Daily Electrical Muscle Stimulation Enhances Functional Recovery and Upregulates Muscular Brain Derived Neurotrophic Factor (BDNF) Following Nerve Transection and Repair in Rats
Michael P. Willand, PhD1; Jennifer J. Zhang1; Cameron D. Chiang1; Elyse Rosa2; Stephen WP Kemp1; Margaret Fahnestock2; Gregory H. Borschel1; Tessa Gordon1 1Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada; 2Department of Psychiatry & Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
Introduction: The use of chronic electrical muscle stimulation for treating partially or completely denervated muscle is controversial. Recently, we used a daily electrical muscle stimulation paradigm over a two week period after nerve injury and immediate repair. We showed that muscle stimulation significantly increases the number of motor nerves reinnervating muscles and axon outgrowth within the distal nerve stump. Activity-dependent intramuscular trophic factor release acts on regenerating axons, which may explain the increased early regeneration in stimulated muscle. However, chronic electrical muscle stimulation applied throughout the entire reinnervation period has not been previously assessed. In the present study we hypothesized that stimulation would enhance functional recovery over three months and that stimulation enhances early intramuscular trophic factor release.
Methods: Six groups of Thy1-GFP transgenic male rats underwent tibial nerve transection and immediate repair using two epineurial sutures. One group of rats underwent daily electrical muscle stimulation of the gastrocnemius with a paradigm producing 600 equally separated contractions throughout one hour, delivered 5 days per week. Rat gastrocnemius muscles were electrically stimulated for 1, 2, or 3 months and then we assessed muscle force, contractile properties, motor unit numbers, and wet muscle weight. Rats in the 3 month group were serially evaluated using a tapered beam test to evaluate skilled locomotion. Muscles underwent immunohistological examination of motor end plate reinnervation. Two additional groups of rats were subjected to the same nerve injury and were used to investigate early intramuscular trophic factor release following two weeks of electrical muscle stimulation or no treatment.
Results: The number of motor units was significantly increased after daily muscle stimulation at all three time points (1, 2, and 3 months). Mean motor unit sizes were significantly smaller in stimulated muscles, suggesting that muscle stimulation may inhibit terminal sprouting as reported by others. This may allow for a more natural course of reinnervation resulting in improved functional recovery. Indeed, skilled locomotion tests showed that stimulated muscles enhanced and maintained recovery at levels no different than normal functioning rats, whereas non-stimulated controls became progressively worse and did not recover to baseline. After two weeks of stimulation, BDNF was significantly upregulated in stimulated muscle compared to non-stimulated muscle.
Conclusions: Treatment of denervated muscle using electrical stimulation significantly enhanced muscle reinnervation, and upregulation of BDNF may explain this enhancement. As the muscle continues to reinnervate, tailoring the stimulation paradigm to improve muscle force and fatigability may further enhance muscle recovery.
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