Abstract
BackgroundAmyotrophic lateral sclerosis (ALS) is characterized by a gradual muscular paralysis resulting from progressive motoneurons death. ALS etiology remains unknown although it has been demonstrated to be a multifactorial disease involving several cellular partners. There is currently no effective treatment. Even if the effect of exercise is under investigation for many years, whether physical exercise is beneficial or harmful is still under debate.Methods and FindingsWe investigated the effect of three different intensities of running exercises on the survival of SOD1G93A mice. At the early-symptomatic stage (P60), males were isolated and randomly assigned to 5 conditions: 2 sedentary groups (“sedentary” and “sedentary treadmill” placed on the inert treadmill), and 3 different training intensity groups (5 cm/s, 10 cm/s and 21 cm/s; 15 min/day, 5days/week). We first demonstrated that an appropriate “control” of the environment is of the utmost importance since comparison of the two sedentary groups evidenced an 11.6% increase in survival in the “sedentary treadmill” group. Moreover, we showed by immunohistochemistry that this increased lifespan is accompanied with motoneurons survival and increased glial reactivity in the spinal cord. In a second step, we showed that when compared with the proper control, all three running-based training did not modify lifespan of the animals, but result in motoneurons preservation and changes in glial cells activation.Conclusions/SignificanceWe demonstrate that increase in survival induced by a slight daily modification of the environment is associated with motoneurons preservation and strong glial modifications in the lumbar spinal cord of SOD1G93A. Using the appropriate control, we then demonstrate that all running intensities have no effect on the survival of ALS mice but induce cellular modifications. Our results highlight the critical importance of the control of the environment in ALS studies and may explain discrepancy in the literature regarding the effect of exercise in ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by a selective motoneurons death in the motor cortex, brainstem and spinal cord that leads to progressive muscular paralysis
The two groups differed by only one parameter: mice from the ‘‘sedentary’’ group constantly remained alone in their cage whereas ‘‘sedentary treadmill’’ mice were placed on the inert treadmill for 15 minutes a day and 5 days a week (Figures S1 and S2)
The labeling intensity of glial fibrillary acidic protein (GFAP) was similar in the ‘‘sedentary treadmill’’, the 10 and 21 cm/s groups (36666136.2, 36316102.6 and 36316161.1 respectively) (Figure 4A, C, E&F, Figure 5, Figure S3D). These results demonstrate that placing the SOD1G93A mice on an inert treadmill for 15 minutes, 5 days a week leads to an increase in the lifespan of the animals, which is correlated with motoneuron preservation and a markedly enhanced glial reactivity
Summary
Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by a selective motoneurons death in the motor cortex, brainstem and spinal cord that leads to progressive muscular paralysis. Pathogenesis of motoneuron degeneration in ALS and mechanisms of selective vulnerability are still largely unknown it has been demonstrated that ALS is a complex multifactorial disease (protein misfolding, glutamatemediated excitotoxicity, oxidative stress, impaired axonal transport...) that involves, besides neurons, several cellular partners such as glial and muscle cells (for reviews see [1,2]). Moderate exercise is reported to increase the life span of several mouse models of motoneuron disease such as SOD1G93A mice [11,12], of spinal muscular atrophy such as survival motor neuron2/SMN2 mice [13] and progressive motor neuronopathy/. Amyotrophic lateral sclerosis (ALS) is characterized by a gradual muscular paralysis resulting from progressive motoneurons death. Even if the effect of exercise is under investigation for many years, whether physical exercise is beneficial or harmful is still under debate
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