HIF1a and angiogenesis are critical for the regenerative effects of exercise.

Neurons whose axons reside in the peripheral nervous system (PNS) mount a limited regenerative program after injury that can be further enhanced by activity-dependent therapies, such as exercise. The mechanism by which neuronal activity enhances axon regeneration is incompletely understood and defining how injured neurons respond to activity-dependent therapies may reveal new therapeutic targets to improve recovery following both CNS and PNS injuries. We hypothesized that exercise utilizes an oxygen-sensitive transcription factor, HIF1a, to enhance axon regeneration following injury. We found that running exercise caused nuclear translocation of HIF1a in axotomized sensory and motoneurons leading to enhanced axon regeneration and improved functional recovery following nerve injury. Conditional genetic deletion of HIF1a blocked the effect of exercise and prevented functional recovery. We then identified a pharmacologic inhibitor of prolyl hydroxylases that stabilizes HIF1a. Prolyl hydroxylase inhibition lead to increased DRG neurite outgrowth in vitro and enhanced axon regeneration in vivo. Manipulation of HIF1a via activity-dependent therapies or pharmacologically enhanced regeneration and improved functional recovery. The quality of the surgical nerve repair also plays a large role in the aggregate success of nerve regeneration. Fibrin glue repaired nerves exhibited greater vasculature within the tissue bridge compared to nerves that were intrinsically repaired. Fibrin glue repaired nerves also exhibited more robust axon regeneration after exercise compared to nerves that were not repaired with fibrin glue. When angiogenesis of the tissue bridge was prevented with a VEGF receptor inhibitor, exercise was unable to enhance regeneration despite the presence of fibrin glue. Thus, HIF1a expression initiates the angiogenic response within the repair site through VEGF, but neuronal HIF1a expression is also required to promote the effects of exercise.