Chen Renyu, Zheng Yingfang, Zhou Chenchen, Dai Hongkai, Wang Yurou, Chu Yun, Luo Jinlong
Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Biomedicines. 2024 Apr 18;12(4):902. doi: 10.3390/biomedicines12040902.
(1) Background: Sepsis-induced muscle atrophy is characterized by a loss of muscle mass and function which leads to decreased quality of life and worsens the long-term prognosis of patients. N-acetylcysteine (NAC) has powerful antioxidant and anti-inflammatory properties, and it relieves muscle wasting caused by several diseases, whereas its effect on sepsis-induced muscle atrophy has not been reported. The present study investigated the effect of NAC on sepsis-induced muscle atrophy and its possible mechanisms. (2) Methods: The effect of NAC on sepsis-induced muscle atrophy was assessed in vivo and in vitro using cecal ligation and puncture-operated (CLP) C57BL/6 mice and LPS-treated C2C12 myotubes. We used immunofluorescence staining to analyze changes in the cross-sectional area (CSA) of myofibers in mice and the myotube diameter of C2C12. Protein expressions were analyzed by Western blotting. (3) Results: In the septic mice, the atrophic response manifested as a reduction in skeletal muscle weight and myofiber cross-sectional area, which is mediated by muscle-specific ubiquitin ligases-muscle atrophy F-box (MAFbx)/Atrogin-1 and muscle ring finger 1 (MuRF1). NAC alleviated sepsis-induced skeletal muscle wasting and LPS-induced C2C12 myotube atrophy. Meanwhile, NAC inhibited the sepsis-induced activation of the endoplasmic reticulum (ER) stress signaling pathway. Furthermore, using 4-Phenylbutyric acid (4-PBA) to inhibit ER stress in LPS-treated C2C12 myotubes could partly abrogate the anti-muscle-atrophy effect of NAC. Finally, NAC alleviated myotube atrophy induced by the ER stress agonist Thapsigargin (Thap). (4) Conclusions: NAC can attenuate sepsis-induced muscle atrophy, which may be related to downregulating ER stress.
(1) 背景：脓毒症诱导的肌肉萎缩的特征是肌肉质量和功能丧失，这会导致生活质量下降并使患者的长期预后恶化。N-乙酰半胱氨酸（NAC）具有强大的抗氧化和抗炎特性，它可减轻多种疾病引起的肌肉萎缩，但其对脓毒症诱导的肌肉萎缩的作用尚未见报道。本研究探讨了NAC对脓毒症诱导的肌肉萎缩的影响及其可能机制。(2) 方法：使用盲肠结扎和穿刺手术（CLP）的C57BL/6小鼠和脂多糖（LPS）处理的C2C12肌管在体内和体外评估NAC对脓毒症诱导的肌肉萎缩的作用。我们使用免疫荧光染色分析小鼠肌纤维的横截面积（CSA）和C2C12的肌管直径的变化。通过蛋白质印迹法分析蛋白质表达。(3) 结果：在脓毒症小鼠中，萎缩反应表现为骨骼肌重量和肌纤维横截面积减少，这是由肌肉特异性泛素连接酶——肌肉萎缩F盒（MAFbx）/Atrogin-1和肌肉环指蛋白1（MuRF1）介导的。NAC减轻了脓毒症诱导的骨骼肌萎缩和LPS诱导的C2C12肌管萎缩。同时，NAC抑制了脓毒症诱导的内质网（ER）应激信号通路的激活。此外，使用4-苯基丁酸（4-PBA）抑制LPS处理的C2C12肌管中的ER应激可部分消除NAC的抗肌肉萎缩作用。最后，NAC减轻了内质网应激激动剂毒胡萝卜素（Thap）诱导的肌管萎缩。(4) 结论：NAC可减轻脓毒症诱导的肌肉萎缩，这可能与下调内质网应激有关。
