Skeletal muscle mitochondrial abnormalities in Alzheimer's Disease

阿尔茨海默病中的骨骼肌线粒体异常

• 批准号: 9474088
• 负责人: John P Thyfault
• 金额: $ 19.13万
• 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: 2017-05-01 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9474088
• 关键词: Accelerometer; Address; Aerobic; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Animal Model; Biopsy; Blood; Blood Platelets; Brain; Cell Line; Cells; Chronic; Chronic Disease; Clinical; Cognition; Dementia; Development; Disease; Disease susceptibility; Energy Metabolism; Exercise; Exercise stress test; Exhibits; Future; Genetic; Genotype; Goals; Hybrid Cells; Hydrogen Peroxide; Impaired cognition; Impairment; Insulin Resistance; Intervention; Knowledge; Lead; Life Style; Link; Measures; Metabolism; Mitochondria; Mitochondrial DNA; Modeling; Muscle Mitochondria; Outcome Measure; Pathologic; Pathology; Patients; Pattern; Physical activity; Play; Prevention therapy; Reporting; Respiratory physiology; Risk; Role; Skeletal Muscle; Statistical Models; Testing; Time; Variant; Weight; apolipoprotein E-4; base; disease diagnosis; enzyme activity; high reward; high risk; insulin sensitivity; mitochondrial dysfunction; mortality; nervous system disorder; non-demented; novel; primary outcome; recruit; respiratory; secondary outcome; sedentary; sedentary activity; sedentary lifestyle; sex

Abstract/Project Summary Emerging evidence suggests mitochondrial dysfunction and impaired energy metabolism play a role in the development of Alzheimer's disease (AD). Our group previously reported reduced mitochondrial function in platelets isolated from blood of AD patients and in cytoplasmic hybrid cell lines generated with mitochondrial DNA from AD patients. Moreover, one of the early signs of AD is hypo-metabolism in the brain, further proof of mitochondrial dysfunction. Skeletal muscle mitochondria play a critical role in whole body aerobic capacity (VO2 peak), a powerful predictor of chronic disease and mortality risk. Mitochondrial dysfunction in skeletal muscle is also involved in whole body insulin resistance, which has emerged as a risk factor for AD. In support of these concepts, we have previously shown that AD patients have both reduced aerobic capacity and reduced insulin sensitivity compared to non-demented (ND) subjects of similar age and weight, strongly suggesting that AD patients also have skeletal muscle mitochondrial dysfunction. Potential causes for skeletal muscle mitochondrial dysfunction in AD patients is unclear but could be linked to an inactive lifestyle (chronic inactivity and sedentary lifestyle), which is increasingly linked to reduced cognition and AD risk and also accelerates skeletal muscle mitochondrial dysfunction that occurs with aging. In addition, genetics may play a role in the mitochondrial dysfunction found in AD. Apolipoprotein E4 (APOE ε4) carriers have the greatest risk for sporadic AD and animal models suggest that APOE ε4 impairs mitochondrial respiratory function via a pathological domain interaction. Therefore, it is possible that both lifestyle and genetic factors impact skeletal muscle mitochondrial function in AD patients but this has not been examined. To address this knowledge gap we will examine skeletal muscle mitochondrial-content, -enzyme activity, -respiratory capacity, and -H202 emission in skeletal muscle biopsies obtained from AD compared to age and sex matched ND subjects. To examine the role of genotype, we will recruit subjects that are APOE ε4 carriers or non-carriers in both the AD and ND groups (half of each group). To examine the role of lifestyle we will measure aerobic capacity (VO2 peak) and daily physical activity and sedentary behavior in all subjects. The first aim will test if skeletal muscle mitochondrial function and whole-body aerobic capacity are compromised in AD and in APOE ε4 carriers compared to ND and non-APOE ε4 carriers. The second aim will rank mitochondrial function and aerobic capacity function dependent upon AD status and genotype. This novel study examines how non-brain targets may drive AD susceptibility via lifestyle and/or genetic factors and could point to skeletal muscle mitochondria as a target for future therapies for prevention of AD.

摘要/项目摘要 新兴的证据表明线粒体功能障碍和能量代谢受损在其中起作用 阿尔茨海默氏病的发展（AD）。 在从AD患者血液中分离出的血小板和与之产生的细胞质杂化细胞系中。 另外，AD患者的线粒体DNA。 大脑，线粒体功能障碍的进一步证明。 人体有氧能力（VO2峰），这是慢性疾病和死亡风险的有力预测指标。 骨骼肌的线粒体功能障碍也参与全身胰岛素耐药性，该抗药性具有 成为支持这些概念的风险因素 与非痴呆（ND）相比，有氧能力降低和胰岛素敏感性降低 年龄和体重相似的受试者，强烈表明AD患者也具有骨骼肌肉 线粒体功能障碍。 不清楚，但可能与不活动的生活方式有关（慢性不活动和久坐的生活方式），这是 越来越多地与降低的认知和AD风险联系在一起，也会使骨骼肌肉线粒体病变 与衰老相关的功能障碍。 在AD中发现。 模型表明APOEε4通过病理域损害线粒体呼吸功能 因此，相互作用。 AD患者的线粒体功能尚未检查以解决此知识差距。 将检查骨骼肌线粒体 - 符号，-enzyme活性，呼应能力和-H202 与年龄和性别匹配的受试者相比，从AD获得的骨骼肌活检中的发射。 为了检查基因型的作用，我们将招募apoeε4载体或非竞争者的受试者 AD和ND组（每组的一半）。 CAPACE（VO2峰）和所有受试者的每日体育锻炼和久坐的行为。 如果骨骼肌线粒体功能和全身有氧运动能力在AD中受到损害 与ND和非APOEε4载体相比，APOEε4载体将排名第二。 该新型研究的功能和有氧能力函数 检查非脑目标如何通过生活方式和/或遗传因素来驱动AD易感性，并可以 将TOIINT指向骨骼肌线粒体，作为AD投影的未来疗法的靶标。