Enhancement of peripheral nerve regeneration due to treadmill training and electrical stimulation is dependent on androgen receptor signaling

Abstract

Moderate exercise in the form of treadmill training and brief electrical nerve stimulation both enhance axon regeneration after peripheral nerve injury. Different regimens of exercise are required to enhance axon regeneration in male and female mice (Wood et al., 2012), and androgens are suspected to be involved. We treated mice with the androgen receptor blocker, flutamide, during either exercise or electrical stimulation, to evaluate the role of androgen receptor signaling in these activity-based methods of enhancing axon regeneration. The common fibular (CF) and tibial (TIB) nerves of thy-1-YFP-H mice, in which axons in peripheral nerves are marked by yellow fluorescent protein (YFP), were transected and repaired using CF and TIB nerve grafts harvested from non-fluorescent donor mice. Silastic capsules filled with flutamide were implanted subcutaneously to release the drug continuously. Exercised mice were treadmill trained five days/week for two weeks, starting on the third day post transection. For electrical stimulation, the sciatic nerve was stimulated continuously for one hour prior to nerve transection. After two weeks, lengths of YFP+ profiles of regenerating axons were measured from harvested nerves. Both exercise and electrical stimulation enhanced axon regeneration, but this enhancement was blocked completely by flutamide treatments. Signaling through androgen receptors is necessary for the enhancing effects of treadmill exercise or electrical stimulation on axon regeneration in cut peripheral nerves.

Electrical Stimulation to Enhance Axon Regeneration After Peripheral Nerve Injuries in Animal Models and Humans

“…These very promising findings anticipate further studies that may form the basis for the adoption of technique of intraoperative brief electrical stimulation at the time of surgical repair of injured nerves to become the standard of practice in management of peripheral nerve injuries. The ability of training programs after surgical repair of peripheral nerves to accelerate nerve regeneration in animal studies also holds considerable promise for the management of peripheral nerve injuries [85,122]. Whilst movement is usually restricted after surgical repair of injured nerves, possibilities such as the adoption of imagined movement in the early stages of recovery followed by adoption of active programs of activity may be explored in the future.…”

“…Over the course of evaluating the extent of activity-mediated axonal regeneration, Sabatier et al [121] and Wood et al [122] discovered a sex difference in the effectiveness of treadmill training when comparing 2 treadmill training paradigms, continuous and interval training. A daily slow training protocol at 10 m/min for 1 h resulted in a marked increase in the length of regenerating axons in male mice 2 weeks after nerve transection and repair, but the protocol had no effect on regeneration in female mice [85,122]. On the other hand, when the female mice were exposed to a faster 20 m/min training protocol for 2-min intervals 4 times daily, an impressive enhancement in axonal regeneration was seen.…”

“…The studies from English's laboratory provide evidence that sex steroid hormones, particularly testosterone, mediate this sex difference in exercised mice [122]. They also demonstrate that androgens are also critical for the efficacy of low-frequency electrical stimulation in promoting axon outgrowth [85]. In the former case, castration of male rats eliminated the enhanced axon regeneration by daily interval training, and treating unexercised 9 Exogenous administration of the neurotrophic factors brainderived neurotrophic factor (BDNF) and glial cell-line derived neurotrophic factor (GDNF) promotes neuronal regeneration of injured motoneurons after delayed nerve repair.…”

“…The decline in motoneuron numbers after 2 months was not only prevented by a month of administration of BDNF (2 μg/day) or GDNF (0.1 μg/day), but also the neurotrophic factors significantly increased the numbers of 2-month chronically axotomized motoneurons that regenerated their axons (* p < 0.05; ** p < 0.01) female mice with an aromatase inhibitor, anastrozole, to block the conversion of testosterone or its precursors into estradiol, enhanced axonal regeneration [122]. Subsequent experiments demonstrated that treating mice with flutamide, an androgen receptor blocker, inhibited the effect of both exercise and electrical stimulation in both sexes [85]. As treadmill training can be readily applied to humans, the translational potential of this modality in combination with electrical stimulation in peripheral nerve injuries is promising, while activity-dependent therapies also simultaneously empower patients to assume responsibility for their own recovery.…”

Effects of Pulsed Electromagnetic Fields on Peripheral Nerve Regeneration Using Allografts in Sciatic Nerve: An Animal Model Study

“…This method has been shown to be effective, but has the several disadvantages, including an extra incision for removal of a healthy sensory nerve ultimately resulting in a sensory deficit at the donor site [2,3]. Surgical therapy in patients with peripheral nerve injuries has not presented changes over the last decades, especially due to the use of autologous grafts, to the development of intraoperative magnification, and to the proven deleterious effects of tension at neural repair site [4].…”