Repeated voluntary exercise induces impairments and disease worsening in the low-copy SOD1G93A mouse model of ALS

Amyotrophic Lateral Sclerosis (ALS) is a disease in which physical activity plays a controversial role. Recent studies indicate a genetic predisposition toward an "athletic" phenotype in individuals that develop ALS combined with exposure to environmental factors. While several studies rely on forced exercise, we hypothesized that voluntary physical activity could represent a better model of the influence of environmental factors in the pathogenesis of ALS. We used an automated home-cage running-wheel system (TSE Systems) that enables individual monitoring of performance. To verify the effect of voluntary running on disease progression, motor and cognitive performance we challenged Tg(SOD1G93A)dl1/GurJ (SOD1-low copy) male and female mice on one (age 24 weeks) or multiple running sessions: age 13, 18 and 24 weeks. During exercise, body weight and food intake were recorded daily. Analysis of muscle, sciatic nerve and spinal cord was also performed. Several parameters were analysed through Principal Component Analysis in order to detect what indices correlate and may be useful for early detection of symptoms. Repeated running anticipated disease onset, disrupted sensorimotor gating and impaired neuromuscular transmission. Food intake was increased in exercised Tg mice compared to WT. All the effects of exercise seem to be more prominent in Tg male mice compared to females. This model with a delayed onset and slower disease progression gives the opportunity to examine the very early stages of pathology and it can be useful to understand pathogenetic mechanisms and to test possible therapeutic interventions (lifestyle, diet, physical activity, drugs).