Endoplasmic reticulum stress may induce apoptosis in gastrocnemius injury of obese mice with OSAHS
Authors: Huang Hanpeng , Sun Qian 
Published: October 2024

Abstract

Background:Obstructive sleep apnea-hypopnea syndrome (OSAHS) combined with obesity exacerbates clinical symptoms of OSAHS and has been associated with increased endoplasmic reticulum stress (ERS) leading to multi-organ damage including kidneys and liver. However, research on skeletal muscle injury in the context of OSAHS combined with obesity remains limited. This study aims to investigate the mechanisms and potential regulatory role of ERS in gastrocnemius muscle damage induced by OSAHS combined with obesity. Using a chronic intermittent hypoxia (CIH) combined with high-fat diet animal and cellular models, this research focuses on elucidating whether ERS plays a regulatory role in this process. Results from this study may contribute to understanding the pathophysiology of skeletal muscle damage in OSAHS patients with obesity and identify potential therapeutic targets.
Method:Forty male C57/BL6 mice aged 6-8 weeks and weighing 25-30g were randomly divided into four groups: Control group (RC), Chronic Intermittent Hypoxia group (RH), High-Fat Diet group (HC), and Chronic Intermittent Hypoxia combined with High-Fat Diet group (HH). The study aims to observe morphological changes in gastrocnemius muscle among these groups. Real-time quantitative PCR and Western blotting will be used to assess mRNA expression of MyHC1, MYH2, MYOG, MYOD, IRE1α, XBP1s, CHOP, and protein expression of MYH7, MYH2x, MYOG, MYOD1, IRE1α, XBP1s, CHOP, Caspase-3, TNF-α, IL-6 in mouse gastrocnemius muscle tissue. Additionally, a cellular model using C2C12 myotubes will be established combining Chronic Intermittent Hypoxia with High-Fat Diet, with groups including Control (CON), Chronic Intermittent Hypoxia (CIH), High-Fat Diet (PA), and Chronic Intermittent Hypoxia combined with High-Fat Diet (CIH+PA). Changes in cellular morphology post-differentiation and gene/protein expressions related to muscle fibers, endoplasmic reticulum stress, inflammation, damage, and apoptosis will be evaluated.
Results:1.In vivo experimental results: Chronic intermittent hypoxia combined with a high-fat diet leads to structural damage in the gastrocnemius muscle of mice, characterized by the transformation of type I muscle fibers to type II muscle fibers, inhibition of myotube formation, and enhanced endoplasmic reticulum stress. This condition further promotes inflammation and apoptosis within the gastrocnemius muscle tissue.2.In vitro cell culture results: Chronic intermittent hypoxia and high-fat treatment may alter the morphology of C2C12 myotube cells, leading to the transformation of type I muscle fibers to type II muscle fibers. This treatment inhibits myotube formation and differentiation, significantly enhances endoplasmic reticulum stress, and promotes cellular inflammation and apoptosis.
Conclusion :This study elucidates that chronic intermittent hypoxia combined with a high-fat diet may lead to structural damage in the gastrocnemius muscle of mice through the activation of endoplasmic reticulum stress, resulting in a transformation of muscle fiber types from type I to type II. Additionally, chronic intermittent hypoxia combined with a high-fat diet may induce excessive endoplasmic reticulum stress, activating apoptotic pathways and causing severe damage to the gastrocnemius muscle in mice.