Wheel Running Adversely Affects Disease Onset and Neuromuscular Interplay in Amyotrophic Lateral Sclerosis Slow Progression Mouse Model

Background: Physical activity in Amyotrophic Lateral Sclerosis (ALS) plays a controversial role. In some epidemiological studies, both recreational or professional sport exercise has been associated to an increased risk for ALS but the mechanisms underlying the effects of exercise have not been fully elucidated in either patients or animal models. Methods: To better reproduce the influence of this environmental factor in the pathogenesis of ALS, we exposed SOD1^G93A low-copy male mice to multiple exercise sessions at asymptomatic and pre-symptomatic disease stages in an automated home-cage running-wheel system for about 3 months. Results: Repeated voluntary running negatively influenced disease progression by anticipating disease onset, impairing neuromuscular transmission, worsening neuromuscular decline, and exacerbating muscle atrophy. Muscle fibers and neuromuscular junctions (NMJ) as well as key molecular players of the nerve-muscle circuit were similarly affected. Conclusion: It thus appears that excessive physical activity can be detrimental in predisposed individuals and these findings could model the increased risk of developing ALS in predisposed and specific professional athletes.