Wang Lu, Pang Xiangsheng, Li Shiming, Li Wenjiong, Chen Xiaoping, Zhang Peng
State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, 100094 Beijing, China.
National Key Laboratory of Human Factors Engineering, China Astronaut Research and Training Center, 100094 Beijing, China.
Front Biosci (Landmark Ed). 2023 Jul 13;28(7):136. doi: 10.31083/j.fbl2807136.
Muscle atrophy resulting wholly or partially from disuse represents a serious medical complication that decreases quality of life and increases morbidity and mortality. The accumulation of misfolded/unfolded proteins disrupts endoplasmic reticulum (ER) homeostasis and thus causes ER stress. Growing evidence indicates that ER stress plays an essential role in skeletal muscle remodeling under various physiological or pathophysiological conditions. However, whether ER stress is involved in disuse-induced muscle atrophy remains unclear.
To induce muscle atrophy, 8-week-old C57BL/6JNifdc male mice were subjected to 3, 7, or 14 days of hindlimb unloading (HU), and rhesus macaques () were subjected to 10∘ head-down tilted bed rest (HDBR) for 6 weeks. Tauroursodeoxycholic acid (TUDCA) (500 mg/kg/d) was orally administered to mice during HU to inhibit ER stress. Quantitative PCR, Western blotting, and immunohistochemistry were conducted to evaluate gene, protein, and structural changes, respectively.
ER stress marker genes were rapidly induced by HU in a similar trend to that observed with atrophy-related genes such as , muscle RING finger 1 (), and muscle ubiquitin ligase of SCF complex in atrophy-1 (). Inhibition of ER stress with TUDCA, a pan-ER stress inhibitor, attenuated HU-induced muscle atrophy and the upregulation of ubiquitin ligases the AKT/forkhead box O3a pathway. In addition, the oxidative-to-glycolytic myofiber type transition caused by HU was also inhibited by TUDCA treatment. ER stress activation was also confirmed in HDBR-induced rhesus soleus muscle atrophy.
The strong positive correlation between ER stress activation and both HU- and HDBR-induced muscle atrophy indicates that ER stress activation is ubiquitously involved in disuse-induced muscle atrophy, regardless of species. Thus, inhibiting ER stress may be an effective therapeutic strategy to prevent muscle atrophy during disuse.
完全或部分由废用引起的肌肉萎缩是一种严重的医学并发症，会降低生活质量并增加发病率和死亡率。错误折叠/未折叠蛋白的积累会破坏内质网（ER）稳态，从而导致内质网应激。越来越多的证据表明，内质网应激在各种生理或病理生理条件下的骨骼肌重塑中起重要作用。然而，内质网应激是否参与废用性肌肉萎缩仍不清楚。
为诱导肌肉萎缩，将8周龄的C57BL/6JNifdc雄性小鼠进行3天、7天或14天的后肢卸载（HU），将恒河猴进行6周的10°头低位卧床休息（HDBR）。在HU期间给小鼠口服牛磺熊去氧胆酸（TUDCA）（500mg/kg/d）以抑制内质网应激。分别进行定量PCR、蛋白质印迹和免疫组织化学以评估基因、蛋白质和结构变化。
HU迅速诱导内质网应激标记基因，其趋势与萎缩相关基因如肌萎缩相关基因1（MuRF1）、肌肉环指蛋白1（MuRF1）和萎缩相关的SCF复合物肌肉泛素连接酶1（MAFbx）相似。用泛内质网应激抑制剂TUDCA抑制内质网应激可减轻HU诱导的肌肉萎缩以及泛素连接酶的上调，并激活AKT/叉头框O3a（FOXO3a）信号通路。此外，TUDCA处理也抑制了HU引起的氧化型向糖酵解型肌纤维类型转变。在HDBR诱导的恒河猴比目鱼肌萎缩中也证实了内质网应激激活。
内质网应激激活与HU和HDBR诱导的肌肉萎缩之间的强正相关表明，内质网应激激活普遍参与废用性肌肉萎缩，与物种无关。因此，抑制内质网应激可能是预防废用期间肌肉萎缩的有效治疗策略。
