Unravelling the unseen metabolic changes in patients with malignant hyperthermia.
Unravelling the unseen metabolic changes in patients with malignant hyperthermia.
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揭示恶性高热患者中看不见的代谢变化。
DOI：
10.1007/s12630-020-01896-x
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Allen,PaulD
中科院分区：
文献类型：
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作者：
Kaura,Vikas;Chang,Leon;Allen,PaulD
Denborough 等人报道了第一例最终被称为恶性高热 (MH) 的病例。 1962 年。1 此后，该领域取得了巨大进展，从识别导致患者发生 MH 反应的大多数基因，到深入了解 MH 患者细胞（以及 MH 动物模型）中观察到的钙稳态失衡的机制。一项反复观察到的结果是，在人类 MH 易感性 (MHS) 样本和 MH 小鼠模型中都发现了胞质细胞内钙 ([Ca2+] i) 的增强。 2-6 仍然存在的一个问题是，尽管 [Ca2+] i 持续升高，但在没有触发麻醉剂的情况下，骨骼肌如何正常发挥功能。 Bojko 等人的研究。本期杂志使用一种新颖的代谢组学方法解决了这个问题，其中使用两种不同的方法来检查来自 MHS 患者和非易感对照 (MHN) 患者的骨骼肌样本中的细胞代谢物。 7 作者发现 MHS 和 MHN 患者之间涉及碳水化合物和脂质代谢的各种途径的代谢物发生显着变化，能量产生从碳水化合物到脂质底物的整体转变。碳水化合物利用的变化与使用人类 MHS 患者和 MH、8、9 小鼠模型的肌肉样本进行的研究结果一致，并且显示出有氧代谢受损，这是能量底物发生这种变化所预期的。 8, 10–12有趣的是，这些作者发现，随着脂肪酸的积累，脂质代谢的转变似乎并不完美。游离脂肪酸是能量代谢的重要底物，其积累通常归因于脂肪酸运输和β氧化的缺陷。人体 MHS 肌肉中游离脂肪酸的积累表明其病理生理学中的潜在作用，并可能反映线粒体功能（脂肪酸 β-氧化部位）的缺陷。在 20 世纪 80 年代，根据对 MHS 猪 13 和人类的类似观察，骨骼肌线粒体被怀疑有助于 MH 的发育。 14 然而，之前的研究样本量有限，并且直到最近才开始对 MH 肌肉进行线粒体研究。这些 MHS 小鼠模型重新引起了人们对 MHS 肌肉线粒体功能的研究兴趣，迄今为止的所有研究都显示了静息状态下线粒体功能障碍的证据。 4, 5, 8 这些线粒体缺陷包括形态、数量和功能能力异常，最近对 MHS 患者肌肉的研究也发现了这些缺陷。 11, 12 Bojko 等人的这项研究。图 7 包含 MH 脂肪酸代谢缺陷的最全面证据，并支持线粒体功能与 MH 发育之间的联系。本文报道的 MHS 患者队列中几种脂质分子的增强令人着迷，因为这些是在固相微萃取 (SPME) 和代谢组平台上检测到的，表明结果至少有一定程度的同质性。然而，这些平台上鉴定的脂质种类存在差异，这可能是由于两种方法本身的直接结果或不同时间的样品储存和处理造成的。一个潜在的问题是
The first case of what eventually became known as malignant hyperthermia (MH) was reported by Denborough et al. in 1962. 1 Since then, great progress has been made in the field, from identifying the majority of genes predisposing patients to an MH reaction to gaining mechanistic insight into the calcium dyshomeostasis observed in cells from patients with MH (as well as in MH animal models). One recurrent observation has been an enhanced cytosolic intracellular calcium ([Ca2+] i) which has been found both in human MH susceptible (MHS) samples and in mouse models of MH. 2–6 A question that remains is how skeletal muscles appear to function normally in the absence of a triggering anesthetic, despite persistent elevations in [Ca2+] i. The study by Bojko et al. in this issue of the Journal has addressed this question using a novel metabolomics approach whereby two different methods were used to examine the cellular metabolites in skeletal muscle samples from MHS patients and non-susceptible control (MHN) patients. 7 The authors found significant changes in the metabolites of various pathways involved in carbohydrate and lipid metabolism between MHS and MHN patients, with an overall shift in energy production from carbohydrate to lipid substrates. Alterations in carbohydrate utilization is consistent with the results of studies using muscle samples from human MHS patients and mouse models of MH, 8, 9 as well as showing an impaired aerobic metabolism that would be expected with such a shift in energy substrate. 8, 10–12Interestingly, these authors found that the shift to lipid metabolism appeared to be imperfect with an accumulation of fatty acids. Free fatty acids are a vital substrate for energy metabolism, and their accumulation is often attributed to defects in fatty acid transport and betaoxidation. The accumulation of free fatty acids in human MHS muscle indicates a potential role in its pathophysiology and may reflect defects in mitochondrial function, the site of fatty acid beta-oxidation. In the 1980s, skeletal muscle mitochondria were suspected to contribute towards MH development based on similar observations in both MHS pigs 13 and humans. 14 Nevertheless, prior studies have been limited in their sample size and efforts in mitochondrial research on MH muscles have not been pursued until recently. These MHS mouse models have renewed research interests into mitochondrial function in MHS muscle, and all studies to date have shown evidence of mitochondrial dysfunction at rest. 4, 5, 8 These mitochondrial defects include abnormal morphology, number, and functional capacity, which have also been found in recent studies of muscle from MHS patients. 11, 12 This present study by Bojko et al. 7 contains the most comprehensive evidence of defective fatty acid metabolism in MH, and supports a connection between mitochondrial function and MH development. The reported enhancement of several lipid molecules in the MHS patient cohort in the current paper is fascinating as these were detected across both the solid phase microextraction (SPME) and Metabolome platforms, indicating at least some degree of homogeneity in the results. Nevertheless, there was variation in the lipid species identified across these platforms, which could be due to either a direct consequence of the two methods themselves or the sample storage and processing at different times. One potential problem with the