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Targeted inhibition of NF\u03baB through its canonical mediator IKK\u03b2 effectively mitigates loss of muscle mass across many conditions, from denervation to unloading to cancer. In this study, we used gain- and loss-of-function mouse models to examine the role of NF\u03baB in muscle atrophy following rotator cuff tenotomy \u2013 a model of chronic rotator cuff tear. IKK\u03b2 was knocked down or constitutively activated in muscle-specific inducible transgenic mice to elicit a twofold gain or loss of NF\u03baB signaling. Surprisingly, neither knockdown of IKK\u03b2 nor overexpression of caIKK\u03b2 significantly altered the loss of muscle mass following tenotomy. This finding was consistent across measures of morphological adaptation (fiber cross-sectional area, fiber length, fiber number), tissue pathology (fibrosis and fatty infiltration), and intracellular signaling (ubiquitin-proteasome, autophagy). Intriguingly, late-stage tenotomy-induced atrophy was exacerbated in male mice compared with female mice. This sex specificity was driven by ongoing decreases in fiber cross-sectional area, which paralleled the accumulation of large autophagic vesicles in male, but not female muscle. These findings suggest that tenotomy-induced atrophy is not dependent on NF\u03baB and instead may be regulated by autophagy in a sex-specific manner.<\/jats:p>","DOI":"10.7554\/elife.82016","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T12:00:18Z","timestamp":1670846418000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.82016","source":"Crossref","is-referenced-by-count":15,"title":["Tenotomy-induced muscle atrophy is sex-specific and independent of NF\u03baB"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9268-3993","authenticated-orcid":true,"given":"Gretchen A","family":"Meyer","sequence":"first","affiliation":[{"name":"Program in Physical Therapy, Washington University School of Medicine","place":["St. Louis, United States"]},{"name":"Department of Orthopaedic Surgery, Washington University School of Medicine","place":["St Louis, United States"]},{"name":"Departments of Neurology and Biomedical 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