Exercise and muscle mitochondria in Alzheimer's Disease

阿尔茨海默病中的运动和肌肉线粒体

• 批准号: 10740455
• 负责人: Josh C Drake
• 金额: $ 66.63万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740455
• 关键词: 5' -AMP-activated protein kinase; APP-PS1; Acute; Address; Age; Age Months; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Bioenergetics; Biogenesis; Biological Models; Brain; Cognitive; Confocal Microscopy; Data; Defect; Development; Diagnosis; Etiology; Exercise; Experimental Designs; Female; Functional disorder; Goals; Health; Hippocampus; Histocytochemistry; Human; Impaired cognition; Impairment; Intervention; Intramuscular; Knock-in Mouse; Knockout Mice; Label; Metabolic; Mission; Mitochondria; Molecular; Motor Neurons; Mus; Muscle; Muscle Fibers; Muscle Mitochondria; Muscle function; Muscular Atrophy; Neuromuscular Junction; Neurons; Pathology; Peripheral; Phase; Physiological; Plasma; Production; Protein Isoforms; Public Health; Reactive Oxygen Species; Reporting; Research; Respiration; Role; Running; Signal Transduction; Skeletal Muscle; Symptoms; System; Testing; Therapeutic; Tissues; Transgenic Mice; disease phenotype; endurance exercise; exercise training; gain of function; improved; in vivo; innovation; insight; loss of function; male; metabolomics; mild cognitive impairment; mouse model; muscle form; neuropathology; neurophysiology; new therapeutic target; novel; pre-clinical; prevent; proteostasis; response; sedentary; sensor; stoichiometry; systems research; therapeutic development

PROJECT SUMMARY During the early stages of Alzheimer’s Disease (AD), skeletal muscle mass and function precipitously declines in comparison to those who are cognitively intact, potentially due to poor mitochondrial health in skeletal muscle. Thus, bioenergetics of peripheral tissues, and skeletal muscle in particular, may have an underappreciated role in AD etiology. Exercise is an effective means to promote mitochondrial, as well as, skeletal muscle health. However, whether regular exercise has therapeutic potential for delaying or preventing AD is an outstanding question. We present evidence of impaired skeletal muscle AMPK-signaling response to exercise in 5xFAD mice, a model of AD. We show in 5xFAD mice that muscle dysfunction is present at a young age before observable cognitive decline and that muscle loss and impaired mitochondrial health manifest along by an age associated with cognitive decline. We present evidence that mitochondrial respiration does not improve following 12 weeks exercise training in 22-week-old 5xFAD mice compared to WT littermates. In sum, bioenergetic dysfunction in muscle may underlie a maladaptive response to exercise prior to overt manifestation of AD-related pathology. There is a critical need therefore to define the adaptive mechanisms in muscle in relation to neurophysiological changes over the continuum of AD pathology to identify novel therapeutic targets. Our central hypothesis is that impaired bioenergetics precedes manifestation of overt AD neuropathology resulting in maladaptation in muscle to exercise training. To test our hypothesis, we propose two aims: Aim 1) Determine the adaptive response of muscle mitochondria to endurance exercise training in AD mice before development of AD. We will assess mitochondrial respiration and reactive oxygen species (ROS production in intact muscle fibers and as well as synthesis (i.e. biogenesis) and breakdown (via D2O labeling - GC/MS) of muscle mitochondria in 22-week-old 5xFAD and APP/PS1 male and female mice following 12 weeks voluntary wheel running (exercise training) (1a), determine pre- and post-exercise training muscle function in vivo (Aurora), neuromuscular junction integrity (histochemistry) and mitochondrial quality (confocal microscopy) in novel MitoTimer/5xFAD transgenic mice (1b), assess central (hippocampus) and peripheral (plasma NfL) neuropathology (1c), and perform untargeted metabolomics of muscle and hippocampus following exercise training (1d). Aim 2) Determine the tissue-specific and functional roles for AMPK⍺1 in AD etiology in 5xFAD mice. We will assess mitochondrial function, proteostasis, development of neuropathology, and metabolomics in both muscle and hippocampus at 3, 6, and 9 months of age in muscle- and motor neuron-specific AMPK⍺1 knock-out mice, as well as novel gain- and loss- of-function AMPK⍺1(T172A) knock-in mice. Our findings will elucidate the maladaptive response of skeletal muscle mitochondria to exercise training in context with AD neuropathology and the integrated isoform-specific functional role of AMPK⍺ in AD etiology. These studies will provide mechanistic to the integrated pathology along the continuum of AD pathology between skeletal muscle and brain and the role of exercise as a therapeutic.

项目摘要 在阿尔茨海默氏病（AD）的早期，骨骼肌质量和功能精确下降 与那些完好无损的人相比，由于骨骼肌的线粒体健康状况不佳。 尤其是外围组织和骨骼肌的生物能学可能没有被低估的作用 在AD病因中。运动是促进线粒体以及骨骼肌健康的有效手段。 但是，定期运动是否具有延迟或预防广告的热潜力是出色的 问题。我们提供了5xFAD小鼠运动骨骼肌AMPK信号反应受损的证据， AD模型。我们在5xfad小鼠中表明，在可观察到的肌肉功能障碍之前 认知能力下降，肌肉损失和线粒体健康受损与年龄相关 认知能力下降。我们提供了证据，表明线粒体呼吸在12周后不会改善 与wt同窝仔相比，在22周大的5xFAD小鼠中进行运动训练。总而言之 在与广告相关病理的公开表现之前，肌肉可能是对运动的不良反应。 因此，至关重要的是定义与神经生理学有关的肌肉的适应性机制 对AD病理的连续体的变化，以鉴定新的治疗靶标。我们的中心假设是 生物能力受损先于明显的AD神经病理学的表现，导致肌肉不适 为了检验我们的假设，我们提出了两个目的：目标1）确定 在AD开发之前，肌肉线粒体进行AD小鼠的耐力运动训练。我们将评估 线粒体呼吸和活性氧（完整的肌肉纤维中的ROS以及 22周大的肌肉线粒体的合成（即生物发生）和分解（通过D2O标记-GC/MS） 12周自愿跑步（锻炼训练）（1A），5XFAD和APP/PS1男性和女性小鼠， 确定体内和运动后训练肌肉功能（Aurora），神经肌肉连接完整性 （组织化学）和线粒体质量（共聚焦显微镜）在新型Mitotimer/5xfad转基因小鼠（1B），，，，，， 评估中央（海马）和外围（等离子体NFL）神经病理学（1C），并执行未靶向的 运动训练后（1D）后肌肉和海马的代谢组学。 AIM 2）确定组织特异性 AMPK⍺1在5xFAD小鼠中的AD病因中的功能作用。我们将评估线粒体功能， 肌肉病，神经病理学的发展和肌肉和海马的代谢组学在3、6和 肌肉和运动神经元特异性AMPK⍺1敲除小鼠的9个月大，以及新颖的增益和损失 - 功能AMPK⍺1（T172A）敲入小鼠。我们的发现将阐明骨骼的适应不良反应 通过AD神经病理学和集成的同工型特异性的肌肉线粒体进行运动训练 AMPK⍺在AD病因中的功能作用。这些研究将为沿综合病理的机械提供机械性 骨骼肌和大脑之间AD病理学的连续性以及运动作为治疗性的作用。