Treadmill exercise induced functional recovery after peripheral nerve repair is associated with increased levels of neurotrophic factors

Abstract

Benefits of exercise on nerve regeneration and functional recovery have been reported in both central and peripheral nervous system disease models. However, underlying molecular mechanisms of enhanced regeneration and improved functional outcomes are less understood. We used a peripheral nerve regeneration model that has a good correlation between functional outcomes and number of motor axons that regenerate to evaluate the impact of treadmill exercise. In this model, the median nerve was transected and repaired while the ulnar nerve was transected and prevented from regeneration. Daily treadmill exercise resulted in faster recovery of the forelimb grip function as evaluated by grip power and inverted holding test. Daily exercise also resulted in better regeneration as evaluated by recovery of compound motor action potentials, higher number of axons in the median nerve and larger myofiber size in target muscles. Furthermore, these observations correlated with higher levels of neurotrophic factors, glial derived neurotrophic factor (GDNF), brain derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), in serum, nerve and muscle suggesting that increase in muscle derived neurotrophic factors may be responsible for improved regeneration.

Figure 1. Effect of exercise on functional outcomes.

Exercise improved both grip strength (A) and time on the inverted holding test (B) in mice with median nerve repair over 6 weeks. (* Denotes statistically significant difference, P>0.05).

Figure 2. Effect of exercise on evoked motor response in nerve conduction study.

Exercise improved both the amplitude of the evoked CMAP response (A) and distal latency (B) 6 weeks after median nerve repair. (* Denotes statistically significant difference, P>0.05).

Figure 3. Impact of exercise on nerve morphometry.

Exercise resulted in improved nerve regeneration as shown cross sections of distal median nerve in uninjured control nerve, regenerated nerve with exercise and regenerated nerve with no-exercise (A). Quantitation of the nerve morphometry showed higher number of axons (B) with larger diameter (C) and thicker myelin (E). This resulted in normalization of the g-ratio (D). (* Denotes statistically significant difference compared to no-exercise group, P>0.05).

Figure 4. Effect of exercise on muscle mass.

Exercise resulted in larger myofiber size as shown in (B) compared to uninjured control (A) or no-exercise group (C). This is quantified in (D). There was also a difference in total muscle weight between the exercise and no-exercise groups (E). (* Denotes statistically significant difference compared to no-exercise group, P>0.05).

Figure 5. Effect of exercise on neurotrophic factor levels.

Tissue and serum levels of GDNF, IGF-1 and BDNF were measured at 6 weeks after nerve repair. In all cases, except serum BDNF, exercised group had higher levels of all three neurotrophic factors in muscle, serum and distal nerve as measured by ELISA. Control is uninjured animals with no exercise program. Exercise and no exercise groups denote animals undergoing median nerve repair and regeneration. (* Denotes statistically significant difference compared to no-exercise group, P>0.05).