Metabolome analysisof the serotonin syndrome rat model: abnormal muscular contraction is relatedto metabolic alterations and hyper-thermogenesis
Metabolome analysisof the serotonin syndrome rat model: abnormal muscular contraction is relatedto metabolic alterations and hyper-thermogenesis
复制标题
血清素综合征大鼠模型代谢组学分析：肌肉收缩异常与代谢改变和过度生热有关
DOI：
10.1016/j.lfs.2018.06.031
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发表时间：
2018
期刊：
影响因子：
6.1
通讯作者：
Akira Ishii.
中科院分区：
文献类型：
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作者：
Kei Zaitsu*;Saki Noda;Akira Iguchi;Yumi Hayashi;Tomomi Ohara;YuyaKimura;Yuta Koketsu;Tomoko Kosaki;Maiko Kusano;Takako Sato;TetsuyaIshikawa;Hitoshi Tsuchihashi;Koichi Suzuki;Akira Ishii.
5-羟色胺综合征（SS）是选择性5-羟色胺再摄取抑制剂的不良反应，其发生机制尚不清楚，也没有特异性的临床生物标志物。本文对SS模型大鼠的代谢特征及代谢物组破坏的原因进行了研究。主要方法气相色谱-串联质谱法代谢物组学分析表明，其中55、22、49和41个在血浆、肝脏、腓肠肌、和古罗马人。特别是，乳酸在模型的腓肠肌中显著积累，而支链氨基酸在腓肠肌中未被消耗，表明模型中异常肌肉收缩的部位差异。UCP-3表达分析证实了这一结果。在模型的肝脏中观察到尿素循环的改变，主要归因于过度骨骼肌活动引起的蛋白质和/或氨基酸的分解，这得到了血浆BUN的支持：模型中的BUN水平显著高于对照组。与此相反，几乎所有的代谢产物，包括氨基酸和TCA循环中间产物在模型的血浆中显著增加，这表明由于无氧呼吸的加速，这些在肌肉的某些部分没有被消耗。显著性代谢谱显示，异常的肌肉收缩发生在特定的骨骼肌中，并通过上调无氧呼吸来增强能量产生，随后是UCP-3的过量表达，这有助于在SS模型中观察到的超生热。
AimsSerotonin syndrome (SS) is an adverse outcome of selective serotonin reuptake inhibitors, though its mechanism is not understood and there is no specific clinical biomarker. In this article, metabolic profiles of the SS model rats and causes of metabolome disruption were investigated.Main methodsGas chromatography-tandem mass spectrometry (GC/MS/MS)-based metabolomics, clinical biomarker measurements and qRT-PCR analysis forUCP-3in skeletal muscles were performed.Key findingsMetabolome analysis demonstrated that 55, 22, 49 and 41 of those were significantly altered in plasma, liver, gastrocnemius muscle, and trapezius, respectively. In particular, lactic acid significantly accumulated in the gastrocnemius muscle of the model, while the branched chain amino acids were not consumed in the trapezius, suggesting site differences in abnormal muscular contractions in the model. This result was supported byUCP-3expression analysis.Alteration of the urea cycle was observed in the liver of the model, attributed mainly to catabolism of proteins and/or amino acids from excess skeletal muscle activity, which was supported by plasma BUN: BUN levels in the model were significantly higher than those in the control. In contrast, almost all metabolites including amino acids and TCA-cycle intermediates significantly increased in plasma of the model, suggesting these were not consumed in some parts of the muscle due to acceleration of anaerobic respiration.SignificanceMetabolic profiling revealed that abnormal muscular contractions occurred in specific skeletal muscles and enhanced energy production by up-regulation of anaerobic respiration, followed by excess expression ofUCP-3, which contributes to the hyper-thermogenesis observed in the SS model.