Exercise-Induced Differential Transcriptional Output of AMPK Signaling 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 behavioral 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 signaling 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 signaling play an integrative role in response to physical exercise to promote functional recovery after axon injury.