Muscle stem cells contribute to long-term tissue repletion following surgical sepsis.
Muscle stem cells contribute to long-term tissue repletion following surgical sepsis.
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DOI：
10.1002/jcsm.13214
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发表时间：
2023-06
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影响因子：
--
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中科院分区：
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在过去的十年中，脓毒症识别和管理的进步导致脓毒症死亡率下降。生存率的增加凸显了一个新的临床障碍：慢性危重症（CCI），目前尚无有效的治疗方案。多达一半的败血症幸存者患有CCI，包括多器官功能障碍、慢性炎症、肌肉萎缩、身体和精神残疾以及虚弱加剧。这些症状使幸存者无法恢复正常的日常活动，并与生活质量差直接相关。采用每日慢性应激（DCS）对小鼠进行盲肠结扎和穿刺（CLP）作为体内模型，研究败血症对骨骼肌成分的后期效应/后遗症。通过磁共振成像、骨骼肌和/或肌肉干细胞（MuSC）测定（例如尸检后湿肌重量、最小Feret直径测量、体外MuSC增殖和分化、再生肌纤维数量和每条肌纤维Pax7阳性细胞核数量）、败血症后全肌肉代谢组学、MuSC分离和高含量转录谱进行纵向监测。我们报告了几项研究结果，支持MuSCs/肌肉再生在脓毒症后肌肉恢复中起关键作用的假设。首先，我们发现肌肉干细胞（MuSCs）的基因消融会损害败血症后的肌肉恢复（与对照组相比，平均瘦质量损失维持在5-8%）。其次，与对照组相比，我们观察到败血症后26天MuSCs的扩张能力受损和形态缺陷（P < 0.001）。第三，当遭受实验性肌肉损伤时，与接受相同肌肉损伤的非脓毒症小鼠相比，脓毒症恢复小鼠表现出肌肉再生受损的证据（CLP/DCS损伤的平均最小Feret是对照组损伤的92.1%,P < 0.01）。第四，我们对脓毒症后小鼠分离的MuSCs进行了纵向RNA测序研究，发现与对照组相比，所有脓毒症后样本的转录差异明显。第28天，与对照组相比，CLP/DCS小鼠卫星细胞有多种代谢途径发生改变，如氧化磷酸化、线粒体功能障碍、sirtuin信号传导和雌激素受体信号传导（P < 0.001）。我们的数据显示，脓毒症后有效的肌肉恢复需要musc和肌肉再生，脓毒症触发musc的形态、功能和转录变化。展望未来，我们努力利用对脓毒症后MuSC/再生缺陷的更全面的了解来确定和测试促进脓毒症幸存者肌肉恢复和提高生活质量的新疗法。
Over the past decade, advances in sepsis identification and management have resulted in decreased sepsis mortality. This increase in survivorship has highlighted a new clinical obstacle: chronic critical illness (CCI), for which there are no effective treatment options. Up to half of sepsis survivors suffer from CCI, which can include multi‐organ dysfunction, chronic inflammation, muscle wasting, physical and mental disabilities, and enhanced frailty. These symptoms prevent survivors from returning to regular day‐to‐day activities and are directly associated with poor quality of life. Mice were subjected to cecal ligation and puncture (CLP) with daily chronic stress (DCS) as an in vivo model to study sepsis late‐effects/sequelae on skeletal muscle components. Longitudinal monitoring was performed via magnetic resonance imaging, skeletal muscle and/or muscle stem cell (MuSCs) assays (e.g., post‐necropsy wet muscle weights, minimum Feret diameter measurements, in vitro MuSC proliferation and differentiation, number of regenerating myofibres and numbers of Pax7‐positive nuclei per myofibre), post‐sepsis whole muscle metabolomics and MuSC isolation and high‐content transcriptional profiling. We report several findings supporting the hypothesis that MuSCs/muscle regeneration are critically involved in post‐sepsis muscle recovery. First, we show that genetic ablation of muscle stem cells (MuSCs) impairs post‐sepsis muscle recovery (maintenance of 5–8% average lean mass loss compared with controls). Second, we observe impaired MuSCs expansion capacity and morphological defects at 26 days post‐sepsis compared with control MuSCs (P < 0.001). Third, when subjected to an experimental muscle injury, sepsis‐recovered mice exhibited evidence of impaired muscle regeneration compared with non‐septic mice receiving the same muscle injury (CLP/DCS injured mean minimum Feret is 92.1% of control injured, P < 0.01). Fourth, we performed a longitudinal RNA sequencing study on MuSCs isolated from post‐sepsis mice and found clear transcriptional differences in all post‐sepsis samples compared with controls. At Day 28, CLP/DCS mice satellite cells have multiple altered metabolic pathways, such as oxidative phosphorylation, mitochondrial dysfunction, sirtuin signalling and oestrogen receptor signalling, compared with controls (P < 0.001). Our data show that MuSCs and muscle regeneration are required for effective post‐sepsis muscle recovery and that sepsis triggers morphological, functional, and transcriptional changes in MuSCs. Moving forward, we strive to leverage a more complete understanding of post‐sepsis MuSC/regenerative defects to identify and test novel therapies that promote muscle recovery and improve quality of life in sepsis survivors.
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影响因子：
3.7
作者：
Battle CE;Davies G;Evans PA
通讯作者：
Evans PA
脓毒症病理生理学、慢性危重疾病、持续性炎症-免疫抑制和分解代谢综合征。
影响因子：
8.8
作者：
Mira JC;Gentile LF;Mathias BJ;Efron PA;Brakenridge SC;Mohr AM;Moore FA;Moldawer LL
通讯作者：
Moldawer LL
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
3.4
作者：
Minnaard, R;Drost, MR;Hesselink, MKC
通讯作者：
Hesselink, MKC
影响因子：
8.8
作者：
Callahan LA;Supinski GS
通讯作者：
Supinski GS