Lin Siming, Wu Jingying, Lian Guili, Wu Weibin, Chen Weixiao, Chen Ai, Luo Li, Xie Liangdi
Department of Emergency, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Department of Emergency, National Regional Medical Center, Binhai Campus of The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Front Pharmacol. 2025 Jun 27;16:1607606. doi: 10.3389/fphar.2025.1607606. eCollection 2025.
Endoplasmic reticulum stress (ERS) plays a critical role in skeletal muscle physiology and pathology, though the precise mechanisms remain unclear. Salubrinal, a selective inhibitor of eIF2α dephosphorylation, has been shown as a potential therapeutic agent for various conditions, but its effects on sarcopenia are not well understood. This study investigated the protective effects of salubrinal against HO-induced muscle cell injury and its impact on the eIF2α/ATF4 signaling pathway.
Gastrocnemius muscle samples from aged mice were used and cultured C2C12 myotubes were also used to explore the effects of Salubrinal through Western blotting, immunofluorescence, and apoptosis assays.
Our results demonstrated that HO treatment induced significant muscle cell damage, evidenced by reduced MHC1 expression and increased apoptosis. Salubrinal, in a concentration-dependent manner, mitigated these effects, preserving MHC1 expression and reducing apoptosis. Furthermore, salubrinal enhanced the expression of p-eIF2α and ATF4, suggesting that its protective effects are mediated through the eIF2α/ATF4 pathway.
These findings highlight salubrinal's potential as a therapeutic agent for muscle wasting conditions, particularly those related to oxidative stress and ERS.
内质网应激（ERS）在骨骼肌生理和病理过程中起关键作用，但其确切机制尚不清楚。Salubrinal是一种eIF2α去磷酸化的选择性抑制剂，已被证明是多种病症的潜在治疗药物，但其对肌肉减少症的影响尚不清楚。本研究调查了Salubrinal对过氧化氢（HO）诱导的肌肉细胞损伤的保护作用及其对eIF2α/激活转录因子4（ATF4）信号通路的影响。
使用老年小鼠的腓肠肌样本，并使用培养的C2C12肌管，通过蛋白质免疫印迹法、免疫荧光法和细胞凋亡检测来探究Salubrinal的作用效果。
我们的结果表明，HO处理诱导了显著的肌肉细胞损伤，这通过肌球蛋白重链1（MHC1）表达降低和细胞凋亡增加得以证明。Salubrinal以浓度依赖性方式减轻了这些影响，维持了MHC1表达并减少了细胞凋亡。此外，Salubrinal增强了磷酸化eIF2α（p-eIF2α）和ATF4的表达，表明其保护作用是通过eIF2α/ATF4途径介导的。
这些发现突出了Salubrinal作为肌肉萎缩病症治疗药物的潜力，特别是那些与氧化应激和ERS相关的病症
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