Sheng Zhiyong, Yu Zhihong, Wang Meng, Zhou Rui, Chen Shenjian, Yu Xin, Li Fuxing
Department of Intensive Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
Department of Neurological Intensive Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
Biochem Biophys Rep. 2023 Dec 16;37:101608. doi: 10.1016/j.bbrep.2023.101608. eCollection 2024 Mar.
Sepsis-induced muscle weakness is a debilitating consequence of prolonged critical illness, often associated with a poor prognosis. While recent research has shown that STAT6 functions as an inhibitor of myogenesis, its role in sepsis-induced muscle weakness remains unclear. In this study, we hypothesized that inhibiting STAT6 could attenuate sepsis-induced muscle atrophy and weakness, and we explored the underlying mechanisms. Leveraging a microarray dataset from sepsis patients, we identified significant enrichment of genes related to muscle function, ferroptosis, and the p53 signalling pathway in muscle tissue from sepsis patients. Using a murine sepsis model induced by cecum ligation and puncture (CLP), we explore the multifaceted role of STAT6 inhibition. Our findings demonstrate that STAT6 inhibition effectively attenuates muscle atrophy, enhances grip strength, preserves mitochondrial integrity, and modulates ferroptosis in septic mice. Additionally, we identify elevated levels of CHI3L1 in septic muscle tissue, which are significantly reduced by STAT6 inhibition. In-depth analysis of primary muscle satellite cells reveals that CHI3L1 overexpression is associated with increased expression of key regulators of satellite cell myogenicity, while negatively impacting cell viability. Silencing CHI3L1 expression mitigates satellite cell injury and loss, highlighting its pivotal role in sepsis-induced muscle damage. In summary, this study unveils the potential of STAT6 as a therapeutic target for mitigating sepsis-induced muscle atrophy and weakness. Our findings underscore the regulation of mitochondrial dysfunction, ferroptosis, and CHI3L1-mediated satellite cell damage by STAT6, offering promising avenues for therapeutic intervention in the management of sepsis-induced muscle weakness.
脓毒症诱导的肌肉无力是长期危重病的一种使人衰弱的后果，通常与不良预后相关。虽然最近的研究表明信号转导和转录激活因子6（STAT6）作为肌生成的抑制剂发挥作用，但其在脓毒症诱导的肌肉无力中的作用仍不清楚。在本研究中，我们假设抑制STAT6可减轻脓毒症诱导的肌肉萎缩和无力，并探讨其潜在机制。利用脓毒症患者的微阵列数据集，我们发现在脓毒症患者的肌肉组织中，与肌肉功能、铁死亡和p53信号通路相关的基因显著富集。使用盲肠结扎和穿刺（CLP）诱导的小鼠脓毒症模型，我们探讨了STAT6抑制的多方面作用。我们的研究结果表明，抑制STAT6可有效减轻脓毒症小鼠的肌肉萎缩，增强握力，维持线粒体完整性，并调节铁死亡。此外，我们发现脓毒症肌肉组织中几丁质酶3样蛋白1（CHI3L1）水平升高，而STAT6抑制可使其显著降低。对原代肌肉卫星细胞的深入分析表明，CHI3L1过表达与卫星细胞肌源性关键调节因子的表达增加相关，同时对细胞活力产生负面影响。沉默CHI3L1表达可减轻卫星细胞损伤和损失，突出了其在脓毒症诱导的肌肉损伤中的关键作用。总之，本研究揭示了STAT6作为减轻脓毒症诱导的肌肉萎缩和无力的治疗靶点的潜力。我们的研究结果强调了STAT6对线粒体功能障碍、铁死亡和CHI3L1介导的卫星细胞损伤的调节作用，为脓毒症诱导的肌肉无力的治疗干预提供了有希望的途径。
