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 在阿尔茨海默病（AD）的早期阶段，骨骼肌质量和功能急剧下降 与那些认知完整的人相比，这可能是由于骨骼肌中线粒体健康状况较差。 因此，外周组织，特别是骨骼肌的生物能量学可能具有未被充分认识的作用 在AD病因学中。运动是促进线粒体以及骨骼肌健康的有效手段。 然而，定期锻炼是否具有延缓或预防AD的治疗潜力仍是一个悬而未决的问题。 问题我们提供了5xFAD小鼠骨骼肌AMPK信号对运动的反应受损的证据， AD的模型。我们在5xFAD小鼠中发现，肌肉功能障碍在可观察到之前就存在于年轻时， 认知能力下降，肌肉损失和受损的线粒体健康表现沿着与年龄相关的 认知能力下降我们提出的证据表明，线粒体呼吸并没有改善后12周 与WT同窝出生小鼠相比，22周龄5xFAD小鼠的运动训练。总而言之， 肌肉可能是在AD相关病理明显表现之前对运动的适应不良反应的基础。 因此，迫切需要确定肌肉中与神经生理学相关的适应机制。 改变AD病理的连续性，以确定新的治疗靶点。我们的核心假设是， 生物能量学受损先于显性AD神经病理学表现，导致肌肉适应不良 进行锻炼训练。为了验证我们的假设，我们提出了两个目标：目标1）确定适应性反应的 肌线粒体对AD小鼠发生AD前耐力运动训练的影响。我们将评估 线粒体呼吸和活性氧（完整肌纤维中的ROS产生，以及 22周龄猪肌肉线粒体的合成（即生物发生）和分解（通过D2 O标记- GC/MS） 5xFAD和APP/PS1雄性和雌性小鼠在12周自愿轮跑（运动训练）后（1a）， 确定运动训练前和运动训练后的体内肌肉功能（Aurora）、神经肌肉接头完整性 （组织化学）和线粒体质量（共聚焦显微镜）（1b）， 评估中枢（海马）和外周（血浆NfL）神经病理学（1c）， 运动训练后肌肉和海马的代谢组学（1d）。目的2）确定组织特异性 以及AMPK β 1在5xFAD小鼠中AD病因学中的功能作用。我们将评估线粒体功能， 蛋白质稳态，神经病理学的发展，以及肌肉和海马在3，6， 9个月大的肌肉和运动神经元特异性AMPK β 1敲除小鼠，以及新的增益和损失， AMPK β 1（T172 A）敲入小鼠。我们的研究结果将阐明骨骼肌的适应不良反应， 在AD神经病理学和整合亚型特异性的背景下，肌肉线粒体对运动训练的影响 AMPK β在AD病因学中的功能作用。这些研究将为沿着病理学的综合研究提供机理依据 骨骼肌和大脑之间AD病理学的连续性以及运动作为治疗剂的作用。