Sex differences in the effectiveness of treadmill training in enhancing axon regeneration in injured peripheral nerves

Abstract

Exercise in the form of daily treadmill training results in significant enhancement of axon regeneration following peripheral nerve injury. Because androgens are also linked to enhanced axon regeneration, we wanted to investigate whether sex differences in the effect of treadmill training might exist. The common fibular nerves of thy-1-YFP-H mice were cut and repaired with a graft of the same nerve from a strain-matched wild type donor mouse. Animals were treated with one of two daily treadmill training paradigms: slow continuous walking for one hour or four higher intensity intervals of two minutes duration separated by five minute rest periods. Training was begun on the third day following nerve injury and continued five days per week for two weeks. Effects on regeneration were evaluated by measuring regenerating axon profile lengths in optical sections through the repair sites and grafts at the end of the training period. No sex differences were found in untrained control mice. Continuous training resulted in significant enhancement of axon regeneration only in males. No effect was found in females or in castrated males. Interval training was effective in enhancing axon regeneration only in females and not in intact males or castrated males. Untrained females treated with the aromatase inhibitor, anastrozole, had significant enhancement of axon regeneration without increasing serum testosterone levels. Two different mechanisms exist to promote axon regeneration in a sex-dependent manner. In males treadmill training utilizes testicular androgens. In females a different cellular mechanism for the effect of treadmill training must exist.

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.…”

“…The significantly (p < 0.05) elevated number of regenerated sciatic nerve axons that grew out and over longer distances from the lesion site after a CL and (iib) the significantly elevated numbers of axons that grew out from the lesion site but did not grow over longer distances after 20Hz electrical stimulation for 1 h. Each point is the mean ± SEM interval training protocol. 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].…”

“…The administration of androgens in conjunction with electrical stimulation, however, sustains their upregulation [81,82]. 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].…”

“…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.…”

“…This regeneration was significantly reduced by a 2-month period of chronic axotomy consistent with the data of Fu and Gordon [17]. 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].…”