Statins: Mitochondrial Function and Aerobic Capacity

项目摘要/摘要 目前有4000多万美国人服用他汀类药物来治疗或预防高脂血症和 心血管疾病(CVD)。他汀类药物治疗并非没有风险。并发症包括轻度到中度 骨骼肌不良反应，报告发生率高达25%。此外，他汀类药物已经被 被证明会加重胰岛素抵抗，增加患2型糖尿病的风险。线粒体的紊乱 呼吸功能已被认为是这些疾病的原因之一，但对此进行测试的研究 在接受他汀类药物治疗的人类受试者中，尚未发现潜在的联系。患者服用 他汀类药物通常也被建议定期锻炼，以进一步降低新陈代谢和 心血管疾病。然而，最近的证据表明，他汀类药物会损害重要的运动。 适应，这可能再次发生，因为他汀类药物对线粒体产生负面影响。 骨骼肌。综上所述，了解长期的他汀类药物治疗如何影响患者的线粒体功能 骨骼肌在临床上极其重要，因为骨骼肌在维持 代谢和心血管健康。因此，此应用程序的目标是确定 他汀类药物治疗对骨骼肌线粒体功能、心肺功能和 人类的新陈代谢。目标1将使用纵向、重复的措施设计来测试安慰剂的影响， 阿托伐他汀20、80 mg/d对骨骼肌线粒体功能、胰岛素敏感性、 和心肺健康。目标2将确定每天服用20毫克和80毫克阿托伐他汀是否存在差异 削弱线粒体、代谢和心肺系统对有氧运动训练的适应能力。现状-- 先进的人体研究将在两个机构之间合作进行，包括： 线粒体功能和含量、胰岛素敏感性、心血管功能的综合评价 功能，和心肺健康。这些研究将提供他汀类药物在以下方面的作用机制数据： 活体和提高他汀类药物治疗成本效益比的临床知识。

Project Summary/Abstract More than 40 million Americans currently take statins for the treatment or prevention of hyperlipidemia and cardiovascular disease (CVD). Statin therapy is not without risk. Complications include mild to moderate skeletal muscle adverse reactions, with reported incidence as high as 25%. In addition, statins have been shown to worsen insulin resistance and increase risk for type 2 diabetes. Disturbances in mitochondrial respiratory function have been implicated as a causal factor in these pathologies, but studies to test these potential links have not been conducted in human subjects undergoing statin therapy. Patients taking statins are also commonly advised to exercise regularly to further lower the risk for metabolic and cardiovascular disease. However, recent evidence suggests that statins can impair important exercise adaptations, and that this, again, may occur as a result of statins negatively impacting mitochondria in skeletal muscle. In summary, understanding how long-term statin therapy affects mitochondrial function in skeletal muscle is extremely important clinically, given the critical role skeletal muscle plays in maintaining metabolic and cardiovascular health. Therefore, the objectives of this application are to determine the impact of statin therapy on skeletal muscle mitochondrial function, cardiorespiratory fitness, and metabolism in humans. Aim 1 will use a longitudinal, repeated measures design to test impact of placebo, 20, and 80 mg/day of atorvastatin therapy on skeletal muscle mitochondrial function, insulin sensitivity, and cardiorespiratory fitness. Aim 2 will determine whether 20 and 80 mg/day of atorvastatin differentially blunt the mitochondrial, metabolic, and cardiorespiratory adaptations to aerobic exercise training. State-of- the-art human studies will be conducted in collaboration between two institutions and will include: comprehensive evaluation of mitochondrial function and content, insulin sensitivity, cardiovascular function, and cardiorespiratory fitness. These studies will provide mechanistic data on statin effects in- vivo and improve clinical knowledge of the cost-to-benefit ratio of statin therapy.