{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T18:23:23Z","timestamp":1791829403264,"version":"4.3.4"},"reference-count":103,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32400956"],"award-info":[{"award-number":["32400956"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai University Young Talents Sailing Plan","award":["N.13-G21022367"],"award-info":[{"award-number":["N.13-G21022367"]}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023M740870"],"award-info":[{"award-number":["2023M740870"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Decreased skeletal muscle mass and function are a serious complication of long-term diabetes, often leading to numerous adverse outcomes. The primary pathological features of diabetic sarcopenia include muscle fiber atrophy and interstitial fibrosis. Although resistance exercise (RE) has been reported to mitigate skeletal muscle atrophy in type 2 diabetes mellitus (T2DM), the underlying mechanisms remain unclear. Fibroblast growth factor 21 (FGF21), an exercise-induced cytokine, has been shown to protect against skeletal muscle atrophy at elevated levels. In this study, a T2DM mouse model was established through 12 weeks of high-fat diet feeding and intraperitoneal injection of streptozotocin (STZ) to investigate the effect and mechanism of RE on skeletal muscle atrophy in T2DM mice. Our results demonstrated that 8 weeks of RE significantly decreased body weight, fat mass, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), and serum insulin levels in T2DM mice. RE also improved lean mass, glucose tolerance (IPGTT), and insulin tolerance (ITT). Additionally, RE increased skeletal muscle mass cross-sectional area (CSA) while attenuating fibrosis and inflammatory responses in skeletal muscle. Notably, RE upregulated FGF21 expression and activated the PI3K\/Akt signaling pathway in diabetic skeletal muscle. RE promoted the phosphorylation of mTOR, 4EBP1, and p70S6K while suppressing the expression of the atrophy-related E3 ubiquitin ligases MuRF1 and MAFbx\/Atrogin-1. Furthermore, RE inhibited lipid synthesis and enhanced both lipid oxidation and glucose utilization in skeletal muscle of T2DM mice. RE also improved mitochondrial biogenesis and dynamics in skeletal muscle of T2DM mice. In summary, 8 weeks of RE alleviated skeletal muscle atrophy in T2DM mice via activation of the FGF21\/PI3K\/Akt signaling pathway, which enhanced protein synthesis, improved glycolipid metabolism and mitochondrial quality control, and attenuated fibrosis and inflammation.<\/jats:p>","DOI":"10.3390\/biom16010003","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T09:29:16Z","timestamp":1766136556000},"page":"3","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Resistance Exercise Counteracts Skeletal Muscle Atrophy in T2DM Mice by Upregulating FGF21 and Activating PI3K\/Akt Pathway"],"prefix":"10.3390","volume":"16","author":[{"given":"Xiaojie","family":"Ma","sequence":"first","affiliation":[{"name":"College of Physical Education, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8873-0088","authenticated-orcid":false,"given":"Zhijian","family":"Rao","sequence":"additional","affiliation":[{"name":"College of Physical Education, Shanghai Normal University, Shanghai 200238, China"},{"name":"Exercise Biological Center, China Institute of Sport Science, Beijing 100061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihai","family":"Jin","sequence":"additional","affiliation":[{"name":"College of Physical Education, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibing","family":"Lu","sequence":"additional","affiliation":[{"name":"College of Physical Education, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhitong","family":"Sun","sequence":"additional","affiliation":[{"name":"College of Physical Education, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6805-5065","authenticated-orcid":false,"given":"Lifang","family":"Zheng","sequence":"additional","affiliation":[{"name":"College of Physical Education, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109119","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res. 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