Statins: Mitochondrial Function and Aerobic Capacity

他汀类药物：线粒体功能和有氧能力

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要目前有超过 4000 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。并发症包括轻度至中度骨骼肌不良反应，报道发生率高达25%。此外，他汀类药物已研究显示，胰岛素抵抗会恶化，并会增加患 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的致病因素，但测试这些疾病的研究尚未在接受他汀类药物治疗的人类受试者中进行潜在的联系。患者服用通常还建议他汀类药物定期锻炼，以进一步降低代谢和疾病风险心血管疾病。然而，最近的证据表明他汀类药物会损害重要的运动适应，这可能是由于他汀类药物对线粒体产生负面影响而发生的骨骼肌。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极其重要，因为骨骼肌在维持机体功能方面发挥着关键作用。代谢和心血管健康。因此，本应用的目标是确定他汀类药物治疗对骨骼肌线粒体功能、心肺健康的影响人体的新陈代谢。目标 1 将使用纵向重复测量设计来测试安慰剂的影响， 20 毫克和 80 毫克/天的阿托伐他汀治疗对骨骼肌线粒体功能、胰岛素敏感性、和心肺健康。目标 2 将确定 20 毫克/天和 80 毫克/天的阿托伐他汀是否存在差异削弱线粒体、代谢和心肺对有氧运动训练的适应。状态- 最先进的人类研究将由两个机构合作进行，包括：线粒体功能及含量、胰岛素敏感性、心血管等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的机制数据：体内并提高他汀类药物治疗成本效益比的临床知识。