Trimetazidine restores the positive adaptation to exercise training by mitigating statin-induced skeletal muscle injury.
Trimetazidine restores the positive adaptation to exercise training by mitigating statin-induced skeletal muscle injury.
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曲美他嗪通过减轻他汀类药物引起的骨骼肌损伤恢复对运动训练的积极适应
DOI：
10.1002/jcsm.12250
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Han L
中科院分区：
文献类型：
--
作者：
Song M;Chen FF;Li YH;Zhang L;Wang F;Qin RR;Wang ZH;Zhong M;Tang MX;Zhang W;Han L
运动康复被证明可以改善冠心病患者的预后。他汀类药物作为冠心病降胆固醇的关键药物，会导致骨骼肌损伤，损害运动训练适应能力。能量代谢障碍被认为是他汀类药物引起骨骼肌损伤的潜在机制。在这项研究中，我们研究了代谢调节剂曲美他嗪对骨骼肌能量代谢和他汀类药物相关运动耐量的影响。高脂喂养载脂蛋白E基因敲除小鼠(ApoE−/−)进行有氧运动，分别给予辛伐他汀、曲美他嗪或辛伐他汀加曲美他嗪灌胃。治疗结束后通过悬栅试验、前肢握力、跑耐力试验评价运动能力。在治疗结束时测量血糖、血脂和肌酸激酶浓度。处死后，保存腓肠肌，用于肌肉形态和纤维类型的评估。能量代谢通过血浆乳酸浓度、粗糙的红色纤维和糖原储存来评估。测定线粒体复合体III活性、柠檬酸合成酶活性和膜电位以评估线粒体功能。氧化应激也通过线粒体中的超氧化物歧化酶活性和谷胱甘肽氧化还原状态来评估。在高脂喂养的载脂蛋白E−/−小鼠中，运动训练对血脂浓度没有影响。加用辛伐他汀治疗后，可观察到肌酸激酶升高可降低血脂浓度。单独进行运动训练后，运动能力显着增加，但加用辛伐他汀后，运动能力减弱。同样，运动组的肌肉纤维横截面积和慢收缩纤维的比例增加，而辛伐他汀加运动组的减少。此外，辛伐他汀通过抑制复合体III的活性增加中心有核纤维和诱导能量代谢功能障碍，从而促进腓肠肌的氧化应激。我们证明曲美他嗪可以逆转辛伐他汀诱导的运动耐受和肌肉损伤。我们还发现曲美他嗪具有恢复肌纤维肥大和促进快慢型转变的能力。曲美他嗪可改善腓肠肌的能量代谢障碍和氧化应激状态。曲美他嗪通过恢复氧化表型和增加运动训练中的纤维横截面积来减轻他汀类药物相关的骨骼肌损伤。相应地，高脂喂养的载脂蛋白E−/−小鼠的运动训练适应能力得到改善。此外，曲美他嗪能够在不影响他汀类药物有益降脂特性的情况下发挥其积极作用。因此，在冠心病患者的心脏康复过程中，曲美他嗪可以用来治疗他汀类药物引起的运动不耐受。
Exercise rehabilitation is demonstrated to improve the prognosis of patients with coronary heart disease (CHD). Statins, as the key medicine to lower cholesterol in CHD, result in skeletal muscle injury and impair exercise training adaptation. Energy metabolism dysfunction is identified as the potential mechanism underlying statin‐induced skeletal muscle injury. In this study, we investigated the effects of the metabolic modulator trimetazidine on skeletal muscle energy metabolism and statin‐associated exercise intolerance. High‐fat fed apolipoprotein E knockout (ApoE−/−) mice were given aerobic exercise and administrated simvastatin, trimetazidine, or simvastatin plus trimetazidine by gavage. Exercise capacity was evaluated at the end of the treatment by hanging grid test, forelimb grip strength, and running tolerance test. Plasma glucose, lipid, and creatine kinase concentrations were measured at the end of the treatment. After sacrifice, gastrocnemii were stored for assessment of muscle morphology and fibre type. Energy metabolism was estimated by plasma lactic acid concentration, ragged red fibres, and glycogen stores. Activities of mitochondrial complex III, citrate synthase activity, and membrane potential were measured to assess mitochondrial function. Oxidative stress was also evaluated by superoxide in mitochondria, superoxide dismutase activity, and glutathione redox state. In high‐fat fed ApoE−/− mice, exercise training had no effect on lipid concentrations. Lower lipid concentrations with increased creatine kinase were observed with additional simvastatin treatment. Exercise capacity increased significantly in response to exercise training alone but was blunted by the addition of simvastatin. Similarly, cross‐sectional area of muscle fibres and the proportion of slow‐twitch fibres increased in the exercise group but decreased in the simvastatin plus exercise group. Additionally, simvastatin increased centronucleated fibres and induced energy metabolism dysfunction by inhibiting complex III activity and thus promoted oxidative stress in gastrocnemius. We demonstrated that trimetazidine could reverse simvastatin‐induced exercise intolerance and muscle damages. We also found the ability of trimetazidine in restoration of muscle fibre hypertrophy and facilitating fast‐to‐slow type shift. The energy metabolism dysfunction and oxidative stress in gastrocnemii were rescued by trimetazidine. Trimetazidine alleviated statin‐related skeletal muscle injury by restoration of oxidative phenotype and increasing fibre cross‐sectional areas in response to exercise training. Correspondingly, the exercise training adaptation were improved in high‐fat fed ApoE−/− mice. Moreover, trimetazidine is able to exert its positive effects without affecting the beneficial lipid‐lowering properties of the statins. Thus, trimetazidine could be prescribed to remedy the undesirable statins‐induced exercise intolerance during cardiac rehabilitation in patients with CHD.
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