Enhancing recovery from peripheral nerve injury using treadmill training

Summary

Full functional recovery after traumatic peripheral nerve injury is rare. We postulate three reasons for the poor functional outcome measures observed. Axon regeneration is slow and not all axons participate. Significant misdirection of regenerating axons to reinnervate inappropriate targets occurs. Seemingly permanent changes in neural circuitry in the central nervous system are found to accompany axotomy of peripheral axons. Exercise in the form of modest daily treadmill training impacts all three of these areas. Compared to untrained controls, regenerating axons elongate considerably farther in treadmill trained animals and do so via an autocrine/paracrine neurotrophin signaling pathway. This enhancement of axon regeneration takes place without an increase in the amount of misdirection of regenerating axons found without training. The enhancement also occurs in a sex-dependent manner. Slow continuous training is effective only in males, while more intense interval training is effective only in females. In treadmill trained, but not untrained mice the extent of coverage of axotomized motoneurons is maintained, thus preserving important elements of the spinal circuitry.

Introduction

Injured axons in peripheral nerves regenerate better than those in the central nervous system, but the functional outcomes observed clinically after peripheral nerves are injured are often so poor that some form of long term disability results (Brushart, 1998, Frostick et al., 1998). The three reasons most often given for these poor outcomes are: (1) that the regeneration of axons in injured peripheral nerves is slow and not all axons participate, leading to a functionally inadequate reinnervation of muscles (Fu and Gordon, 1995, Fu and Gordon, 1997, Gordon, 2009); (2) that regenerating motor axons are misdirected and reinnervate functionally inappropriate targets (Evans et al., 1991, de Ruiter et al., 2008); and (3) that plastic changes in the central nervous system (CNS) that accompany peripheral axotomy alter the relationship of circuitry in the CNS and the reinnervated muscles (Alvarez et al., 2010). Currently, there is no accepted medical treatment for traumatic peripheral nerve injuries that addresses these concerns. The standard of care is to provide a tension free repair of cut nerves and allow the process of regeneration to proceed.

Exercise as a means of improving brain health and function has received considerable recent attention (Adlard and Cotman, 2004, Adlard et al., 2004) at least in part because it has been shown to induce the synthesis of both brain derived neurotrophic factor (BDNF) and its receptor, trkB, in rats and to promote recovery after CNS injury (Gomez-Pinilla et al., 2001, Hutchinson et al., 2004, Molteni et al., 2004, Ploughman et al., 2005). Therapeutic exercise thus could form a useful means of stimulation to the growth of regenerating peripheral axons that would require very little clinical intervention. Because it activates motor and primary afferent neurons naturally, via their own neural circuits, one might expect that exercise could produce enhanced axon regeneration without increasing the misdirection of those axons to inappropriate targets. Additionally, this natural activation might have effects on the CNS consequences of peripheral nerve injury. Indeed, we have found that exercise in the form of treadmill training has beneficial effects on all three of the critical aspects of recovery from peripheral nerve injury listed above. In the review that follows, we will delineate these effects and discuss the need for and direction of future studies.