Moderate Chronic Treadmill Exercise Slows Dopaminergic Neuron Loss in a Rat Model of Parkinson's Disease and Alters RNA Content of Circulating Plasma Exosomes

Abstract

Exercise has been reported to improve outcomes in patients with Parkinson's disease, but the exact biological mechanisms remain incompletely understood. This study was conducted to determine whether chronic moderate treadmill exercise prevents dopaminergic neuron loss and Lewy body-like inclusion burden in a preclinical model of PD. This study also sought to identify plasma exosome bound “exerkines” with potential to induce neuroprotective brain adaptations. Benefits of exercise are thought to be achieved in part through nucleic acids, lipids, and peptides termed exerkines abundant during exercise. These exerkines can induce cell-specific exercise adaptations culminating in neuroprotection. Membrane-free exerkines are subject to degradation in blood and may not effectively cross the blood-brain barrier to induce brain adaptations to exercise, limiting their inter-organ signaling potential. This led us to hypothesize that exerkines, bioactive RNAs in particular, may be selectively packaged into exosomes and released into plasma during exercise. Exosomes are small extracellular vesicles, selectively packaged and released by cells, with likely important differences in composition at rest, during injury and disease, and in response to exercise. Exosomes have been demonstrated to play a major role in inter-organ communication. Chronic exercise was found to provide neuroprotection to dopaminergic neurons in the substantia nigra pars compacta, without affecting Lewy body-like inclusion burden in the nigra or the striatum. Plasma exosomal RNA was isolated from age-matched exercising and sedentary non-PD rats and sequenced. We report 27 unique RNAs upregulated in the exosomes of exercisers, 3 mRNAs with clear neuroprotective potential.