Yao Huiming, Xie Qian, Yang Yuting, Zhou Chaoqi, Zeng Zhenguo, Zhang Wei
Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China; Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
Int Immunopharmacol. 2025 Jan 10;144:113619. doi: 10.1016/j.intimp.2024.113619. Epub 2024 Nov 26.
In intensive care units, sepsis-related muscle atrophy is a severe complication of numerous diseases, yet the underlying mechanism and potential therapeutic options remain elusive. Recent research has identified melatonin as a promising candidate for attenuating organ dysfunction triggered by sepsis.
We used in vitro and in vivo models to simulate sepsis, C2C12 myotubes were treated with LPS, and the mice underwent cecal ligation and puncture (CLP) surgery. Following a pretreatment regimen involving melatonin and the AKT inhibitor MK-2206 2HCl, we analyzed changes in p-Akt and MuRF1 protein levels, fiber cross-sectional areas, and myotube diameters. The analyses included RNA sequencing, Western blotting, qRT-PCR, and immunofluorescence staining.
Activation of the PI3K/Akt pathway in skeletal muscle occurred 24 h post-CLP surgery in mice. This was accompanied by upregulated MuRF1 expression and reduced muscle fiber cross-sectional area, which culminated in muscle atrophy. However, these detrimental effects were attenuated when the mice were pretreated with melatonin via intraperitoneal injection for seven consecutive days. Similarly, LPS treatment of C2C12 myotubes activated the PI3K/Akt pathway, elevated MuRF1 expression, and markedly reduced myotube diameter after 48 h, leading to muscle atrophy. Pretreatment of C2C12 myotubes with melatonin 24 h in advance mitigated these adverse effects. However, cotreatment of C2C12 myotubes with melatonin and MK-2206 2HCl attenuated the beneficial effects of melatonin.
Melatonin can attenuate sepsis-induced muscle atrophy by regulating the PI3K/Akt pathway.
在重症监护病房中，脓毒症相关的肌肉萎缩是许多疾病的严重并发症，但其潜在机制和可能的治疗方法仍不明确。最近的研究表明，褪黑素是减轻脓毒症引发的器官功能障碍的一个有潜力的候选物质。
我们使用体外和体内模型模拟脓毒症，用脂多糖处理C2C12肌管，并对小鼠进行盲肠结扎和穿刺（CLP）手术。在采用褪黑素和AKT抑制剂MK-2206 2HCl进行预处理后，我们分析了p-Akt和MuRF1蛋白水平、纤维横截面积和肌管直径的变化。分析方法包括RNA测序、蛋白质免疫印迹、qRT-PCR和免疫荧光染色。
小鼠CLP手术后24小时，骨骼肌中的PI3K/Akt通路被激活。这伴随着MuRF1表达上调和肌纤维横截面积减小，最终导致肌肉萎缩。然而，当小鼠连续7天腹腔注射褪黑素进行预处理时，这些有害影响得到了减轻。同样，脂多糖处理C2C12肌管会激活PI3K/Akt通路，提高MuRF1表达，并在48小时后显著减小肌管直径，导致肌肉萎缩。提前24小时用褪黑素预处理C2C12肌管可减轻这些不良反应。然而，C2C12肌管用褪黑素和MK-2206 2HCl共同处理会减弱褪黑素的有益作用。
褪黑素可通过调节PI3K/Akt通路减轻脓毒症诱导的肌肉萎缩。
