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Mechanisms of skeletal muscle atrophy in type 2 diabetes mellitus
Jingyi Yang1, Yingdong Wang1, Yuzhe Xu1
1Department of Pathophysiology, Mudanjiang Medical University, Mudanjiang, China.
Introduction:
ERS-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.
Methods:
Leptin 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.
Results:
Transcriptomic 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.
Discussion:
These 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.
Insights
Endoplasmic reticulum stress (ERS) drives diabetic skeletal muscle atrophy through apoptosis and by suppressing Akt signaling, leading to increased protein breakdown. Targeting ERS pathways may offer a therapeutic strategy for diabetic myopathy.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Diabetic skeletal muscle atrophy is a significant complication of type 2 diabetes mellitus (T2DM).
- The precise mechanisms linking endoplasmic reticulum stress (ERS) to diabetic muscle wasting remain incompletely understood.
- ERS-induced apoptosis is implicated in muscle atrophy, but its regulatory role in diabetes requires further elucidation.
Purpose of the Study:
- To investigate the impact of endoplasmic reticulum stress (ERS) on skeletal muscle atrophy in a mouse model of type 2 diabetes mellitus (T2DM).
- To elucidate the molecular mechanisms by which ERS contributes to muscle wasting in the context of diabetes.
Main Methods:
- Utilized leptin receptor-deficient *Db/db* mice as a T2DM model and age-matched C57BL/6J mice as controls.
- Performed transcriptome sequencing and pathway enrichment analysis focusing on apoptosis, ERS, and ubiquitin-proteasome pathways.
- Assessed skeletal muscle morphology and protein expression of ERS markers, apoptosis-related proteins, Akt, and the atrophy marker Atrogin1 via immunoblotting and Laminin Staining.
Main Results:
- Transcriptomic analysis confirmed activation of apoptosis, ERS, and ubiquitin-proteasome pathways in *Db/db* mice.
- Immunoblotting revealed upregulated ERS and apoptotic proteins, decreased p-Akt, and elevated Atrogin1 levels, indicating enhanced proteolysis.
- Skeletal muscle atrophy was evident, characterized by reduced muscle fiber cross-sectional area in *Db/db* mice.
Conclusions:
- Diabetic muscle atrophy involves a dual mechanism: direct atrophy via ERS-mediated apoptosis and indirect atrophy through Akt suppression and Atrogin1 upregulation.
- Sustained ERS in the diabetic microenvironment exacerbates muscle wasting by promoting proteolysis.
- The ERS signaling network presents a potential therapeutic target for mitigating skeletal muscle atrophy in diabetes.
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