Exercise and muscle mitochondria in Alzheimer's Disease

项目总结 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 与认知完好的人相比，这可能是由于骨骼肌中线粒体健康状况不佳所致。 因此，外周组织的生物能量学，特别是骨骼肌的生物能量学，其作用可能被低估。 在阿尔茨海默病病因学。运动是促进线粒体和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的治疗潜力是一个突出的问题 问题。我们提出了5xFAD小鼠骨骼肌AMPK信号反应受损的证据， AD的一个模型。我们在5xFAD小鼠中发现，肌肉功能障碍在年轻时就出现了，在可观察到之前 认知能力下降，肌肉丧失和线粒体健康受损的表现与年龄相关 认知能力下降。我们提出的证据表明，线粒体呼吸在12周后没有改善。 比较22周龄5xFAD小鼠和WT仔鼠的运动训练。总而言之，中国的生物能量障碍 在AD相关病理的明显表现之前，肌肉可能是运动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有关的适应机制。 在AD病理的连续体上的变化以确定新的治疗靶点。我们的中心假设是 生物能量学受损先于阿尔茨海默病的神经病理表现，导致肌肉适应不良 进行运动训练。为了验证我们的假设，我们提出了两个目标：目标1)确定 AD小鼠发病前肌肉线粒体对耐力运动训练的影响。我们将评估 线粒体呼吸和活性氧(ROS在完整的肌肉纤维中的产生以及 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12周自愿轮跑(运动训练)(1a)， 测定运动前后在体肌肉功能(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)在新的MitoTimer/5xFAD转基因小鼠(1b)， 评估中枢(海马体)和外周(血浆NFL)神经病理(1c)，并执行非靶向 运动训练后肌肉和海马体的代谢组学(1D)。目的2)确定组织特异性 以及AMPK⍺1在5xFAD小鼠AD病因学中的作用。我们将评估线粒体的功能， 在肌肉和海马区的蛋白稳定、神经病理学发展和代谢组学 肌肉和运动神经元特异性AMPK⍺1基因敲除小鼠出生9个月，以及新的获得和损失- 功能缺失的AMPK⍺1(T172a)敲入小鼠。我们的发现将阐明骨骼的不良适应反应 运动训练中肌肉线粒体与AD神经病理及整合异构体的特异性 AMPK⍺在AD病因学中的功能作用这些研究将为本病的综合病理提供机制。 骨骼肌和脑之间AD病理的连续体以及运动作为治疗的作用。

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.