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Although the glucocorticoid signalling pathway is relatively well characterized, there is a need to identify modulators of this pathway that may be useful for drug targeting to ameliorate muscle atrophy. SIRT2 is a mammalian Sirtuin isoform known to mediate the longevity benefits of calorie restriction and exercise. Currently, the role of SIRT2 in regulating stress-induced skeletal muscle atrophy is unclear. Our study found that SIRT2 is a critical regulator of muscle homeostasis and is required to protect against stress-induced muscle atrophy. Interestingly, SIRT2 levels are reduced during glucocorticoid-induced muscle atrophy in mice. SIRT2 depletion exacerbates glucocorticoid-induced reduction in myotube diameter and atrophy gene expression. In contrast, SIRT2 overexpression ameliorates myotube atrophy in primary myotubes. Our findings indicate that SIRT2 knockout mice are susceptible to glucocorticoid-induced muscle atrophy, while muscle-specific SIRT2-transgenic mice exhibit improved muscle function and are protected from glucocorticoid-induced atrophy. Mechanistically, SIRT2 binds to the glucocorticoid receptor to negatively regulate its activity, possibly via deacetylation of critical residues in its DNA-binding domain. Our findings suggest that SIRT2 activation may protect against glucocorticoid-induced skeletal muscle atrophy and serve as a potential therapeutic target for treating muscle atrophy.<\/jats:p>","DOI":"10.1101\/2025.10.22.683887","type":"posted-content","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T20:35:16Z","timestamp":1761251716000},"source":"Crossref","is-referenced-by-count":0,"title":["SIRT2 attenuates stress-induced skeletal muscle atrophy by inhibiting glucocorticoid receptor signalling"],"prefix":"10.64898","author":[{"given":"Ankit Kumar","family":"Tamta","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhoomika","family":"Shivanaiah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arathi 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