnormalities both in male and female mice.…”

“…SIRT6 knockout (KO) mice manifest acute degenerative and aging-like abnormalities and succumb to death by 4 weeks of age. Before death, these mice have a smaller-than-normal body size in combination with lymphopenia, osteoporosis, and muscle atrophy, which resembles aging-induced sarcopenia and frailty (Mostoslavsky et al, 2006;Samant, Kanwal, Pillai, Bao, & Gupta, 2017). Furthermore, SIRT6 was found to regulate glucose homeostasis because SIRT6 deficiency induces excessive glucose uptake and glycolysis and reduces mitochondrial respiration (Zhong et al, 2010).…”

Interval running training improves age‐related skeletal muscle wasting and bone loss: Experiments with ovariectomized rats

“…A recent study reported that the expression of SIRT6 may form the basis of a new therapeutic strategy to reduce muscle wasting in ageing‐associated diseases (Samant, Kanwal, Pillai, Bao, & Gupta, ). Furthermore, SIRT6 negatively regulates the expression of myostatin via the suppression of nuclear factor‐κB signalling (Samant et al., ). In particular, activation of exercise‐dependent SIRT1 in skeletal muscle provides protection against muscle weakening and atrophy induced by disuse and ageing‐related diseases (Canto et al., ; Lee & Goldberg, ).…”