Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis.
Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis.
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DOI：
10.1371/journal.pone.0286525
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
重编程代谢对于降低脓毒症诱导的危重病期间的发病率和死亡率具有极大的治疗意义。针对脓毒症患者谷氨酰胺和抗氧化剂代谢的随机对照试验结果令人失望，这要求更深入地了解脓毒症的组织特异性代谢反应。目前的研究试图填补这一空白。我们分析了重症患者的骨骼肌转录组学，与择期手术对照组相比，发现参与线粒体代谢和电子传递的基因表达减少，谷胱甘肽循环、谷氨酰胺、支链和芳香族氨基酸转运增加。然后，我们进行了非靶向代谢组学和13 C同位素示踪，以分析小鼠多微生物败血症模型中的全身和组织特异性代谢表型。我们发现肝、肾和脾的代谢组之间的相关性增加，心脏和四头肌以及所有其他器官之间的相关性丧失，这表明重要腹部器官内的代谢特征是共享的，败血症期间肌肉的代谢特征是独特的。降低GSH：GSSG和升高AMP：ATP比在肝脏的基础上显着上调同位素标记的谷氨酰胺的贡献TCA循环回补和谷氨酰胺衍生的谷胱甘肽生物合成;同时，骨骼肌和脾脏是唯一的器官，谷氨酰胺的贡献TCA循环显着抑制。这些结果强调了组织特异性线粒体重编程以支持肝脏能量需求和抗氧化剂合成，而不是作为脓毒症的代谢结果的整体线粒体功能障碍。
Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged a deeper understanding of the tissue-specific metabolic response to sepsis. The current study sought to fill this gap. We analyzed skeletal muscle transcriptomics of critically ill patients, versus elective surgical controls, which revealed reduced expression of genes involved in mitochondrial metabolism and electron transport, with increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. We then performed untargeted metabolomics and 13C isotope tracing to analyze systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model. We found an increased number of correlations between the metabolomes of liver, kidney, and spleen, with loss of correlations between the heart and quadriceps and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for muscles during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamine’s contribution to TCA cycle anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamine’s contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming to support liver energetic demands and antioxidant synthesis, rather than global mitochondrial dysfunction, as a metabolic consequence of sepsis.
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