Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
J Appl Physiol (1985). 2012 Aug;113(3):479-86. doi: 10.1152/japplphysiol.01362.2011. Epub 2012 May 31.
Statins are cholesterol-lowering drugs widely used in the prevention of cardiovascular diseases; however, they are associated with various types of myopathies. Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and thus decrease biosynthesis of low-density lipoprotein cholesterol and may also reduce ubiquinones, essential coenzymes of a mitochondrial electron transport chain, which contain isoprenoid residues, synthesized through an HMG-CoA reductase-dependent pathway. Therefore, we hypothesized that statin treatment might influence physical performance through muscular mitochondrial dysfunction due to ubiquinone deficiency. The effect of two statins, atorvastatin and pravastatin, on ubiquinone content, mitochondrial function, and physical performance was examined by using statin-treated mice. Changes in energy metabolism in association with statin treatment were studied by using cultured myocytes. We found that atorvastatin-treated mice developed muscular mitochondrial dysfunction due to ubiquinone deficiency and a decrease in exercise endurance without affecting muscle mass and strength. Meanwhile, pravastatin at ten times higher dose of atorvastatin had no such effects. In cultured myocytes, atorvastatin-related decrease in mitochondrial activity led to a decrease in oxygen utilization and an increase in lactate production. Conversely, coenzyme Q(10) treatment in atorvastatin-treated mice reversed atorvastatin-related mitochondrial dysfunction and a decrease in oxygen utilization, and thus improved exercise endurance. Atorvastatin decreased exercise endurance in mice through mitochondrial dysfunction due to ubiquinone deficiency. Ubiquinone supplementation with coenzyme Q(10) could reverse atorvastatin-related mitochondrial dysfunction and decrease in exercise tolerance.
他汀类药物是广泛用于预防心血管疾病的降胆固醇药物；然而，它们与各种类型的肌病有关。他汀类药物抑制 3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶，从而减少低密度脂蛋白胆固醇的生物合成，也可能减少泛醌，线粒体电子传递链的必需辅酶，含有异戊二烯残基，通过 HMG-CoA 还原酶依赖性途径合成。因此，我们假设他汀类药物治疗可能会通过肌肉线粒体功能障碍影响身体表现，因为泛醌缺乏。使用他汀类药物治疗的小鼠检查了两种他汀类药物，阿托伐他汀和普伐他汀对泛醌含量、线粒体功能和身体表现的影响。通过培养的肌细胞研究了与他汀类药物治疗相关的能量代谢变化。我们发现，阿托伐他汀治疗的小鼠由于泛醌缺乏和运动耐力下降而发生肌肉线粒体功能障碍，而不影响肌肉质量和力量。同时，普伐他汀的剂量是阿托伐他汀的十倍，没有这种作用。在培养的肌细胞中，阿托伐他汀相关的线粒体活性降低导致氧利用减少和乳酸产量增加。相反，在阿托伐他汀治疗的小鼠中用辅酶 Q(10)治疗逆转了阿托伐他汀相关的线粒体功能障碍和氧利用减少，并因此改善了运动耐力。阿托伐他汀通过泛醌缺乏引起的线粒体功能障碍降低了小鼠的运动耐力。用辅酶 Q(10)补充泛醌可以逆转阿托伐他汀相关的线粒体功能障碍和运动耐量下降。
