Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China.
J Cachexia Sarcopenia Muscle. 2024 Feb;15(1):81-97. doi: 10.1002/jcsm.13379. Epub 2023 Nov 28.
Sepsis-associated muscle weakness is common in patients of intensive care units (ICUs), and it is closely associated with poor outcomes. The mechanism of sepsis-induced muscle weakness is unclear. Recent studies have found that gut microbiota and metabolites are involved in the regulation of skeletal muscle mass and metabolism. This study aimed to investigate the effects of gut microbiota and metabolites on sepsis-associated muscle weakness.
In a lipopolysaccharide (LPS)-induced inflammation mouse model, mice with different sensitivities to LPS-induced inflammation were considered as donor mice for the faecal microbiota transplantation (FMT) assay, and recipient mice were divided into sensitive (Sen) and resistant (Res) groups. Skeletal muscle mass and function, as well as colonic barrier integrity were tested and gut microbiota and metabolite composition were analysed in both groups of mice. The effect of intestinal differential metabolite vitamin K1 on LPS-triggered muscle damage was investigated, and the underlying mechanism was explored.
Recipients exhibited varying LPS-triggered muscle damage and intestinal barrier disruption. Tibialis anterior (TA) muscle of Sen exhibited upregulated expression levels of MuRF-1 (0.825 ± 0.063 vs. 0.304 ± 0.293, P = 0.0141) and MAFbx (1.055 ± 0.079 vs. 0.456 ± 0.3, P = 0.0092). Colonic tight junction proteins ZO-1 (0.550 ± 0.087 vs. 0.842 ± 0.094, P = 0.0492) and occludin (0.284 ± 0.057 vs. 0.664 ± 0.191, P = 0.0487) were significantly downregulated in the Sen group. Metabolomic analysis showed significantly higher vitamin K1 in the faeces (P = 0.0195) and serum of the Res group (P = 0.0079) than those of the Sen group. After vitamin K1 intervention, muscle atrophy-related protein expression downregulated (P < 0.05). Meanwhile SIRT1 protein expression were upregulated (0.320 ± 0.035 vs. 0.685 ± 0.081, P = 0.0281) and pNF-κB protein expression were downregulated (0.815 ± 0.295 vs. 0.258 ± 0.130, P = 0.0308). PI3K (0.365 ± 0.142 vs. 0.763 ± 0.013, P = 0.0475), pAKT (0.493 ± 0.159 vs. 1.183 ± 0.344, P = 0.0254) and pmTOR (0.509 ± 0.088 vs. 1.110 ± 0.190, P = 0.0368) protein expression levels were upregulated in TA muscle. Meanwhile, vitamin K1 attenuated serum inflammatory factor levels.
Vitamin K1 might ameliorate LPS-triggered skeletal muscle damage by antagonizing NF-κB-mediated inflammation through upregulation of SIRT1 and regulating the balance between protein synthesis and catabolism.
脓毒症相关的肌肉无力在重症监护病房（ICU）的患者中很常见，与不良预后密切相关。脓毒症引起的肌肉无力的机制尚不清楚。最近的研究发现，肠道微生物群和代谢物参与调节骨骼肌质量和代谢。本研究旨在探讨肠道微生物群和代谢物对脓毒症相关肌肉无力的影响。
在脂多糖（LPS）诱导的炎症小鼠模型中，对 LPS 诱导的炎症敏感性不同的小鼠被视为粪便微生物群移植（FMT）检测的供体小鼠，受体小鼠分为敏感（Sen）和抗性（Res）组。测试两组小鼠的骨骼肌质量和功能以及结肠屏障完整性，并分析肠道微生物群和代谢物组成。研究了肠道差异代谢物维生素 K1 对 LPS 触发的肌肉损伤的影响，并探讨了其潜在机制。
受体小鼠表现出不同的 LPS 触发的肌肉损伤和肠道屏障破坏。Sen 组的比目鱼肌（TA）肌肉中 MuRF-1（0.825±0.063 vs. 0.304±0.293，P=0.0141）和 MAFbx（1.055±0.079 vs. 0.456±0.3，P=0.0092）的表达水平上调。结肠紧密连接蛋白 ZO-1（0.550±0.087 vs. 0.842±0.094，P=0.0492）和 occludin（0.284±0.057 vs. 0.664±0.191，P=0.0487）的表达水平明显下调。代谢组学分析显示，Res 组粪便（P=0.0195）和血清中的维生素 K1 水平明显高于 Sen 组。维生素 K1 干预后，肌肉萎缩相关蛋白表达下调（P<0.05）。同时 SIRT1 蛋白表达上调（0.320±0.035 vs. 0.685±0.081，P=0.0281），pNF-κB 蛋白表达下调（0.815±0.295 vs. 0.258±0.130，P=0.0308）。PI3K（0.365±0.142 vs. 0.763±0.013，P=0.0475）、pAKT（0.493±0.159 vs. 1.183±0.344，P=0.0254）和 pmTOR（0.509±0.088 vs. 1.110±0.190，P=0.0368）蛋白表达水平在 TA 肌肉中上调。同时，维生素 K1 降低了血清炎症因子水平。
维生素 K1 可能通过上调 SIRT1 拮抗 NF-κB 介导的炎症，调节蛋白合成和分解代谢之间的平衡，从而改善 LPS 触发的骨骼肌损伤。
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