Statins: Mitochondrial Function and Aerobic Capacity

他汀类药物：线粒体功能和有氧能力

• 批准号: 9260468
• 负责人: P Darrell Neufer
• 金额: $ 61.69万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-20 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260468
• 关键词: Address; Adult; Adverse effects; Adverse reactions; Aerobic; Aerobic Exercise; Affect; Age-Years; Aging; American; American Heart Association; Animal Model; Biology; Cardiology; Cardiovascular Diseases; Cardiovascular Physiology; Cell Culture Techniques; Clinical; Collaborations; Coupled; Data; Diabetes Mellitus; Dose; Employee Strikes; Evaluation; Exercise; Fatigue; Guidelines; High Prevalence; Human; Hyperlipidemia; Impairment; In Situ; Incidence; Institutes; Institution; Insulin Resistance; Knowledge; Link; Measures; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Morbidity - disease rate; Muscle; Muscle Weakness; Myalgia; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Outcome Measure; Pain; Pathology; Patients; Placebos; Play; Prevention; Randomized; Recommendation; Reporting; Resources; Respiratory physiology; Risk; Risk Factors; Role; Secondary to; Selection Criteria; Skeletal Muscle; Symptoms; Testing; Very Light Exercise; atorvastatin; base; cardiorespiratory fitness; cardiovascular disorder risk; cardiovascular health; college; cost; design; diabetes risk; disorder risk; exercise program; exercise training; experience; human subject; improved; in vivo; insulin sensitivity; mortality; response; risk benefit ratio; sedentary; sedentary lifestyle

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.

项目总结/摘要 目前有超过4000万美国人服用他汀类药物治疗或预防高脂血症， 心血管疾病（CVD）。他汀类药物治疗并非没有风险。并发症包括轻度至中度 骨骼肌不良反应，据报道发生率高达25%。此外，他汀类药物已被 会恶化胰岛素抵抗，增加患2型糖尿病的风险。线粒体紊乱 呼吸功能被认为是这些病理学中的一个因果因素，但测试这些疾病的研究表明， 在接受他汀类药物治疗的人类受试者中尚未进行潜在的联系。病人服用 他汀类药物通常也被建议定期锻炼，以进一步降低代谢和 心血管疾病然而，最近的证据表明，他汀类药物可以损害重要的运动 适应，这可能是他汀类药物对线粒体产生负面影响的结果， 骨骼肌总之，了解长期他汀类药物治疗如何影响线粒体功能， 骨骼肌在临床上是极其重要的，因为骨骼肌在维持 代谢和心血管健康。因此，本申请的目的是确定 他汀类药物治疗对骨骼肌线粒体功能、心肺适应性和 人体的新陈代谢目标1将使用纵向重复测量设计来检验安慰剂的影响， 20和80 mg/天阿托伐他汀治疗对骨骼肌线粒体功能，胰岛素敏感性， 和心肺功能目的2将确定20和80 mg/天阿托伐他汀是否有差异 减弱线粒体、代谢和心肺对有氧运动训练的适应。国家 最先进的人体研究将由两个机构合作进行，包括： 线粒体功能和含量、胰岛素敏感性、心血管 功能和心肺功能。这些研究将提供他汀类药物作用的机制数据- 提高他汀类药物治疗的成本效益比的临床知识。