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Kr\u00fcppel\u2010like factor 13 (KLF13), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscles and implicated in the pathogenesis of several diseases. This study investigated the role of KLF13 in muscle atrophy, which could be a novel therapeutic target.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The effects of gene knockdown and pharmacological targeting of <jats:italic>KLF13<\/jats:italic> on skeletal muscle atrophy were investigated using cell\u2010based and animal models. Clofoctol, an antibiotic and KLF13 agonist, was also investigated as a candidate for repurposing. The mechanisms related to skeletal muscle atrophy were assessed by measuring the expression levels and activation statuses of key regulatory pathways and validated using gene knockdown and RNA sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In a dexamethasone\u2010induced muscle atrophy mouse model, the <jats:italic>KLF13<\/jats:italic> knockout group had decreased muscle strength (N) (1.77\u00a0\u00b1\u00a00.10 vs. 1.48\u00a0\u00b1\u00a00.16, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), muscle weight (%) [gastrocnemius (Gas): 76.0\u00a0\u00b1\u00a05.69 vs. 60.7\u00a0\u00b1\u00a07.23, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; tibialis anterior (TA): 75.8\u00a0\u00b1\u00a06.21 vs. 67.5\u00a0\u00b1\u00a05.01, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05], and exhaustive running distance (m) (495.5\u00a0\u00b1\u00a064.8 vs. 315.5\u00a0\u00b1\u00a060.9, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) compared with the control group. <jats:italic>KLF13<\/jats:italic> overexpression preserved muscle mass (Gas: 100\u00a0\u00b1\u00a06.38 vs. 120\u00a0\u00b1\u00a014.4, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and the exhaustive running distance (423.8\u00a0\u00b1\u00a059.04 vs. 530.2\u00a0\u00b1\u00a077.45, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) in an in vivo diabetes\u2010induced skeletal muscle atrophy model. Clofoctol treatment protected against dexamethasone\u2010induced muscle atrophy. Myotubes treated with dexamethasone, an atrophy\u2010inducing glucocorticoid, were aggravated by <jats:italic>KLF13<\/jats:italic> knockout, but anti\u2010atrophic effects were achieved by inducing <jats:italic>KLF13<\/jats:italic> overexpression. We performed a transcriptome analysis and luciferase reporter assays to further explore this mechanism, finding that delta\u2010like 4 (<jats:italic>Dll4<\/jats:italic>) was a novel target gene of KLF13. The KLF13 transcript repressed Dll4, inhibiting the Dll4\u2010Notch2 axis and preventing muscle atrophy. Dexamethasone inhibited <jats:italic>KLF13<\/jats:italic> expression by inhibiting myogenic differentiation 1 (i.e., MYOD1)\u2010mediated KLF13 transcriptional activation and promoting F\u2010Box and WD repeat domain containing 7 (i.e., FBXW7)\u2010mediated KLF13 ubiquitination.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study sheds new light on the mechanisms underlying skeletal muscle atrophy and potential drug targets. KLF13 regulates muscle atrophy and is a potential therapeutic target. Clofoctol is an attractive compound for repurposing studies to treat skeletal muscle atrophy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13538","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T08:57:36Z","timestamp":1720429056000},"page":"1869-1882","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["KLF13 restrains Dll4\u2010muscular Notch2 axis to improve the muscle atrophy"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4912-777X","authenticated-orcid":false,"given":"Shu","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital (Shenzhen People's Hospital) Southern University of Science and Technology  Shenzhen China"},{"name":"Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, The Second Clinical Medical College Jinan University (Shenzhen People's Hospital)  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijiao","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital (Shenzhen People's Hospital) Southern University of Science and Technology  Shenzhen China"},{"name":"Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, The Second Clinical Medical College Jinan University (Shenzhen People's Hospital)  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital (Shenzhen People's Hospital) Southern University of Science and Technology  Shenzhen China"},{"name":"Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, The Second Clinical Medical College Jinan University (Shenzhen People's Hospital)  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqing","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital (Shenzhen People's Hospital) Southern University of Science and Technology  Shenzhen China"},{"name":"Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, The Second Clinical Medical College Jinan University (Shenzhen People's Hospital)  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital (Shenzhen People's Hospital) Southern University of Science and Technology  Shenzhen China"},{"name":"Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, The Second Clinical Medical College Jinan University (Shenzhen People's Hospital)  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital (Shenzhen People's Hospital) Southern University of Science and Technology  Shenzhen China"},{"name":"Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, The Second Clinical Medical College Jinan University (Shenzhen People's Hospital)  Shenzhen China"},{"name":"The Biobank of National Innovation Center for Advanced Medical Devices Shenzhen People's Hospital  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital (Shenzhen People's Hospital) Southern University of Science and Technology  Shenzhen China"},{"name":"Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, The Second Clinical Medical College Jinan University (Shenzhen People's Hospital)  Shenzhen 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