Xiong Guolin, Xie Yuqing, Tan Yufen, Ye Yuanyuan, Tan Xiaoyu, Jiang Limei, Qin Enyuan, Wei Xinyan, Li Jie, Liang Tong, Tang Xianyan, Bin Yanfei
Department of Epidemiology and Biostatistics, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.
Guangxi University of Chinese Medicine, Nanning, Guangxi, China.
Am J Physiol Cell Physiol. 2025 Jul 1;329(1):C325-C340. doi: 10.1152/ajpcell.01014.2024. Epub 2025 May 30.
Skeletal muscle atrophy and dysfunction are common comorbidities in chronic obstructive pulmonary disease (COPD), with cigarette smoke (CS) exposure being a significant contributing factor. However, the underlying mechanisms remain unclear. Inflammation driven by damage-associated molecular patterns (DAMPs), such as High-mobility group box 1 (HMGB1), may play a crucial role. This study investigated the involvement of HMGB1-mediated pyroptosis associated with skeletal muscle atrophy in COPD. Serum HMGB1 levels were measured in healthy nonsmokers and patients with COPD. Additionally, midthigh circumference and body mass index (BMI) were assessed in patients with COPD, and their correlations with HMGB1 levels were analyzed. Treatment with glycyrrhizin (GL, a direct inhibitor of HMGB1) in CS-exposed mice was further used to demonstrate the effect of HMGB1 on skeletal muscle. A C2C12 cell model exposed to cigarette smoke extract (CSE) was employed to elucidate the role of the HMGB1/Toll-like receptor 4 (TLR4)-NLR family pyrin domain-containing 3 (NLRP3)-gasdermin D (GSDMD)-Caspase-1 pathway. In patients with COPD, serum HMGB1 levels were significantly higher than in healthy individuals and negatively correlated with midthigh circumference and BMI. Treatment with GL in CS-exposed mice led to the reversal of muscle atrophy and dysfunction, alongside a reduction in the expression of TLR4 and pyroptosis-associated factors within skeletal muscle. In vitro experiments demonstrated that CSE increased HMGB1, which promoted skeletal muscle atrophy by driving inflammation through the HMGB1/TLR4-NLRP3-GSDMD-Caspase-1 pathway. HMGB1 induced by CS may trigger skeletal muscle atrophy. It promotes inflammation through HMGB1/TLR4-NLRP3-GSDMD-Caspase-1-mediated pyroptosis, thereby exacerbating muscle wasting. Therefore, the pathway represents a potential novel therapeutic target for skeletal muscle atrophy. This study reveals that the levels of High-mobility group box 1 (HMGB1) protein in patients with chronic obstructive pulmonary disease (COPD) are significantly higher than in healthy nonsmoking individuals and are negatively correlated with the degree of skeletal muscle atrophy. Through in vivo and in vitro experiments, we have confirmed that HMGB1 promotes inflammatory responses through the HMGB1/TLR4-NLRP3-GSDMD-Caspase-1-mediated pyroptosis pathway, thereby exacerbating muscle wasting. This pathway represents a potential novel therapeutic target for the treatment of skeletal muscle atrophy.
骨骼肌萎缩和功能障碍是慢性阻塞性肺疾病（COPD）常见的合并症，接触香烟烟雾（CS）是一个重要的促成因素。然而，其潜在机制仍不清楚。由损伤相关分子模式（DAMPs）驱动的炎症，如高迁移率族蛋白B1（HMGB1），可能起关键作用。本研究调查了COPD中与骨骼肌萎缩相关的HMGB1介导的细胞焦亡的参与情况。在健康非吸烟者和COPD患者中测量血清HMGB1水平。此外，评估了COPD患者的大腿中部周长和体重指数（BMI），并分析了它们与HMGB1水平的相关性。在暴露于CS的小鼠中用甘草甜素（GL，HMGB1的直接抑制剂）进行治疗，以进一步证明HMGB1对骨骼肌的影响。采用暴露于香烟烟雾提取物（CSE）的C2C12细胞模型来阐明HMGB1/Toll样受体4（TLR4）-NLR家族含pyrin结构域3（NLRP3）-gasdermin D（GSDMD）-半胱天冬酶-1途径的作用。在COPD患者中，血清HMGB1水平显著高于健康个体，且与大腿中部周长和BMI呈负相关。在暴露于CS的小鼠中用GL治疗导致肌肉萎缩和功能障碍的逆转，同时骨骼肌中TLR4和细胞焦亡相关因子的表达降低。体外实验表明，CSE增加了HMGB1，HMGB1通过HMGB1/TLR4-NLRP3-GSDMD-半胱天冬酶-1途径驱动炎症，从而促进骨骼肌萎缩。CS诱导的HMGB1可能触发骨骼肌萎缩。它通过HMGB1/TLR4-NLRP3-GSDMD-半胱天冬酶-1介导的细胞焦亡促进炎症，从而加剧肌肉消耗。因此，该途径代表了骨骼肌萎缩潜在的新型治疗靶点。本研究表明，慢性阻塞性肺疾病（COPD）患者的高迁移率族蛋白B1（HMGB1）蛋白水平显著高于健康非吸烟个体，且与骨骼肌萎缩程度呈负相关。通过体内和体外实验，我们证实HMGB1通过HMGB1/TLR4-NLRP3-GSDMD-半胱天冬酶-1介导的细胞焦亡途径促进炎症反应，从而加剧肌肉消耗。该途径代表了治疗骨骼肌萎缩潜在的新型治疗靶点。
