{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:24:09Z","timestamp":1790645049427,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T00:00:00Z","timestamp":1711670400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014717","name":"National Outstanding Youth Science Fund Project of National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81900753"],"award-info":[{"award-number":["81900753"]}],"id":[{"id":"10.13039\/100014717","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2021MH376"],"award-info":[{"award-number":["ZR2021MH376"]}],"id":[{"id":"10.13039\/501100007129","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":[[2024,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Diabetic sarcopenia is a disease\u2010related skeletal muscle disorder that causes progressive symptoms. The complete understanding of its pathogenesis is yet to be unravelled, which makes it difficult to develop effective therapeutic strategies. This study investigates how MFG\u2010E8 affects mitophagy and the protective role of D\u2010pinitol (DP) in diabetic sarcopenia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In vivo, streptozotocin\u2010induced diabetic SAM\u2010R1 (STZ\u2010R1) and SAM\u2010P8 (STZ\u2010P8) mice (16\u2010week\u2010old) were used, and STZ\u2010P8 mice were administrated of DP (150\u00a0mg\/kg per day) for 6\u00a0weeks. Gastrocnemius muscles were harvested for histological analysis including transmission electron microscopy. Proteins were evaluated via immunohistochemistry (IHC), immunofluorescence (IF), and western blotting (WB) assay. In vitro, advanced glycation end products (AGEs) induced diabetic and D\u2010galactose (DG) induced senescent C2C12 models were established and received DP, MFG\u2010E8 plasmid (Mover)\/siRNA (MsiRNA), or 3\u2010MA\/Torin\u20101 intervention. Proteins were evaluated by IF and WB assay. Immunoprecipitation (IP) and co\u2010immunoprecipitation (CO\u2010IP) were used for hunting the interacted proteins of MFG\u2010E8.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In vivo, sarcopenia, mitophagy deficiency, and up\u2010regulated MFG\u2010E8 were confirmed in the STZ\u2010P8 group. DP exerted protective effects on sarcopenia and mitophagy (DP\u00a0+\u00a0STZ\u2010P8 vs. STZ\u2010P8; all <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), such as increased lean mass (8.47\u00a0\u00b1\u00a00.81\u00a0g vs. 7.08\u00a0\u00b1\u00a01.64\u00a0g), grip strength (208.62\u00a0\u00b1\u00a039.45\u00a0g vs. 160.87\u00a0\u00b1\u00a026.95\u00a0g), rotarod tests (109.7\u00a0\u00b1\u00a011.81\u00a0s vs. 59.3\u00a0\u00b1\u00a020.97\u00a0s), muscle cross\u2010sectional area (CSA) (1912.17\u00a0\u00b1\u00a0535.61\u00a0\u03bcm<jats:sup>2<\/jats:sup> vs. 1557.19\u00a0\u00b1\u00a0588.38\u00a0\u03bcm<jats:sup>2<\/jats:sup>), autophagosomes (0.07\u00a0\u00b1\u00a00.02 per \u03bcm<jats:sup>2<\/jats:sup> vs. 0.02\u00a0\u00b1\u00a00.01 per \u03bcm<jats:sup>2<\/jats:sup>), and cytolysosome (0.07\u00a0\u00b1\u00a00.03 per \u03bcm<jats:sup>2<\/jats:sup> vs. 0.03\u00a0\u00b1\u00a00.01 per \u03bcm<jats:sup>2<\/jats:sup>). DP down\u2010regulated MFG\u2010E8 in both serum (DP\u00a0+\u00a0STZ\u2010P8: 253.19\u00a0\u00b1\u00a034.75\u00a0pg\/mL vs. STZ\u2010P8: 404.69\u00a0\u00b1\u00a078.97\u00a0pg\/mL; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and gastrocnemius muscle (WB assay. DP\u00a0+\u00a0STZ\u2010P8: 0.39\u00a0\u00b1\u00a00.04 vs. STZ\u2010P8: 0.55\u00a0\u00b1\u00a00.08; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). DP also up\u2010regulated PINK1, Parkin and LC3B\u2010II\/I ratio, and down\u2010regulated P62 in gastrocnemius muscles (all <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). In vitro, mitophagy deficiency and MFG\u2010E8 up\u2010regulation were confirmed in diabetic and senescent models (all <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). DP and MsiRNA down\u2010regulated MFG\u2010E8 and P62, and up\u2010regulated PINK1, Parkin and LC3B\u2010II\/I ratio to promote mitophagy as Torin\u20101 does (all <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). HSPA1L was confirmed as an interacted protein of MFG\u2010E8 in IP and CO\u2010IP assay. Mover down\u2010regulated the expression of Parkin via the HSPA1L\u2010Parkin pathway, leading to mitophagy inhibition. MsiRNA up\u2010regulated the expression of PINK1 via SGK1, FOXO1, and STAT3 phosphorylation pathways, leading to mitophagy stimulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>MFG\u2010E8 is a crucial target protein of DP and plays a distinct role in mitophagy regulation. DP down\u2010regulates the expression of MFG\u2010E8, reduces mitophagy deficiency, and alleviates the symptoms of diabetic sarcopenia, which could be considered a novel therapeutic strategy for diabetic sarcopenia.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13459","type":"journal-article","created":{"date-parts":[[2024,3,30]],"date-time":"2024-03-30T05:45:48Z","timestamp":1711777548000},"page":"934-948","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["The regulation of MFG\u2010E8 on the mitophagy in diabetic sarcopenia via the HSPA1L\u2010Parkin pathway and the effect of D\u2010pinitol"],"prefix":"10.1002","volume":"15","author":[{"given":"Wenqian","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine Shandong University  Jinan China"},{"name":"Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Cheeloo 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