Wen Ya, Zhang Xiang, Larsson Lars
Department of Physiology and Pharmacology, Karolinska Institutet, Bioclinicum, Stockholm, Sweden.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Bioclinicum, Stockholm, Sweden.
Front Cell Dev Biol. 2022 Mar 22;10:849973. doi: 10.3389/fcell.2022.849973. eCollection 2022.
Critical illness myopathy (CIM) and ventilator-induced diaphragm dysfunction (VIDD) are characterized by severe muscle wasting, muscle paresis, and extubation failure with subsequent increased medical costs and mortality/morbidity rates in intensive care unit (ICU) patients. These negative effects in response to modern critical care have received increasing attention, especially during the current COVID-19 pandemic. Based on experimental and clinical studies from our group, it has been hypothesized that the ventilator-induced lung injury (VILI) and the release of factors systemically play a significant role in the pathogenesis of CIM and VIDD. Our previous experimental/clinical studies have focused on gene/protein expression and the effects on muscle structure and regulation of muscle contraction at the cell and motor protein levels. In the present study, we have extended our interest to alterations at the metabolomic level. An untargeted metabolomics approach was undertaken to study two respiratory muscles (diaphragm and intercostal muscle) and lung tissue in rats exposed to five days controlled mechanical ventilation (CMV). Metabolomic profiles in diaphragm, intercostal muscles and lung tissue were dramatically altered in response to CMV, most metabolites of which belongs to lipids and amino acids. Some metabolites may possess important biofunctions and play essential roles in the metabolic alterations, such as pyruvate, citrate, S-adenosylhomocysteine, alpha-ketoglutarate, glycerol, and cysteine. Metabolic pathway enrichment analysis identified pathway signatures of each tissue, such as decreased metabolites of dipeptides in diaphragm, increased metabolites of branch-chain amino acid metabolism and purine metabolism in intercostals, and increased metabolites of fatty acid metabolism in lung tissue. These metabolite alterations may be associated with an accelerated myofibrillar protein degradation in the two respiratory muscles, an active inflammatory response in all tissues, an attenuated energy production in two respiratory muscles, and enhanced energy production in lung. These results will lay the basis for future clinical studies in ICU patients and hopefully the discovery of biomarkers in early diagnosis and monitoring, as well as the identification of future therapeutic targets.
危重病性肌病（CIM）和呼吸机诱导的膈肌功能障碍（VIDD）的特征是严重的肌肉萎缩、肌肉无力以及脱机失败，继而导致重症监护病房（ICU）患者的医疗费用增加以及死亡率/发病率上升。这些因现代重症监护而产生的负面影响日益受到关注，尤其是在当前的新冠疫情期间。基于我们团队的实验和临床研究，有人提出呼吸机诱导的肺损伤（VILI）和全身因子释放，在CIM和VIDD的发病机制中起着重要作用。我们之前的实验/临床研究聚焦于基因/蛋白质表达，以及在细胞和运动蛋白水平上对肌肉结构和肌肉收缩调节的影响。在本研究中，我们将兴趣扩展到了代谢组学水平的改变。采用非靶向代谢组学方法，研究了接受五天控制性机械通气（CMV）的大鼠的两块呼吸肌（膈肌和肋间肌）以及肺组织。响应CMV时，膈肌、肋间肌和肺组织中的代谢组学图谱发生了显著改变，其中大多数代谢物属于脂质和氨基酸。一些代谢物可能具有重要的生物功能，并在代谢改变中发挥关键作用，比如丙酮酸、柠檬酸、S-腺苷同型半胱氨酸、α-酮戊二酸、甘油和半胱氨酸。代谢途径富集分析确定了每个组织的途径特征，例如膈肌中双肽代谢物减少，肋间肌中支链氨基酸代谢和嘌呤代谢的代谢物增加，以及肺组织中脂肪酸代谢的代谢物增加。这些代谢物改变可能与两块呼吸肌中肌原纤维蛋白降解加速、所有组织中的活跃炎症反应、两块呼吸肌中能量产生减弱以及肺中能量产生增强有关。这些结果将为未来对ICU患者的临床研究奠定基础，并有望发现早期诊断和监测中的生物标志物，以及确定未来的治疗靶点。
