Exercise and muscle mitochondria in Alzheimer's Disease

阿尔茨海默病中的运动和肌肉线粒体

基本信息

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
项目类别：
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&apos -AMP-activated protein kinase APP-PS1 Acute Address Age Age Months Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

项目概要在阿尔茨海默病 (AD) 的早期阶段，骨骼肌质量和功能急剧下降与认知能力完好的人相比，这可能是由于骨骼肌线粒体健康状况不佳所致。因此，外周组织，特别是骨骼肌的生物能学可能具有未被充分认识的作用在 AD 病因学中，运动是促进线粒体和骨骼肌健康的有效手段。然而，定期运动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。我们提出了 5xFAD 小鼠骨骼肌 AMPK 信号传导反应受损的证据，我们在 5xFAD 小鼠的 AD 模型中发现，在可观察到的年轻时期就存在肌肉功能障碍。认知能力下降以及肌肉损失和线粒体健康受损与年龄相关我们提供的证据表明线粒体呼吸在 12 周后没有改善。与 WT 同窝小鼠相比，22 周龄 5xFAD 小鼠的运动训练总而言之，生物能功能障碍。在 AD 相关病理的明显表现之前，肌肉可能是对运动的适应不良反应的基础。因此，迫切需要定义与神经生理学相关的肌肉适应机制。我们的中心假设是，改变 AD 病理学的连续体来确定新的治疗靶点。生物能学受损先于明显的 AD 神经病理学表现，导致肌肉适应不良为了检验我们的假设，我们提出了两个目标：目标 1）确定的适应性反应我们将在 AD 发生之前评估 AD 小鼠的肌肉线粒体对耐力运动训练的影响。线粒体呼吸和活性氧（完整肌纤维中的活性氧产生以及 22 周龄肌肉线粒体的合成（即生物发生）和分解（通过 D2O 标记 - GC/MS） 5xFAD 和 APP/PS1 雄性和雌性小鼠经过 12 周自愿轮跑（运动训练）(1a)，确定运动前和运动后训练后的体内肌肉功能（Aurora）、神经肌肉接头完整性新型 MitoTimer/5xFAD 转基因小鼠的（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)，并执行非针对性运动训练后肌肉和海马的代谢组学 (1d) 目标 2) 确定组织特异性。以及 AMPK⍺1 在 5xFAD 小鼠 AD 病因学中的功能作用我们将评估线粒体功能， 3、6 和 3 岁肌肉和海马的蛋白质稳态、神经病理学发展和代谢组学 9 个月大的肌肉和运动神经元特异性 AMPK⍺1 敲除小鼠，以及新的增益和损失功能丧失的 AMPK⍺1(T172A) 敲入小鼠我们的研究结果将阐明骨骼的适应不良反应。肌肉线粒体与 AD 神经病理学背景下的运动训练和整合亚型特异性 AMPK⍺ 在 AD 病因学中的功能作用这些研究将为综合病理学提供机制。骨骼肌和大脑之间 AD 病理学的连续体以及运动作为治疗的作用。