Exercise-induced differential transcriptional output of AMPK signalling improves axon regeneration and functional recovery

Abstract

In adulthood, the regenerative capacity of the injured brain circuit is poor preventing functional restoration. Rehabilitative physical exercise is a promising approach to overcome such functional impairment and the metabolic sensor AMPK has emerged to be a critical mediator for this. However, the mechanistic understanding of upstream and downstream components of AMPK signalling in the physical exercise-mediated enhancement of axon regeneration is not clear. We combined swimming exercise with laser axotomy of posterior lateral microtubule (PLM) neurons of Caenorhabditis elegans to address this question. We found that direct activation of AMPK through AICAR treatment is sufficient to improve axon regeneration and functional recovery. The PAR-4/Liver kinase B1 (LKB1) acts upstream of AMPK to enhance functional recovery following swimming exercise. Using genetics, tissue-specific RNAi, and AICAR treatment, we found that the transcriptional regulators DAF-16 and MDT-15 act downstream of AMPK in mediating the positive effects of swimming. We found that MDT-15 acts in neuron to mediate the benefit of AMPK activation in axon regeneration, whereas DAF-16 acts both in neuron and muscle to promote regrowth downstream to AMPK. We also showed that swimming exercise induces nuclear localization of DAF-16 in an AMPK-dependent manner. Our results showed that neuronal and non-neuronal arms of AMPK signalling play an integrative role in response to physical exercise to promote functional recovery after axon injury. Significance statementFinding ways to promote functional recovery after accidental damage to the nervous system has been challenging as adult neurons lose the capability to regenerate. Rehabilitation therapy is the most promising approach to improve the health condition of patients with nervous system injury. Even in the roundworm C. elegans, axon regeneration could be enhanced through swimming exercise, which is mediated by the metabolic energy sensor AMP Kinase. In this study, using sensory neurons in worm, we found that PAR-4/ Liver kinase B1 acts upstream of AMPK. Whereas, the transcription factor DAF-16/ FOXO and the transcriptional co-regulator MDT-15 act as downstream signalling arms in muscle and neuron tissues. Excitingly, both of these arms could be harnessed through agonist-mediated activation of AMPK to promote functional recovery in adulthood.