Exercise and Peripheral Nerve Grafts as a Strategy To Promote Regeneration after Acute or Chronic Spinal Cord Injury

Abstract

Therapeutic interventions after spinal cord injury (SCI) routinely are designed to address multiple aspects of the primary and/or secondary damage that occurs. Exercise has a demonstrated efficacy for post-SCI complications such as cardiovascular dysfunction, neuropathic pain, and chronic inflammation, yet there is little understanding of the mechanisms by which improvements might result from this non-invasive approach. Here we review several of our observations of molecular and cellular changes within the injured spinal cord following acute or delayed exercise regimens that illustrate the potential for positive effects on neuroprotection and rehabilitation. Further, we provide new information about the role of exercise in promoting the regeneration of spinal axons into peripheral nerve grafts (PNGs) placed immediately or 6 weeks after injury. Acute and chronically injured propriospinal neurons within the lumbar spinal cord displayed the greatest propensity for enhanced regeneration after exercise, which correlates with the direct sensory input to this region from exercised hindlimb muscles. Future studies will extend these observations by testing whether exercise will boost the regenerative effort of axons to extend beyond the graft, interact with intraspinal targets, and establish functional connections across a lesion.

Keywords: exercise; regeneration; transplantation.

FIG. 1.

Time line and schematic of injury, grafting, and exercise. (A) Time line of experiments showing acute PNGs placed at the time of SCI and chronic PNGs placed 6 weeks post-SCI. Exercise begins either acutely 5 days after initial SCI or with a delay at 5 weeks post-SCI, and it continues until the time of sacrifice. Animals are euthanized at 6 weeks post-SCI in acute PNG experiments or 12 weeks post-SCI in chronic PNG experiments. TB retrograde tracer is applied to distal ends of PNGs 5 days before euthanasia in all experiments. The group colors correspond to the colored bars in Figure 2. (B) Schematic showing initial SCI, apposition of aPNG to caudal lesion boundary and dPNG to rostral lesion boundary, and TB labeling of distal ends of PNGs in order to retrogradely label cell bodies of neurons extending axons into the grafts. aPNG, ascending PNG; dPNG, descending PNG; PNG, peripheral nerve graft; SCI, T12 spinal cord transection injury; TB, True Blue retrograde tracer.

FIG. 2.

Quantification of TB positive neurons in spinal cord segments rostral and caudal to the lesion. Top left: T11 thoracic spinal cord neurons labeled by axons extending into the dPNG. Top right: T13 thoracic spinal cord neurons labeled by axons extending into the aPNG. Bottom left: T1–T10 thoracic spinal cord neurons labeled by axons extending into the dPNG. Bottom right: L1–L5 lumbar spinal cord neurons labeled by axons extending into the aPNG (error bars reflect standard deviation [SD]; *indicates p < 0.05).