对于慢性粒细胞白血病 (CML) 患者来说，一种突出、安全且有效的治疗方法是使用酪氨酸激酶抑制剂伊马替尼有针对性地抑制致癌蛋白 BCR::ABL1。相当一部分接受伊马替尼治疗的患者报告了影响其生活质量的骨骼肌肉不良事件。 OCTN2 膜转运蛋白参与伊马替尼转运至细胞内的过程。同时，OCTN2 的关键生理作用是细胞摄取肉碱，肉碱是线粒体 β-氧化途径的重要辅助因子。本工作探讨伊马替尼治疗对肉碱摄入和肌肉细胞能量代谢的影响。采用HTB-153（人横纹肌肉瘤）细胞系和KCL-22（CML细胞系）研究伊马替尼治疗对细胞内肉碱水平的影响反之亦然。对伊马替尼处理的细胞中能量代谢的变化进行了量化，并与暴露于高度特异性 OCTN2 抑制剂长春瑞滨的细胞的变化进行比较。使用小鼠模型来测试体外观察结果是否也能在体内大腿肌肉组织中实现。使用 Prominence HPLC 系统和串联质谱仪对感兴趣的分析物进行定量。这项工作表明，通过肉碱特异性转运蛋白 OCTN2，伊马替尼和肉碱的摄入量竞争不均匀，细胞内肉碱浓度显着降低。相反，肉碱预孵育不会影响伊马替尼细胞摄入或干扰白血病细胞靶向。用伊马替尼阻断细胞内肉碱供应可显着减少大多数克雷布斯循环代谢物和 ATP 的产生。然而，随后的肉碱补充挽救了线粒体的能量产生。由于特异性抑制 OCTN2 活性，体外肌肉细胞和小鼠模型大腿肌肉组织中肉碱的流入受阻，线粒体能量代谢受损。这项临床前实验研究揭示了伊马替尼对肉碱介导的能量代谢的不利影响肌肉细胞的分布为伊马替尼治疗期间经常发生的副作用（例如疲劳、肌肉疼痛和痉挛）提供了可能的分子背景。版权所有 © 2024 作者。由 Elsevier GmbH 出版。保留所有权利。

A prominent, safe and efficient therapy for patients with chronic myeloid leukemia (CML) is inhibiting oncogenic protein BCR::ABL1 in a targeted manner with imatinib, a tyrosine kinase inhibitor. A substantial part of patients treated with imatinib report skeletomuscular adverse events affecting their quality of life. OCTN2 membrane transporter is involved in imatinib transportation into the cells. At the same time, the crucial physiological role of OCTN2 is cellular uptake of carnitine which is an essential co-factor for the mitochondrial β-oxidation pathway. This work investigates the impact of imatinib treatment on carnitine intake and energy metabolism of muscle cells.HTB-153 (human rhabdomyosarcoma) cell line and KCL-22 (CML cell line) were used to study the impact of imatinib treatment on intracellular levels of carnitine and vice versa. The energy metabolism changes in cells treated by imatinib were quantified and compared to changes in cells exposed to highly specific OCTN2 inhibitor vinorelbine. Mouse models were used to test whether in vitro observations are also achieved in vivo in thigh muscle tissue. The analytes of interest were quantified using a Prominence HPLC system coupled with a tandem mass spectrometer.This work showed that through the carnitine-specific transporter OCTN2, imatinib and carnitine intake competed unequally and intracellular carnitine concentrations were significantly reduced. In contrast, carnitine preincubation did not influence imatinib cell intake or interfere with leukemia cell targeting. Blocking the intracellular supply of carnitine with imatinib significantly reduced the production of most Krebs cycle metabolites and ATP. However, subsequent carnitine supplementation rescued mitochondrial energy production. Due to specific inhibition of OCTN2 activity, the influx of carnitine was blocked and mitochondrial energy metabolism was impaired in muscle cells in vitro and in thigh muscle tissue in a mouse model.This preclinical experimental study revealed detrimental effect of imatinib on carnitine-mediated energy metabolism of muscle cells providing a possible molecular background of the frequently occurred side effects during imatinib therapy such as fatigue, muscle pain and cramps.Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.