SCIATIC DENERVATION-INDUCED SKELETAL MUSCLE ATROPHY IS ASSOCIATED WITH PERSISTENT INFLAMMATION AND INCREASED MORTALITY DURING SEPSIS
SCIATIC DENERVATION-INDUCED SKELETAL MUSCLE ATROPHY IS ASSOCIATED WITH PERSISTENT INFLAMMATION AND INCREASED MORTALITY DURING SEPSIS
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DOI：
10.1097/shk.0000000000002053
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发表时间：
2022-11
期刊：
影响因子：
3.1
通讯作者：
Sumika Osa;Y. Enoki;Taichi Miyajima;M. Akiyama;Yukio Fujiwara;K. Taguchi;Yun-Gi Kim;Kazuaki Matsumoto
中科院分区：
文献类型：
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作者：
Sumika Osa;Y. Enoki;Taichi Miyajima;M. Akiyama;Yukio Fujiwara;K. Taguchi;Yun-Gi Kim;Kazuaki Matsumoto
摘要背景：患有潜在骨骼肌萎缩的患者可能会出现严重脓毒症。然而，尚无研究通过实验验证脓毒症的预后与肌肉萎缩之间的关联，并且肌肉萎缩下脓毒症加重的机制仍不清楚。在这项研究中，我们研究了坐骨神经去神经术（DN）（一种实验性肌肉萎缩模型）引起的骨骼肌萎缩对脓毒症预后的影响。方法：C57BL/6J雄性小鼠坐骨神经DN诱导骨骼肌萎缩。进行盲肠结扎穿刺（CLP）以诱导败血症。结果：CLP 后 7 天，假手术组和 DN 组的存活率分别为 63% 和 35%，其中 DN 组观察到约 30% 的存活率下降（与假手术 CLP 相比，P < 0.05）。 CLP 后 48 小时，DN 组血液中细菌计数较高（与假 CLP 相比，P < 0.05）。值得注意的是，CLP 后 DN 小鼠的 NOx（一氧化氮代谢物）浓度高于假手术小鼠（P < 0.05，与假 CLP 相比），而 CLP 后 48 小时血清血小板水平较低（P < 0.05，与假手术 CLP 相比）。在器官损伤分析中，DN 小鼠在 CLP 后肾损伤分子 (KIM-1) 和中性粒细胞明胶酶相关脂质运载蛋白 (NGAL)（一种肾损伤标志物）的蛋白表达增加（CLP 后 48 小时 NGAL，P < 0.05，与假 CLP 相比；CLP 后 24 小时 KIM-1，P < 0.01，与假 CLP 相比）。此外，与假 CLP 小鼠相比，CLP 后 48 小时 DN 小鼠肾脏中硝基酪氨酸水平较高，表明硝基应激的积累（与假 CLP 相比，P < 0.05）。 CLP 后两组血清细胞因子水平均升高，但 CLP 后 48 小时假手术组降低，DN 组持续较高（肿瘤坏死因子 [TNF]-α：P < 0.05，假手术 CLP 与 DN-CLP；白细胞介素 (IL)-1β：P < 0.01，假手术 CLP 与 DN-CLP；IL-6：P < 0.05， DN 与 DN-CLP；IL-10：P < 0.05，假-CLP 与 DN-CLP）。结论：我们证实 DN 引起的骨骼肌萎缩与 CLP 引起的脓毒症后不良预后相关。重要的是，骨骼肌萎缩的小鼠在发病后期表现出败血症预后恶化，包括长期感染、持续炎症和肾脏损伤累积，导致恢复延迟。
ABSTRACT Background: Patients with underlying skeletal muscle atrophy are likely to develop aggravated sepsis. However, no study has experimentally verified the association between the prognosis of sepsis and muscle atrophy, and the mechanism of aggravation of sepsis under muscle atrophy remains unclear. In this study, we investigated the effect of skeletal muscle atrophy induced by sciatic denervation (DN), an experimental muscle atrophy model, on sepsis prognosis. Methods: Skeletal muscle atrophy was induced by DN of the sciatic nerve in C57BL/6J male mice. Cecal ligation and puncture (CLP) was performed to induce sepsis. Results: The survival rates of the sham and DN groups 7 days after CLP were 63% and 35%, respectively, wherein an approximately 30% reduction was observed in the DN group (P < 0.05, vs. sham-CLP). The DN group had a higher bacterial count in the blood 48 h after CLP (P < 0.05, vs. sham-CLP). Notably, NOx (a metabolite of nitric oxide) concentrations in DN mice were higher than those in sham mice after CLP (P < 0.05, vs. sham-CLP), whereas serum platelet levels were lower 48 h after CLP (P < 0.05, vs. sham-CLP). In organ damage analysis, DN mice presented increased protein expression of the kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), a kidney injury marker, after CLP (NGAL 48 h after CLP, P < 0.05, vs. sham-CLP; KIM-1 24 h after CLP, P < 0.01, vs. sham-CLP). Furthermore, nitro tyrosine levels in the kidneys of DN mice were higher 48 h after CLP compared with those in sham-CLP mice, indicating the accumulation of nitrative stress (P < 0.05, vs. sham-CLP). Serum cytokine levels were increased in both groups after CLP, but decreased in the sham group 48 h after CLP and remained consistently higher in the DN group (tumor necrosis factor [TNF]-α: P < 0.05, sham-CLP vs. DN-CLP; interleukin (IL)-1β: P < 0.01, sham-CLP vs. DN-CLP; IL-6: P < 0.05, DN vs. DN-CLP; IL-10: P < 0.05, sham-CLP vs. DN-CLP). Conclusions: We verified that skeletal muscle atrophy induced by DN is associated with poor prognosis after CLP-induced sepsis. Importantly, mice with skeletal muscle atrophy presented worsening sepsis prognosis at late onset, including prolonged infection, persistent inflammation, and kidney damage accumulation, resulting in delayed recovery.