Untargeted metabolomics profiling of skeletal muscle samples from malignant hyperthermia susceptible patients.
Untargeted metabolomics profiling of skeletal muscle samples from malignant hyperthermia susceptible patients.
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DOI：
10.1007/s12630-020-01895-y
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Pawliszyn J
中科院分区：
文献类型：
--
作者：
Bojko B;Vasiljevic T;Boyaci E;Roszkowska A;Kraeva N;Ibarra Moreno CA;Koivu A;Wąsowicz M;Hanna A;Hamilton S;Riazi S;Pawliszyn J
恶性高热（MH）是一种潜在致命的代谢亢进病症，由某些麻醉剂引发，并由骨骼肌细胞中钙稳态缺陷引起。最近的证据表明，在没有麻醉剂的情况下，MH 易感患者的各种生化途径会受到损害。我们假设 MH 易感个体和对照个体之间的临床差异反映在肌质代谢物的可测量差异上。我们对 MH 阴性（对照）个体和接受肌肉活检的 MH 易感患者的骨骼肌样本进行了代谢组学分析，以诊断 MH 易感性。分别使用固相微萃取和 Metabolon® 非靶向生化分析平台从 33 个新鲜和 87 个冷冻人体肌肉样品中提取细胞代谢物。采用超高效液相色谱-高分辨率质谱法进行代谢物鉴定和验证，然后分析MH敏感组和MH阴性组之间代谢物的差异。发现 MH 易感组和对照组之间不同途径的代谢物存在显着的倍数变化差异（P 值范围：0.009 至 < 0.001）。这些包括长链酰基肉碱、二酰基甘油、磷酸烯醇丙酮酸、组氨酸途径代谢物、溶血磷脂酰胆碱、氧化应激标记物和磷酸肌醇的积累，以及单酰基甘油水平的降低。两个分析平台的结果是一致的。这项代谢组学研究表明，MH 易感个体从利用碳水化合物转向利用脂质来产生能量。这种转变可能导致β-氧化效率低下，并增加肌肉蛋白周转、氧化应激和/或溶血磷脂酰胆碱水平。
Malignant hyperthermia (MH) is a potentially fatal hypermetabolic condition triggered by certain anesthetics and caused by defective calcium homeostasis in skeletal muscle cells. Recent evidence has revealed impairment of various biochemical pathways in MH-susceptible patients in the absence of anesthetics. We hypothesized that clinical differences between MH-susceptible and control individuals are reflected in measurable differences in myoplasmic metabolites. We performed metabolomic profiling of skeletal muscle samples from MH-negative (control) individuals and MH-susceptible patients undergoing muscle biopsy for diagnosis of MH susceptibility. Cellular metabolites were extracted from 33 fresh and 87 frozen human muscle samples using solid phase microextraction and Metabolon® untargeted biochemical profiling platforms, respectively. Ultra-performance liquid chromatography-high resolution mass spectrometry was used for metabolite identification and validation, followed by analysis of differences in metabolites between the MH-susceptible and MH-negative groups. Significant fold-change differences between the MH-susceptible and control groups in metabolites from various pathways were found (P value range: 0.009 to < 0.001). These included accumulation of long chain acylcarnitines, diacylglycerols, phosphoenolpyruvate, histidine pathway metabolites, lysophosphatidylcholine, oxidative stress markers, and phosphoinositols, as well as decreased levels of monoacylglycerols. The results from both analytical platforms were in agreement. This metabolomics study indicates a shift from utilization of carbohydrates towards lipids for energy production in MH-susceptible individuals. This shift may result in inefficiency of beta-oxidation, and increased muscle protein turnover, oxidative stress, and/or lysophosphatidylcholine levels.
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