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

In adulthood, the regenerative capacity of the injured brain circuit is poor, thereby preventing functional restoration. Rehabilitative physical exercise is a promising approach for enhancing the behavioural recovery after neuronal injury to both the central and peripheral nervous systems. The metabolic energy sensor AMPK acts as a mediator for the exercise benefit in Caenorhabditis elegans axon regeneration. However, the mechanistic understanding of upstream and downstream components of AMPK signalling in the physical exercise-mediated enhancement of axon regeneration is still unclear. Here, we addressed this question by combining swimming exercise with laser axotomy of C. elegans posterior lateral microtubule (PLM) neurons. Using a genetically encoded ATP sensor iATPsnFR1.0, we observed that immediately after swimming exercise, ATP level is decreased both in neuron and muscle. Further, we found that AICAR-mediated AMPK activation is sufficient to promote axon regeneration and functional recovery. The PAR-4/Liver kinase B1 acts upstream of AMPK to improve functional recovery through swimming exercise. We also found that the transcriptional regulators DAF-16 and MDT-15 mediate the beneficial effects of swimming by acting downstream of AMPK. MDT-15 functions within neuron to mediate the benefit of AMPK activation, whereas DAF-16 acts both in neuron and muscle to promote functional restoration. Additionally, we demonstrated 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 statement Finding ways to promote functional recovery after nervous system injury has been challenging, as the axons of adult neurons can not regenerate well. Rehabilitation therapy is a promising approach to improve the health condition of patients with nervous system injuries. Swimming exercise can promote axon regeneration in the roundworm C. elegans, 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.