Exercise and muscle mitochondria in Alzheimer's Disease

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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.