Concurrent CVT and RT is as effective in eliciting improvements in cardiovascular fitness and 5RM performance as CVT or RT, respectively. Moreover, incorporating both CVT and RT in exercise programs for older adults may be more effective in optimizing aspects of functional fitness than programs that involve only one component.

Physical activity after spinal cord injury promotes improvements in motor function, but its effects following peripheral nerve injury are less clear. Although axons in peripheral nerves are known to regenerate better than those in the CNS, methods of accelerating regeneration are needed due to the slow overall rate of growth. Therefore we studied the effect of two weeks of treadmill locomotion on the growth of regenerating axons in peripheral nerves following injury. The common fibular nerves of thy-1-YFP-H mice, in which a subset of axons in peripheral nerves express yellow fluorescent protein (YFP), were cut and repaired with allografts from non-fluorescent littermates, and then harvested two weeks later. Mice were divided into groups of low-intensity continuous training (CT, 60 minutes), low-intensity interval training (IT; one group, 10 reps, 20 minutes total), and high-intensity IT (three groups, 2, 4, and 10 reps). One repetition consisted of two minutes of running and five minutes of rest. Sixty minutes of CT resulted in the highest exercise volume, whereas two reps of IT resulted in the lowest volume of exercise. The lengths of regenerating YFP + axons were measured in images of longitudinal optical sections of nerves. Axon profiles were significantly longer than control in all exercise groups except the low-intensity IT group. In the CT group and the high-intensity IT groups that trained with four or 10 repetitions axons were more than twice as long as unexercised controls. The number of intervals did not impact axon elongation. Axon sprouting was enhanced in IT groups but not the CT group. Thus exercise, even in very small quantities, increases axon elongation in injured peripheral nerves whereas continuous exercise resulting in higher volume (total steps) may have no net impact on axon sprouting.

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 of cut peripheral nerves at the time of their surgical repair results in an enhancement of axon regeneration. Regeneration of axons through nerve allografts was used to evaluate whether this effect is due to an augmentation of cell autonomous neurotrophin signaling in the axons or signaling from neurotrophins produced in the surrounding environment. In the thy-1-YFP-H mouse, a single one hour application of electrical stimulation at the time of surgical repair of the cut common fibular nerve results in a significant increase in the proportion of YFP+ dorsal root ganglion neurons that were also immunoreactive for BDNF or trkB as well as an increase in the length of regenerating axons through allografts from wild type litter mates, both one and two weeks later. Axon growth through allografts from neurotrophin-4/5 knockout mice or grafts made acellular by repeated cycles of freezing and thawing is normally very poor, but electrical stimulation results in a growth of axons through these grafts which is similar to that observed through grafts from wild type mice after electrical stimulation. When cut nerves in NT-4/5 knockout mice were electrically stimulated, no enhancement of axon regeneration was found. Electrical stimulation thus produces a potent enhancement of the regeneration of axons in cut peripheral nerves which is independent of neurotrophin production by cells in their surrounding environment but is dependent on stimulation of trkB and its ligands in the regenerating axons themselves.

We investigated the extent of misdirection of regenerating axons when that regeneration was enhanced using treadmill training. Retrograde fluorescent tracers were applied to the cut proximal stumps of the tibial and common fibular nerves two or four weeks after transection and surgical repair of the mouse sciatic nerve. The spatial locations of retrogradely labeled motoneurons were studied in untreated control mice and in mice receiving two weeks of treadmill training, either according to a continuous protocol (10 m/min, one hour/day, five day/week) or an interval protocol (20 m/min for two minutes, followed by a five minute rest, repeated 4 times, five days/week). More retrogradely labeled motoneurons were found in both treadmill trained groups. The magnitude of this increase was as great as or greater than that found after using other enhancement strategies. In both treadmill trained groups, the proportions of motoneurons labeled from tracer applied to the common fibular nerve that were found in spinal cord locations reserved for tibial motoneurons in intact mice was no greater than in untreated control mice and significantly less than found after electrical stimulation or chondroitinase treatment. Treadmill training in the first two weeks following peripheral nerve injury produces a marked enhancement of motor axon regeneration without increasing the propensity of those axons to choose pathways leading to functionally inappropriate targets.