Abstract：
Statins are the first line of choice for the treatment for atherosclerosis, but their use can cause myotoxicity, a common side effect that may require dosage reduction or discontinuation. The exact mechanism of statin-induced myotoxicity is unknown. Previous research has demonstrated that the combination of idebenone and statin yielded superior anti-atherosclerotic outcomes. Here, we investigated the mechanism of statin-induced myotoxicity in atherosclerotic ApoE-/- mice and whether idebenone could counteract it. After administering simvastatin to ApoE-/- mice, we observed a reduction in plaque formation as well as a decrease in their exercise capacity. We observed elevated levels of lactic acid and creatine kinase, along with a reduction in the cross-sectional area of muscle fibers, an increased presence of ragged red fibers, heightened mitochondrial crista lysis, impaired mitochondrial complex activity, and decreased levels of CoQ9 and CoQ10. Two-photon fluorescence imaging revealed elevated H2O2 levels in the quadriceps, indicating increased oxidative stress. Proteomic analysis indicated that simvastatin inhibited the tricarboxylic acid cycle. Idebenone treatment not only further reduced plaque formation but also ameliorated the impaired exercise capacity caused by simvastatin. Our study represents the inaugural comprehensive investigation into the mechanisms underlying statin-induced myotoxicity. We have demonstrated that statins inhibit CoQ synthesis, impair mitochondrial complex functionality, and elevate oxidative stress, ultimately resulting in myotoxic effects. Furthermore, our research marks the pioneering identification of idebenone\'s capability to mitigate statin-induced myotoxicity by attenuating oxidative stress, thereby safeguarding mitochondrial complex functionality. The synergistic use of idebenone and statin not only enhances the effectiveness against atherosclerosis but also mitigates statin-induced myotoxicity.
摘要：
他汀类药物是治疗动脉粥样硬化的首选药物，但是它们的使用会导致肌肉毒性，一种常见的副作用，可能需要减少剂量或停药。他汀类药物诱导的肌毒性的确切机制尚不清楚。先前的研究表明，艾地苯醌和他汀类药物的组合产生了更好的抗动脉粥样硬化结果。这里,我们研究了他汀类药物诱导动脉粥样硬化ApoE-/-小鼠肌毒性的机制以及艾地苯醌是否可以抵消它。给ApoE-/-小鼠服用辛伐他汀后，我们观察到斑块形成减少，运动能力下降。我们观察到乳酸和肌酸激酶水平升高，随着肌肉纤维横截面积的减少，参差不齐的红色纤维的增加，线粒体crista裂解增强，线粒体复合物活性受损，CoQ9和CoQ10水平下降。双光子荧光成像显示股四头肌中H2O2水平升高，表明氧化应激增加。蛋白质组分析表明辛伐他汀抑制三羧酸循环。艾地苯醌治疗不仅进一步减少了斑块形成，而且改善了辛伐他汀引起的运动能力受损。我们的研究代表了对他汀类药物诱导的肌毒性机制的首次全面研究。我们已经证明他汀类药物抑制CoQ合成，损害线粒体复合物的功能，并提高氧化应激，最终导致肌毒性效应。此外，我们的研究标志着开创性的鉴定艾地苯醌的能力，以减轻他汀类药物诱导的肌毒性通过减弱氧化应激，从而保护线粒体复合物的功能。艾地苯醌和他汀类药物的协同使用不仅增强了抗动脉粥样硬化的有效性，而且减轻了他汀类药物诱导的肌毒性。
