Department of Chemistry, University of Waterloo, Waterloo, ON, Canada.
Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland.
Can J Anaesth. 2021 Jun;68(6):761-772. doi: 10.1007/s12630-020-01895-y. Epub 2021 Jan 6.
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.
恶性高热（MH）是一种潜在致命的代谢亢进状态，由某些麻醉剂触发，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，易患 MH 的患者的各种生化途径受损。我们假设易患 MH 和对照个体之间的临床差异反映在细胞质代谢物的可测量差异中。
我们对来自 MH 阴性（对照）个体和接受肌肉活检以诊断 MH 易感性的易患 MH 患者的骨骼肌样本进行代谢组学分析。使用固相微萃取和 Metabolon®非靶向生化分析平台分别从 33 个新鲜和 87 个冷冻的人肌肉样本中提取细胞代谢物。使用超高效液相色谱-高分辨率质谱对代谢物进行鉴定和验证，然后分析易患 MH 组和 MH 阴性组之间代谢物的差异。
在来自各种途径的代谢物中发现易患 MH 组和对照组之间存在显著的倍数变化差异（P 值范围：0.009 至 <0.001）。这些差异包括长链酰基肉碱、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、氧化应激标志物和磷酸肌醇的积累，以及单酰基甘油水平的降低。两种分析平台的结果均一致。
这项代谢组学研究表明，易患 MH 的个体的能量产生从碳水化合物向脂质转移。这种转变可能导致β-氧化效率降低，肌肉蛋白周转率增加、氧化应激和/或溶血磷脂酰胆碱水平升高。
