{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:45:08Z","timestamp":1792680308016,"version":"4.5.0"},"reference-count":40,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T00:00:00Z","timestamp":1740960000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T00:00:00Z","timestamp":1740960000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370351"],"award-info":[{"award-number":["82370351"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170355"],"award-info":[{"award-number":["82170355"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82001476"],"award-info":[{"award-number":["82001476"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013795","name":"Fujian Medical University","doi-asserted-by":"publisher","award":["2023QH2030"],"award-info":[{"award-number":["2023QH2030"]}],"id":[{"id":"10.13039\/501100013795","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Muscle atrophy is a severe complication of diabetes, with autophagy playing a critical role in its progression. Zinc has been shown to alleviate hyperglycaemia and several diabetes\u2010related complications, but its direct role in mediating diabetic muscle atrophy remains unclear. This study explores the potential role of zinc in the pathogenesis of diabetic muscle atrophy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In vivo, C57BL\/6J mice were induced with diabetes by streptozotocin (STZ) and treated with ZnSO\u2084 (25\u2009mg\/kg\/day) for six weeks. Gastrocnemius muscles were collected for histological analysis, including transmission electron microscopy (TEM). Serum zinc levels were measured by ICP\u2010MS. Protein expression was evaluated using immunofluorescence (IF), immunohistochemistry (IHC) and Western blotting (WB). Bioinformatics analysis was used to identify key genes associated with muscle atrophy. In\u00a0vitro, a high\u2010glucose\u2010induced diabetic C2C12 cell model was established and received ZnSO\u2084, rapamycin, SRT1720, TC\u2010G\u20101008, or GPR39\u2010CRISPR Cas9 intervention. Autophagy was observed by TEM, and protein expression was assessed by IF and WB. Intracellular zinc concentrations were measured using fluorescence resonance energy transfer (FRET).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In vivo, muscle atrophy, autophagy activation, and upregulation of SIRT1 and FoxO1, along with downregulation of GPR39, were confirmed in the T1D group. ZnSO\u2084 protected against muscle atrophy and inhibited autophagy (T1D\u2009+\u2009ZnSO\u2084 vs. T1D, all\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001), as evidenced by increased grip strength (212.40\u2009\u00b1\u200911.08 vs. 163.90\u2009\u00b1\u200910.95 gf), gastrocnemius muscle index (10.67\u2009\u00b1\u20090.44 vs. 8.80\u2009\u00b1\u20090.72\u2009mg\/g), muscle fibre cross\u2010sectional area (978.20\u2009\u00b1\u2009144.00 vs. 580.20\u2009\u00b1\u2009103.30\u2009\u03bcm\n                      <jats:sup>2<\/jats:sup>\n                      ), and serum zinc levels (0.2335\u2009\u00b1\u20090.0227 vs. 0.1561\u2009\u00b1\u20090.0123\u2009mg\/L). ZnSO\u2084 down\u2010regulated the expression of Atrogin\u20101 and MuRF1, and decreased the formation of autophagosomes in the gastrocnemius muscle of T1D mice (all\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). RNA\u2010seq analysis indicated activation of the SIRT1\/FoxO1 signalling pathway in diabetic mice. ZnSO\u2084 down\u2010regulated LC3B, SIRT1 and FoxO1, while upregulating P62 and GPR39 (all\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). In\u00a0vitro, muscle atrophy, autophagy activation, and down\u2010regulation of GPR39 were confirmed in the diabetic cell model (all\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Both ZnSO\u2084 and TC\u2010G\u20101008 down\u2010regulated Atrogin\u20101, LC3B, SIRT1, and FoxO1, and up\u2010regulated P62 and GPR39, inhibiting autophagy and improving muscle atrophy (all\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). The beneficial anti\u2010atrophic effects of ZnSO\u2084 are diminished following treatment with SRT1720 or RAPA. Upon GPR39 knockout, SIRT1, FoxO1, and Atrogin\u20101 were upregulated, while P62 was downregulated. Intracellular zinc concentrations in ZnSO\u2084\u2010treated group remained unchanged (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&gt;\u20090.05), indicating that zinc supplementation did not affect zinc ion entry but acted through the cell surface receptor GPR39.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      ZnSO\n                      <jats:sub>4<\/jats:sub>\n                      inhibits excessive autophagy in skeletal muscle and alleviates muscle atrophy in diabetic mice via the GPR39\u2010SIRT1\/FoxO1 axis. These findings suggest that zinc supplementation may offer a potential therapeutic strategy for managing diabetic muscle atrophy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13771","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T03:50:23Z","timestamp":1740973823000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Zinc Alleviates Diabetic Muscle Atrophy via Modulation of the SIRT1\/FoxO1 Autophagy Pathway Through GPR39"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7709-870X","authenticated-orcid":false,"given":"Xing","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Geriatrics The First Affiliated Hospital of Fujian Medical University  Fuzhou Fujian China"},{"name":"Fujian Hypertension Research Institute The First Affiliated Hospital of Fujian Medical University  Fuzhou Fujian 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