P2X7 Receptor acts as a novel target for ameliorating Sepsis-induced skeletal muscle atrophy in mice model.

IF 2.9 3区医学 Q2 CRITICAL CARE MEDICINE

SHOCK Pub Date : 2025-09-05 DOI:10.1097/SHK.0000000000002703

Yukun Liu, Qinxin Liu, Zhikai Xu, Xuan Zhao, Fan Yang, Zhanfei Li, Xiangjun Bai, Jian Yang, Yuchang Wang

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引用次数: 0

Abstract

Background and objective: Sepsis, a systemic inflammatory syndrome, frequently leads to substantial skeletal muscle loss and dysfunction, severely impairing patient prognosis. The P2X7 receptor is an ATP-gated cation channel implicated in inflammation and cell death. Although its role in the immune system has been extensively studied, its expression profile and pathogenic mechanism in sepsis-induced skeletal muscle atrophy remain unclear. This study aimed to investigate the functional role of the P2X7 receptor in sepsis-associated muscle injury and its potential as a therapeutic target.

Methods: A murine sepsis model was established using cecal ligation and puncture (CLP) surgery. Temporal changes in P2X7 receptor expression in the gastrocnemius (GP) and tibialis anterior (TA) muscles were assessed. Functional studies were performed using P2X7 knockout (P2X7⁻/⁻) mice and the P2X7-specific antagonist A-740003. Skeletal muscle atrophy, inflammatory responses, and activation of the NLRP3 inflammasome signaling pathway were systematically evaluated through Western blotting, qPCR, hematoxylin-eosin staining, muscle fiber cross-sectional area analysis, and measurement of inflammatory cytokines.

Results: In the CLP-induced sepsis model, P2X7 receptor expression in both GP and TA muscles was upregulated in a time-dependent manner. P2X7 gene deletion significantly attenuated body weight loss, muscle mass reduction, and muscle fiber atrophy, restored grip strength, and suppressed the expression of atrophy-related genes (Myostatin, Atrogin-1, and MuRF1). Moreover, it markedly reduced IL-6, IL-18, and IL-1β levels in both skeletal muscle and plasma, indicating an anti-inflammatory effect. P2X7 deficiency also significantly inhibited the expression of NLRP3 inflammasome components, caspase-1, and GSDMD, thereby blocking the pyroptosis signaling pathway. Pharmacological inhibition with A-740003 showed dose-dependent mitigation of muscle atrophy, further supporting the therapeutic potential of targeting P2X7.

Conclusion: The P2X7 receptor contributes to sepsis-induced skeletal muscle atrophy by promoting inflammation and muscle protein degradation through activation of the NLRP3 inflammasome and pyroptosis pathways. Genetic or pharmacological inhibition of P2X7 significantly alleviates muscle damage and functional loss. These findings provide strong experimental evidence supporting P2X7 as a potential therapeutic target for sepsis-associated myopathy.

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P2X7受体是改善脓毒症小鼠骨骼肌萎缩的新靶点。

背景与目的：脓毒症是一种全身性炎症综合征，常导致骨骼肌大量丧失和功能障碍，严重影响患者预后。P2X7受体是atp门控的阳离子通道，与炎症和细胞死亡有关。尽管其在免疫系统中的作用已被广泛研究，但其在败血症诱导的骨骼肌萎缩中的表达谱和致病机制尚不清楚。本研究旨在探讨P2X7受体在脓毒症相关肌肉损伤中的功能作用及其作为治疗靶点的潜力。方法：采用盲肠结扎穿刺法（CLP）建立小鼠脓毒症模型。评估腓肠肌（GP）和胫前肌（TA）中P2X7受体表达的时间变化。功能研究是用P2X7敲除（P2X7毒血症/毒血症）小鼠和P2X7特异性拮抗剂A-740003进行的。通过Western blotting、qPCR、苏木精-伊红染色、肌纤维横截面积分析和炎症因子测量，系统评估骨骼肌萎缩、炎症反应和NLRP3炎症小体信号通路的激活。结果：在clp诱导的脓毒症模型中，GP和TA肌肉中P2X7受体的表达均呈时间依赖性上调。P2X7基因缺失显著减轻了体重下降、肌肉质量减少和肌纤维萎缩，恢复了握力，抑制了萎缩相关基因（肌生长抑制素、Atrogin-1和MuRF1）的表达。此外，它还能显著降低骨骼肌和血浆中IL-6、IL-18和IL-1β的水平，表明它具有抗炎作用。P2X7缺乏也显著抑制NLRP3炎性小体组分、caspase-1和GSDMD的表达，从而阻断焦亡信号通路。A-740003的药理学抑制显示出肌肉萎缩的剂量依赖性缓解，进一步支持靶向P2X7的治疗潜力。结论：P2X7受体通过激活NLRP3炎性小体和焦亡途径，促进炎症和肌肉蛋白降解，参与败血症诱导的骨骼肌萎缩。基因或药理学抑制P2X7可显著减轻肌肉损伤和功能丧失。这些发现提供了强有力的实验证据，支持P2X7作为败血症相关肌病的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

SHOCK 医学-外科

CiteScore

6.20

自引率

3.20%

发文量

199

审稿时长

1 months

期刊介绍： SHOCK®: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches includes studies of novel therapeutic approaches, such as immunomodulation, gene therapy, nutrition, and others. The mission of the Journal is to foster and promote multidisciplinary studies, both experimental and clinical in nature, that critically examine the etiology, mechanisms and novel therapeutics of shock-related pathophysiological conditions. Its purpose is to excel as a vehicle for timely publication in the areas of basic and clinical studies of shock, trauma, sepsis, inflammation, ischemia, and related pathobiological states, with particular emphasis on the biologic mechanisms that determine the response to such injury. Making such information available will ultimately facilitate improved care of the traumatized or septic individual.