线粒体保护在他汀类药物骨骼肌毒性中的作用

他汀类药物因其有效降低胆固醇的作用成为目前临床应用最广泛的降脂药，但他汀类药物的临床不良反应报告在逐年增多，其中以肌病（1%-10%）及致死性横纹肌溶解症（0.1%）报道最为严重，且无有效预防手段，并且运动能增加他汀药物相关性肌病的发病风险。目前他汀类药物导致肌细胞坏死的机制尚不明确，他汀药物抑制甲羟戊酸途径的同时，抑制线粒体内膜辅酶Q10合成，可导致线粒体氧化呼吸功能障碍、自由基生成增加和线粒体内源途径凋亡，引起肌肉损伤，但目前尚无相关研究。因此本课题采用高脂血症大鼠模型，探讨线粒体ATP耗竭和自由基爆发在他汀药物肌毒性中作用，同时观察运动是否通过加剧ATP耗竭而恶化他汀药物的肌毒性，以及联合补充电子传递体辅酶Q10和线粒体能量保护剂核黄素是否能有效预防他汀药物对横纹肌损伤。本研究创新性提出线粒体代谢异常在他汀药物肌毒性中的关键作用，为预防以及改善他汀药物相关肌病奠定基础。

Statins are the most popular lipid-lowering drug due to its effect on cholesterol control. But clinical reports on its adverse effects are gradually increasing, including statin-associated myopathy (1%-10%) and rhabdomyolysis (0.1%), and no effective prevention can be adopted. Some studies also show that exercise can increase the risk of statin-associated myopathy. Until now, the mechanism underlying statin-associated myopathy is unknown. Statins inhibit mevalonate pathway could lead to the inhibition of coenzyme Q10 synthesis on mitochondrial inner membrane, which may cause mitochondrial oxidative respiratory dysfunction, free radical increase and mitochondrial apoptosis pathway up-regulation, but more research data is needing. Therefore, in this study we use hyperlipidemia rat model to investigate the role of mitochondrial ATP depletion and the outbreak of free radicals in statin-associated myopathy, and whether ATP depletion is the reason that exercise exacerbates statin-associated myopathy. Also whether the combination supplementation of coenzyme Q10 and riboflavin is effective in the prevention of statin-associated myopathy is also investigated.The theory that mitochondrial metabolic abnormalities may play an essential role in statin-associated myopathy could contribute to the development of prevention drugs.