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.
Highlights
Cachexia, a complex metabolic syndrome, is associated with many end-stage diseases, including congestive heart failure (CHF), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), cancer and AIDS1
A recent study has reported that increased expression of Mstn in skeletal muscle from mice with chronic kidney disease could be blocked by subcutaneous injection of an anti-myostatin peptibody, suggesting auto-regulation of Mstn expression[15]
Myostatin (Mstn) is a master negative regulator of skeletal muscle mass, and its increased expression is considered as a molecular signature of muscle-wasting phenotype[4,25]
Summary
A complex metabolic syndrome, is associated with many end-stage diseases, including congestive heart failure (CHF), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), cancer and AIDS1. Increased serum levels of Mstn are observed in large population of patients with chronic heart failure These patients develop cardiac cachexia (cardiac atrophy) together with skeletal muscle wasting. A recent study has reported that increased expression of Mstn in skeletal muscle from mice with chronic kidney disease could be blocked by subcutaneous injection of an anti-myostatin peptibody, suggesting auto-regulation of Mstn expression[15]. TNF-α treatment of muscle cells was found to increase Mstn expression Such Mstn upregulation as well as TNF-α-mediated degradation of skeletal muscle proteins was shown to be dependent on activation of NF-κB, the pro-inflammatory transcription factor[15,20,21]. NF-κB is regulated transiently under physiological conditions; it is constitutively activated in skeletal muscles-associated pathologies, such as atrophy/cachexia, muscular dystrophies, rhabdomyosarcomas, inflammatory idiopathic myopathies etc[22]. SIRT6 is considered a longevity factor, and it has been shown to extend healthy life span by curtailing aging associated inflammation by blocking NF-κB signaling
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