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Perturbation of the skeletal muscle metabolism elevates the risk of a variety of diseases including metabolic disorders. However, the regulatory pathways and molecules are not completely understood. The discovery of relevant responsible molecules and the associated network could be an attractive strategy to overcome diseases associated with muscle problems.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An initial screening using quantitative trait locus analysis enabled us to extract a set of genes including ubiquitin\u2010specific proteases21 (USP21) (<jats:italic>r<\/jats:italic>\u00a0=\u00a00.738; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.004) as potential targets associated with fasting blood glucose content. Given tight regulation of the ubiquitination status of proteins in muscle, we focused on USP21 and generated whole\u2010body (KO) and skeletal muscle\u2010specific USP21 knockout (MKO) mice. Transcriptomics, proteomics, and lipidomics assays in combination with various <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> experiments were performed to understand the functions of USP21 and underlying mechanisms. A high\u2010fat diet (60%)\u2010fed mouse model and diabetic patient\u2010derived samples were utilized to assess the effects of USP21 on energy metabolism in skeletal muscle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>USP21 was highly expressed in both human and mouse skeletal muscle, and controlled skeletal muscle oxidative capacity and fuel consumption. USP21\u2010KO or USP21\u2010MKO significantly promoted oxidative fibre type changes (\u039436.6% or \u039447.2%), muscle mass increase (\u039413.8% to \u039422.8%), and energy expenditure through mitochondrial biogenesis, fatty acid oxidation, and UCP2\/3 induction (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05 or <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Consistently, cold exposure repressed USP21 expression in mouse skeletal muscle (\u039455.3%), whereas loss of USP21 increased thermogenesis (+1.37\u00b0C or +0.84\u00b0C; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Mechanistically, USP21 deubiquitinated DNA\u2010PKcs and ACLY, which led to AMPK inhibition. Consequently, USP21 ablation diminished diet\u2010induced obesity (WT vs. USP21\u2010KO, \u03948.02\u00a0g, 17.1%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01; litter vs. USP21\u2010MKO, \u03943.48\u00a0g, 7.7%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and insulin resistance. These findings were corroborated in a skeletal muscle\u2010specific gene KO mouse model. USP21 was induced in skeletal muscle of a diabetic patient (1.94\u2010fold), which was reciprocally changed to p\u2010AMPK (0.30\u2010fold).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The outcomes of this research provide novel information as to how USP21 in skeletal muscle contributes to systemic energy homeostasis, demonstrating USP21 as a key molecule in the regulation of myofibre type switch, muscle mass control, mitochondrial function, and heat generation and, thus, implicating the potential of this molecule and its downstream substrates network as targets for the treatment and\/or prevention of muscle dysfunction and the associated metabolic diseases.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12777","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T12:20:42Z","timestamp":1631708442000},"page":"1669-1689","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Ablation of USP21 in skeletal muscle promotes oxidative fibre phenotype, inhibiting obesity and type 2 diabetes"],"prefix":"10.1002","volume":"12","author":[{"given":"Ayoung","family":"Kim","sequence":"first","affiliation":[{"name":"College of Pharmacy Seoul National University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ja Hyun","family":"Koo","sequence":"additional","affiliation":[{"name":"College of Pharmacy Seoul National University  Seoul South Korea"},{"name":"Department of Physiology, College of Medicine The Catholic University of Korea  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Jin","sequence":"additional","affiliation":[{"name":"College of Pharmacy Seoul National University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wondong","family":"Kim","sequence":"additional","affiliation":[{"name":"Nephrology Division Massachusetts General Hospital  Boston MA USA"},{"name":"Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Science and Technology Hanyang University  Ansan South 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 College of Medicine  Incheon South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunghyouk","family":"Park","sequence":"additional","affiliation":[{"name":"College of Pharmacy Seoul National University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene P.","family":"Rhee","sequence":"additional","affiliation":[{"name":"Nephrology Division Massachusetts General Hospital  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheol Soo","family":"Choi","sequence":"additional","affiliation":[{"name":"Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute Gachon University College of Medicine  Incheon South Korea"},{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Gil Medical Center Gachon University College of Medicine  Incheon South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5266-1722","authenticated-orcid":false,"given":"Sang Geon","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Integrated Research Institute for Drug Development 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