{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T21:01:07Z","timestamp":1790974867331,"version":"4.1.0"},"reference-count":79,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,9,19]],"date-time":"2017-09-19T00:00:00Z","timestamp":1505779200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,9,19]],"date-time":"2017-09-19T00:00:00Z","timestamp":1505779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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 <jats:italic>in vivo<\/jats:italic> model of cancer cachexia, Mstn expression coupled with downregulation of SIRT6. Furthermore, SIRT6 overexpression downregulated the cytokine (TNF\u03b1-IFN\u03b3)-induced Mstn expression in C2C12 cells, and promoted myogenesis. From the ChIP assay, we found that SIRT6 controls Mstn expression by attenuating NF-\u03baB 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.<\/jats:p>","DOI":"10.1038\/s41598-017-10838-5","type":"journal-article","created":{"date-parts":[[2017,9,13]],"date-time":"2017-09-13T11:33:45Z","timestamp":1505302425000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["The histone deacetylase SIRT6 blocks myostatin expression and development of muscle atrophy"],"prefix":"10.1038","volume":"7","author":[{"given":"Sadhana A.","family":"Samant","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhinav","family":"Kanwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinodkumar B.","family":"Pillai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6105-1704","authenticated-orcid":false,"given":"Riyue","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahesh P.","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,9,19]]},"reference":[{"key":"10838_CR1","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1097\/MCO.0b013e32833862df","volume":"13","author":"DJ Glass","year":"2010","unstructured":"Glass, D. J. Signaling pathways perturbing muscle mass. Curr Opin Clin Nutr Metab Care \n                           13, 225\u2013229 (2010).","journal-title":"Curr Opin Clin Nutr Metab Care"},{"key":"10838_CR2","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1016\/j.clnu.2008.06.013","volume":"27","author":"WJ Evans","year":"2008","unstructured":"Evans, W. J. et al. Cachexia: a new definition. Clin Nutr \n                           27, 793\u2013799, doi:10.1016\/j.clnu.2008.06.013 (2008).","journal-title":"Clin Nutr"},{"key":"10838_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s13539-010-0002-6","volume":"1","author":"S von Haehling","year":"2010","unstructured":"von Haehling, S. & Anker, S. D. Cachexia as a major underestimated and unmet medical need: facts and numbers. 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J Cell Physiol \n                           180, 1\u20139, doi:10.1002\/(sici)1097-4652(199907)180:1<1::aid-jcp1>3.0.co;2-v (1999).","journal-title":"J Cell Physiol"},{"key":"10838_CR6","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1146\/annurev.cellbio.20.012103.135836","volume":"20","author":"SJ Lee","year":"2004","unstructured":"Lee, S. J. Regulation of muscle mass by myostatin. Annu Rev Cell Dev Biol \n                           20, 61\u201386, doi:10.1146\/annurev.cellbio.20.012103.135836 (2004).","journal-title":"Annu Rev Cell Dev Biol"},{"key":"10838_CR7","doi-asserted-by":"publisher","first-page":"30","DOI":"10.2337\/db08-0943","volume":"58","author":"DS Hittel","year":"2009","unstructured":"Hittel, D. S., Berggren, J. R., Shearer, J., Boyle, K. & Houmard, J. A. Increased secretion and expression of myostatin in skeletal muscle from extremely obese women. Diabetes \n                           58, 30\u201338, doi:10.2337\/db08-0943 (2009).","journal-title":"Diabetes"},{"key":"10838_CR8","doi-asserted-by":"publisher","first-page":"2023","DOI":"10.1249\/MSS.0b013e3181e0b9a8","volume":"42","author":"DS Hittel","year":"2010","unstructured":"Hittel, D. S. et al. Myostatin decreases with aerobic exercise and associates with insulin resistance. Med Sci Sports Exerc \n                           42, 2023\u20132029, doi:10.1249\/MSS.0b013e3181e0b9a8 (2010).","journal-title":"Med Sci Sports Exerc"},{"key":"10838_CR9","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1093\/eurjhf\/hfq039","volume":"12","author":"I George","year":"2010","unstructured":"George, I. et al. Myostatin activation in patients with advanced heart failure and after mechanical unloading. Eur J Heart Fail \n                           12, 444\u2013453, doi:10.1093\/eurjhf\/hfq039 (2010).","journal-title":"Eur J Heart Fail"},{"key":"10838_CR10","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1161\/CIRCULATIONAHA.109.882068","volume":"121","author":"J Heineke","year":"2010","unstructured":"Heineke, J. et al. Genetic deletion of myostatin from the heart prevents skeletal muscle atrophy in heart failure. Circulation \n                           121, 419\u2013425, doi:10.1161\/circulationaha.109.882068 (2010).","journal-title":"Circulation"},{"key":"10838_CR11","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1016\/S0140-6736(03)12892-9","volume":"361","author":"SD Anker","year":"2003","unstructured":"Anker, S. D. et al. Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study. 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