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Ankyrin repeat and suppressor of cytokine signalling box protein 2 (<jats:italic>Asb2<\/jats:italic>), an E3 ligase, has been implicated in regulating muscle mass; however, its roles on muscle strength remain unclear, with mixed findings from previous studies. Overexpression of <jats:italic>Asb2<\/jats:italic> decreases muscle mass, whereas its knockdown delays myoblast differentiation and reduces contractile proteins. Given these contradictory findings, we aimed to clarify the role of <jats:italic>Asb2<\/jats:italic> in muscle mass and strength using a skeletal muscle\u2010specific <jats:italic>Asb2<\/jats:italic> knockout (<jats:italic>Asb2<\/jats:italic> MKO) mouse model. Additionally, we investigate the long\u2010term effects of <jats:italic>Asb2<\/jats:italic> on aged muscle, underlying mechanisms on muscle regulation and metabolic effects of <jats:italic>Asb2<\/jats:italic> MKO mice to better understand its role in muscle function and age\u2010related metabolic diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>Asb2<\/jats:italic> MKO mice were generated using <jats:italic>Acta1<\/jats:italic>\u2010Cre recombinase. Body composition was quantified in male and female mice up to 18\u2009months of age. Muscle strength, energy expenditure and glucose metabolism were evaluated using the grip strength test, mitochondrial oxygen consumption measurement, indirect calorimetry and glucose\/insulin tolerance tests. Transcriptomic analyses and siRNA studies were performed to elucidate the mechanisms underlying the <jats:italic>Asb2<\/jats:italic> deletion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The MKO mice were born healthy and exhibited selective <jats:italic>Asb2<\/jats:italic> deletion in the skeletal muscle, leaving the cardiac muscle unaffected. This deletion led to an increase in the mass of various skeletal muscles (9%\u201323%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and improved grip strength (~10%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), both of which were sustained throughout the ageing process. The MKO mice also revealed enhanced mitochondrial function, energy expenditure and whole\u2010body insulin sensitivity. Transcriptomic data supported the muscle phenotype observed in the MKO mice. Notably, desmin, a protein critical for structural integrity and mitochondrial function, was identified as a target protein of the ASB2 E3 ligase.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Skeletal muscle\u2010specific deletion of <jats:italic>Asb2<\/jats:italic> led to increased muscle mass and strength, potentially through preservation of desmin levels. These findings suggest that targeting <jats:italic>Asb2<\/jats:italic> may enhance muscle growth and prevent age\u2010related muscle decline, with potential benefits for metabolic health, particularly by improving mitochondrial function and insulin sensitivity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.70007","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T05:54:04Z","timestamp":1752213244000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Skeletal Muscle\u2010Specific Deletion of E3 Ligase <i>Asb2<\/i> Enhances Muscle Mass and Strength"],"prefix":"10.1002","volume":"16","author":[{"given":"Hye\u00a0Rim","family":"Jang","sequence":"first","affiliation":[{"name":"Laboratory of Mitochondria and Metabolic Diseases, Lee Gil Ya Cancer and Diabetes Institute Gachon University  Incheon Republic of Korea"},{"name":"Department of Health Sciences and Technology. GAIHST Gachon University  Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi\u2010Young","family":"Park","sequence":"additional","affiliation":[{"name":"Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute Gachon University  Incheon Republic of Korea"},{"name":"Gachon Biomedical Convergence Institute Gachon University Gil Medical Center  Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeonmi","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondria and Metabolic Diseases, Lee Gil Ya Cancer and Diabetes Institute Gachon University  Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongjin","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondria and Metabolic Diseases, Lee Gil Ya Cancer and Diabetes Institute Gachon University  Incheon Republic of Korea"},{"name":"Department of Health Sciences and Technology. GAIHST Gachon University  Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jongjun","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondria and Metabolic Diseases, Lee Gil Ya Cancer and Diabetes Institute Gachon University  Incheon Republic of Korea"},{"name":"Department of Health Sciences and Technology. GAIHST Gachon University  Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoonil","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology. GAIHST Gachon University  Incheon Republic of Korea"},{"name":"Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute Gachon University  Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheol\u00a0Soo","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology. GAIHST Gachon University  Incheon Republic of Korea"},{"name":"Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute Gachon University  Incheon Republic of Korea"},{"name":"Department of Molecular Medicine Gachon University School of Medicine  Incheon Republic of Korea"},{"name":"Department of Internal Medicine, Gil Medical Center Gachon University  Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3464-6382","authenticated-orcid":false,"given":"Hui\u2010Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondria and Metabolic Diseases, Lee Gil Ya Cancer and Diabetes Institute Gachon University  Incheon Republic of Korea"},{"name":"Department of Health Sciences and Technology. 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