Mechanisms of skeletal muscle atrophy in type 2 diabetes mellitus
IntroductionERS-induced apoptosis may play a pivotal role in diabetic skeletal muscle atrophy. However, the specific mechanisms by which ERS regulates skeletal muscle atrophy in diabetes remain unclear. The research examines the impact of endoplasmic reticulum stress (ERS) on skeletal muscle atrophy...
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2025.1607873/full |
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| author | Jingyi Yang Yingdong Wang Yuzhe Xu Xinqi Jia Fangping Lu |
| author_facet | Jingyi Yang Yingdong Wang Yuzhe Xu Xinqi Jia Fangping Lu |
| author_sort | Jingyi Yang |
| collection | DOAJ |
| description | IntroductionERS-induced apoptosis may play a pivotal role in diabetic skeletal muscle atrophy. However, the specific mechanisms by which ERS regulates skeletal muscle atrophy in diabetes remain unclear. The research examines the impact of endoplasmic reticulum stress (ERS) on skeletal muscle atrophy in type 2 diabetes mellitus (T2DM) mice.MethodsLeptin receptor-deficient Db/db mice (n = 7, 24-week-old, male) were employed as a type 2 diabetes model, while age-matched male C57BL/6J mice (n = 7) served as normal controls. Pathway enrichment analysis of differentially expressed genes was performed based on transcriptome sequencing data, focusing on apoptosis, ERS, and ubiquitin-proteasome pathways. Skeletal muscle morphology was assessed via anatomical observation, Laminin Staining, and immunoblotting analysis (WB). WB was used to detect ERS markers (ATF6, p-eIF2α, Bip, p-JNK, Chop), apoptosis-related proteins (Bcl2, Bax, Cleaved Caspase-3, CytC), p-Akt, and muscle atrophy marker Atrogin1.ResultsTranscriptomic enrichment analysis confirmed specific activation of apoptosis, ERS, and ubiquitin-proteasome pathways. WB revealed upregulated ERS-related proteins, increased apoptotic proteins, decreased p-Akt expression, elevated Atrogin1 levels, and enhanced proteolytic activity. Db/db mice exhibited significant skeletal muscle atrophy, with Laminin Staining demonstrating reduced cross-sectional area (CSA) of muscle fibers.DiscussionThese findings uncovers a dual regulatory mechanism underlying diabetic muscle atrophy. The diabetic skeletal muscle microenvironment exhibits elevated oxidative stress and significantly enhanced ER stress, which promotes direct muscle atrophy through ER stress sensor-mediated apoptosis. Concurrently, sustained ER stress suppresses Akt activity while upregulating the muscle-specific E3 ubiquitin ligase Atrogin1, thereby accelerating proteolysis and inducing indirect muscle wasting. These findings provide crucial mechanistic insights into diabetic skeletal myopathy, highlighting the ER stress signaling network as a promising therapeutic target for mitigating muscle atrophy in diabetes. |
| format | Article |
| id | doaj-art-805e57e194354929bcc5d98571ec00be |
| institution | DOAJ |
| issn | 1664-042X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Physiology |
| spelling | doaj-art-805e57e194354929bcc5d98571ec00be2025-08-20T03:24:00ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2025-06-011610.3389/fphys.2025.16078731607873Mechanisms of skeletal muscle atrophy in type 2 diabetes mellitusJingyi Yang0Yingdong Wang1Yuzhe Xu2Xinqi Jia3Fangping Lu4Department of Pathophysiology, Mudanjiang Medical University, Mudanjiang, ChinaDepartment of Pathophysiology, Mudanjiang Medical University, Mudanjiang, ChinaDepartment of Pathophysiology, Mudanjiang Medical University, Mudanjiang, ChinaDepartment of General Surgery, Mudanjiang Medical University Affiliated Hongqi Hospital, Mudanjiang, ChinaDepartment of Pathophysiology, Mudanjiang Medical University, Mudanjiang, ChinaIntroductionERS-induced apoptosis may play a pivotal role in diabetic skeletal muscle atrophy. However, the specific mechanisms by which ERS regulates skeletal muscle atrophy in diabetes remain unclear. The research examines the impact of endoplasmic reticulum stress (ERS) on skeletal muscle atrophy in type 2 diabetes mellitus (T2DM) mice.MethodsLeptin receptor-deficient Db/db mice (n = 7, 24-week-old, male) were employed as a type 2 diabetes model, while age-matched male C57BL/6J mice (n = 7) served as normal controls. Pathway enrichment analysis of differentially expressed genes was performed based on transcriptome sequencing data, focusing on apoptosis, ERS, and ubiquitin-proteasome pathways. Skeletal muscle morphology was assessed via anatomical observation, Laminin Staining, and immunoblotting analysis (WB). WB was used to detect ERS markers (ATF6, p-eIF2α, Bip, p-JNK, Chop), apoptosis-related proteins (Bcl2, Bax, Cleaved Caspase-3, CytC), p-Akt, and muscle atrophy marker Atrogin1.ResultsTranscriptomic enrichment analysis confirmed specific activation of apoptosis, ERS, and ubiquitin-proteasome pathways. WB revealed upregulated ERS-related proteins, increased apoptotic proteins, decreased p-Akt expression, elevated Atrogin1 levels, and enhanced proteolytic activity. Db/db mice exhibited significant skeletal muscle atrophy, with Laminin Staining demonstrating reduced cross-sectional area (CSA) of muscle fibers.DiscussionThese findings uncovers a dual regulatory mechanism underlying diabetic muscle atrophy. The diabetic skeletal muscle microenvironment exhibits elevated oxidative stress and significantly enhanced ER stress, which promotes direct muscle atrophy through ER stress sensor-mediated apoptosis. Concurrently, sustained ER stress suppresses Akt activity while upregulating the muscle-specific E3 ubiquitin ligase Atrogin1, thereby accelerating proteolysis and inducing indirect muscle wasting. These findings provide crucial mechanistic insights into diabetic skeletal myopathy, highlighting the ER stress signaling network as a promising therapeutic target for mitigating muscle atrophy in diabetes.https://www.frontiersin.org/articles/10.3389/fphys.2025.1607873/fulltype 2 diabetes mellitusendoplasmic reticulum stressapoptosisskeletal muscle atrophyproteostasis |
| spellingShingle | Jingyi Yang Yingdong Wang Yuzhe Xu Xinqi Jia Fangping Lu Mechanisms of skeletal muscle atrophy in type 2 diabetes mellitus Frontiers in Physiology type 2 diabetes mellitus endoplasmic reticulum stress apoptosis skeletal muscle atrophy proteostasis |
| title | Mechanisms of skeletal muscle atrophy in type 2 diabetes mellitus |
| title_full | Mechanisms of skeletal muscle atrophy in type 2 diabetes mellitus |
| title_fullStr | Mechanisms of skeletal muscle atrophy in type 2 diabetes mellitus |
| title_full_unstemmed | Mechanisms of skeletal muscle atrophy in type 2 diabetes mellitus |
| title_short | Mechanisms of skeletal muscle atrophy in type 2 diabetes mellitus |
| title_sort | mechanisms of skeletal muscle atrophy in type 2 diabetes mellitus |
| topic | type 2 diabetes mellitus endoplasmic reticulum stress apoptosis skeletal muscle atrophy proteostasis |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2025.1607873/full |
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