Endoplasmic reticulum stress promotes sepsis-induced muscle atrophy via activation of STAT3 and Smad3.
Yingfang ZhengHongkai DaiRenyu ChenYanxia ZhongChenchen ZhouYurou WangChengye ZhanJinlong LuoPublished in: Journal of cellular physiology (2023)
Endoplasmic reticulum (ER) stress is involved in skeletal muscle atrophy in various conditions, but the role of ER stress in sepsis-induced muscle atrophy is not well understood. In this study, we conducted experiments in wild-type (WT) mice and C/EBP homologous protein knockout (CHOP KO) mice to explore the role and mechanism of ER stress in sepsis-induced muscle atrophy. Cecal ligation and puncture (CLP) was used to establish a mouse model of sepsis. In WT mice, the body weight, muscle mass, and cross-sectional area of muscle fibers in CLP group both decreased significantly compared with sham group, which revealed that sepsis-induced dramatic muscle atrophy. Additionally, sepsis activated the ubiquitin-proteasome system (UPS), accompanied by the activation of ER stress. In vitro, inhibition of ER stress suppressed the activity of E3 ubiquitin ligases and alleviated the myotube atrophy. In vivo, CHOP KO also reduced the expression of E3 ubiquitin ligases and UPS-mediated protein degradation, and significantly attenuated sepsis-induced muscle atrophy. Deletion of CHOP also decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and Smad3, and inhibition of STAT3 and Smad3 partly reduced proteolysis caused by ER stress in vitro. These findings confirm that ER stress activates UPS-mediated proteolysis and promotes sepsis-induced muscle atrophy, which is partly achieved by activating STAT3 and Smad3.
Keyphrases
- skeletal muscle
- intensive care unit
- acute kidney injury
- high glucose
- septic shock
- diabetic rats
- endoplasmic reticulum stress
- mouse model
- wild type
- cell proliferation
- body weight
- drug induced
- cross sectional
- small molecule
- insulin resistance
- diffuse large b cell lymphoma
- dna damage
- type diabetes
- endoplasmic reticulum
- endothelial cells
- oxidative stress
- immune response
- high fat diet induced
- dna repair
- binding protein
- single cell
- protein protein
- toll like receptor