BACKGROUND: Alzheimer’s disease (AD) develops along a continuum that spans years to possible decades prior to cognitive decline and clinical diagnosis. Notably, pre-clinical AD is associated with a significant loss of muscle mass and strength (sarcopenia, and dynapenia) and impaired skeletal muscle mitochondrial respiration compared to age matched individuals. Exercise is a potent and reproducible means to promote skeletal muscle and cognitive health and function, thus, exercise may serve to be a potential therapeutic for AD. The purpose of this study was to characterize neuromuscular function in an AD-like context and to assess whether the adaptation of skeletal muscle to aerobic exercise is altered in early AD-like pathology prior to manifestation of overt cognitive impairment. METHODS: Using 5xFAD mice and wild type littermates we longitudinally assed tibial nerve and direct muscle stimulated plantar flexor torque in-vivo from 3-6 months of age. Additionally, at 7 months we assessed sciatic nerve compound (motor) neuron action potential (CNAP). In a separate cohort we exercise trained 5xFAD and wild type liter mates starting at 10 weeks of age via voluntary running wheel for 12 weeks and assessed exhaustive exercise capacity, T-maze cognition, and skeletal muscle mitochondrial respiration and gene expression. Data were analyzed via Graphpad Prism 9.5.1 using Student’s t-test, two-way ANOVA, or repeated measures two-way ANOVA when appropriate. Post-hoc analyses were performed when a significant interaction between a categorical and a quantitative variable was found. Statistical significance was established a priori as p < 0.05. RESULTS: Our data shows early tibial nerve stimulated muscle function impairment beginning at 4 months of age p<0.01. Sciatic nerve CNAP was significantly slower in 5xFAD mice at 7 months p<0.01. Post-exercise training, skeletal muscle mitochondria respiration adaptation was impaired p<0.05, prior to overt cognitive impairment in 5xFAD mice. Additionally, gene changes in skeletal muscle with exercise were particularly contrasting in expression patterns from the wild type in 5xFAD mice. CONCLUSIONS: Changes in peripheral systems, particularly neural communication to skeletal muscle, may be precursors for AD and have repercussions for lifestyle intervention strategies (e.g. exercise) in AD afflicted populations.

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