SIRT2 attenuates stress-induced skeletal muscle atrophy by inhibiting glucocorticoid receptor signalling
Year: 2025
Type: preprint
Abstract: Skeletal muscle atrophy occurs in several diseases and is associated with chronic stress. Studies indicate that glucocorticoid receptor signalling is the major signalling pathway that mediates stress-induced muscle degeneration. 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.
Authors: Ankit Kumar Tamta, Bhoomika Shivanaiah, Arathi Bangalore Prabhashankar, Sunayana Ningaraju, Seemadri Subhadarshini, Anurag Nagaraja Sharma, Harsha Mambully Jayaprakasan, Meera Krishnan E R, Apeksha Bhuyar, Devika Sunil, Amarjeet Shrama, Dimple Nagesh, Aastha Munjal, Sukanya Raghu, Manepalli Bhavya Madhuri, Dhevi Rajesh, Venketsubbu Ramasubbu, Mohsen Sarikhani, Himani Tandon, Perumal Arumugam Desingu, Latha Diwakar, Utpal Nath, Deepak Nair, Amit Singh, Ramanathan Sowdhamini, Narayanaswamy Srinivasan, Raul Mostoslavsky, Ninitha Asirvatham-Jeyaraj, Nagalingam Ravi Sundaresan
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Arthritis National Research Foundation, Indian Institute of Science, Wellcome Trust, National Research Foundation, Department of Biotechnology, Ministry of Science and Technology, India, Indian Council of Medical Research, Indian Institute of Technology Madras, The Wellcome Trust DBT India Alliance, National Institutes of Health, Directorate for Biological Sciences, Science and Engineering Research Board, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences
OpenAlex ID: W4415484897