{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:52:53Z","timestamp":1787025173615,"version":"build-2736575974"},"reference-count":0,"publisher":"American Diabetes Association","license":[{"start":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T00:00:00Z","timestamp":1738022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Insulin resistance, a hallmark of type 2 diabetes, accelerates muscle breakdown and impairs energy metabolism. However, the role of Ubiquitin Specific Peptidase 2 (USP2), a key regulator of insulin resistance, in sarcopenia remains unclear. Peroxisome proliferator activated receptor \u03b3 (PPAR\u03b3) plays a critical role in regulating muscle atrophy. This study investigates the role of deubiquitinase USP2 in mitigating muscle atrophy. Our findings revealed reduced USP2 expression in skeletal muscles of patients with type 2 diabetes. In mouse models of diabetes- and dexamethasone (DEX)-induced muscle atrophy, USP2 expression was downregulated in skeletal muscles. Usp2 knockout exacerbated muscle loss and functional impairment induced by diabetes or DEX. Moreover, skeletal muscle-specific Usp2 knockout further aggravated muscle loss and functional impairment induced by diabetes. Local injection of AAV-Usp2 into the gastrocnemius muscles of diabetic mice increased muscle mass, and improved skeletal muscle performance and endurance. It enhanced insulin sensitivity in diabetic mice, shown by lower fasting serum glucose and insulin levels and better glucose tolerance. Mechanistic analysis showed USP2 directly interacted with PPAR\u03b3 by deubiquitinating it, stabilizing its protein levels, enhancing insulin signaling and sensitivity, and maintaining muscle mass. Loss of PPAR\u03b3 abolishes the regulatory effects of USP2 on insulin sensitivity and muscle atrophy. MYOD1 activates USP2 transcription by binding to its promoter region. This study demonstrates the protective role of USP2 in mitigating muscle atrophy by stabilizing PPAR\u03b3 through deubiquitination, particularly in models of diabetic and DEX-induced muscle atrophy. Targeting the USP2-PPAR\u03b3 axis may offer promising therapeutic strategies for metabolic disorders and sarcopenia.<\/jats:p>","DOI":"10.2337\/db24-0375","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T14:19:27Z","timestamp":1738073967000},"update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":3,"title":["Deubiquitinating enzyme USP2 alleviates muscle atrophy by stabilizing PPAR\u03b3"],"prefix":"10.2337","author":[{"given":"Shu","family":"Yang","sequence":"first","affiliation":[{"name":"1Department of Geriatrics, Peking University Shenzhen Hospital, Shenzhen, China"},{"name":"3Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijiao","family":"Xiong","sequence":"additional","affiliation":[{"name":"2Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People\u2019s Hospital), Shenzhen, Guangdong 518020, China"},{"name":"3Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingfeng","family":"Liao","sequence":"additional","affiliation":[{"name":"2Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People\u2019s Hospital), Shenzhen, Guangdong 518020, China"},{"name":"3Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixing","family":"Li","sequence":"additional","affiliation":[{"name":"2Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People\u2019s Hospital), Shenzhen, Guangdong 518020, China"},{"name":"3Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanchun","family":"Li","sequence":"additional","affiliation":[{"name":"2Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People\u2019s Hospital), Shenzhen, Guangdong 518020, China"},{"name":"3Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Kang","sequence":"additional","affiliation":[{"name":"2Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People\u2019s Hospital), Shenzhen, Guangdong 518020, China"},{"name":"3Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China"},{"name":"5The Biobank of National Innovation Center for Advanced Medical Devices, Shenzhen People\u2019s Hospital, Shenzhen, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyan","family":"Yang","sequence":"additional","affiliation":[{"name":"1Department of Geriatrics, Peking University Shenzhen Hospital, Shenzhen, China"},{"name":"4Shantou University Medical College, Shantou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Liang","sequence":"additional","affiliation":[{"name":"1Department of Geriatrics, Peking University Shenzhen Hospital, Shenzhen, China"},{"name":"3Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2025,1,28]]},"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/doi\/10.2337\/db24-0375\/795831\/db240375.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/doi\/10.2337\/db24-0375\/795831\/db240375.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T14:19:27Z","timestamp":1738073967000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/doi\/10.2337\/db24-0375\/157797\/Deubiquitinating-enzyme-USP2-alleviates-muscle"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,28]]},"references-count":0,"URL":"https:\/\/doi.org\/10.2337\/db24-0375","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,28]]},"article-number":"db240375"}}