{"doi":"10.1038/s41467-022-32905-w","title":"Sirtuin 6 inhibition protects against glucocorticoid-induced skeletal muscle atrophy by regulating IGF/PI3K/AKT signaling","abstract":"Chronic activation of stress hormones such as glucocorticoids leads to skeletal muscle wasting in mammals. However, the molecular events that mediate glucocorticoid-induced muscle wasting are not well understood. Here, we show that SIRT6, a chromatin-associated deacetylase indirectly regulates glucocorticoid-induced muscle wasting by modulating IGF/PI3K/AKT signaling. Our results show that SIRT6 levels are increased during glucocorticoid-induced reduction of myotube size and during skeletal muscle atrophy in mice. Notably, overexpression of SIRT6 spontaneously decreases the size of primary myotubes in a cell-autonomous manner. On the other hand, SIRT6 depletion increases the diameter of myotubes and protects them against glucocorticoid-induced reduction in myotube size, which is associated with enhanced protein synthesis and repression of atrogenes. In line with this, we find that muscle-specific SIRT6 deficient mice are resistant to glucocorticoid-induced muscle wasting. Mechanistically, we find that SIRT6 deficiency hyperactivates IGF/PI3K/AKT signaling through c-Jun transcription factor-mediated increase in IGF2 expression. The increased activation, in turn, leads to nuclear exclusion and transcriptional repression of the FoxO transcription factor, a key activator of muscle atrophy. Further, we find that pharmacological inhibition of SIRT6 protects against glucocorticoid-induced muscle wasting in mice by regulating IGF/PI3K/AKT signaling implicating the role of SIRT6 in glucocorticoid-induced muscle atrophy.","journal":"Nature Communications","year":2022,"id":238565,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":54,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":23514,"name":"Claudia Cosentino","orcid":"0000-0002-9817-5030","position":1,"is_corresponding":false},{"id":662490,"name":"Ankit Kumar Tamta","orcid":null,"position":2,"is_corresponding":false},{"id":661448,"name":"Danish Khan","orcid":"0000-0003-1376-8716","position":3,"is_corresponding":false},{"id":862922,"name":"Shalini Srinivasan","orcid":"0000-0003-1108-4687","position":4,"is_corresponding":false},{"id":661450,"name":"V. Ravi","orcid":"0000-0002-1409-682X","position":5,"is_corresponding":false},{"id":862923,"name":"Elena Abbotto","orcid":"0000-0001-7161-6353","position":6,"is_corresponding":false},{"id":863761,"name":"Bangalore Prabhashankar Arathi","orcid":null,"position":7,"is_corresponding":false},{"id":238371,"name":"Shweta Kumar","orcid":"0000-0001-9170-1686","position":8,"is_corresponding":false},{"id":512061,"name":"Aditi Jain","orcid":"0000-0001-9383-7501","position":9,"is_corresponding":false},{"id":863762,"name":"Anand S. Ramaian","orcid":null,"position":10,"is_corresponding":false},{"id":863763,"name":"Shruti M. Kizkekra","orcid":null,"position":11,"is_corresponding":false},{"id":661451,"name":"Raksha Rajagopal","orcid":"0000-0002-0580-6236","position":12,"is_corresponding":false},{"id":862924,"name":"Swathi Rao","orcid":"0000-0003-1127-9046","position":13,"is_corresponding":false},{"id":661455,"name":"Swati Krishna","orcid":"0000-0001-5780-8535","position":14,"is_corresponding":false},{"id":384880,"name":"Ninitha Asirvatham‐Jeyaraj","orcid":"0000-0001-9348-0493","position":15,"is_corresponding":false},{"id":863764,"name":"Elizabeth R. Haggerty","orcid":null,"position":16,"is_corresponding":false},{"id":23509,"name":"Dafne M. Silberman","orcid":"0000-0002-1698-7191","position":17,"is_corresponding":false},{"id":266142,"name":"Irwin J. Kurland","orcid":"0000-0002-9633-1917","position":18,"is_corresponding":false},{"id":862925,"name":"Ravindra P. 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