Swimming exercise promotes post-injury axon regeneration and functional restoration through AMPK

Restoration of lost function following a nervous system injury is limited in adulthood as the regenerative capacity of nervous system declines with age. Pharmacological approaches have not been very successful in alleviating the consequences of nervous system injury. On the contrary, physical activity and rehabilitation interventions are often beneficial to improve the health conditions in the patients with neuronal injuries. Using touch neuron circuit of Caenorhabditis elegans, we investigated the role of physical exercise in the improvement of functional restoration after axotomy. We found that a swimming session of 90 minutes following the axotomy of Posterior Lateral Microtubule (PLM) neuron can improve functional recovery in larval and adult stage animals. In older age, multiple exercise sessions were required to enhance the functional recovery. Genetic analysis of axon regeneration mutants showed that exercise-mediated enhancement of functional recovery depends on the ability of axon to regenerate. Exercise promotes early initiation of regrowth, self-fusion of proximal and distal ends, as well as post-regrowth enhancement of function. We further found that the swimming exercise promotes axon regeneration through the activity of cellular energy sensor AAK2/AMPK in both muscle and neuron. Our study established a paradigm where systemic effects of exercise on functional regeneration could be addressed at the single neuron level.

Automated summary

Restoration of lost function following a nervous system injury is limited in adulthood due to decreased regenerative capacity, with pharmacological approaches showing limited success. Physical activity and rehabilitation interventions, particularly swimming exercise, have been found beneficial in improving functional recovery after axotomy. Multiple exercise sessions are required in older age to enhance function restoration, with genetic analysis showing the dependence of exercise-mediated recovery enhancement on axon regeneration ability. Exercise promotes early regrowth initiation, proximal and distal end fusion, and post-regrowth function enhancement, mediated by the activity of cellular energy sensor AAK2/AMPK in muscle and neuron. This study established a paradigm demonstrating the systemic effects of exercise on functional regeneration at the single neuron level.