Neuromuscular denervation is a common consequence of peripheral nerve injuries and neurological diseases. There is a pressing need to seek novel approaches of reinnervation for restoration of paralyzed muscles as the presently used methods generally result in poor functional recovery. The global hypothesis driving this project is that better outcomes could be achieved by reinnervating a paralyzed muscle with an abundant source of intact nerve terminals and motor endplates. This idea promoted us to develop a nerve- muscle-endplate band grafting (NMEG) method to reinnervate paralyzed muscles. Cervical strap muscles were selected to perform feasibility studies in a rat model. The NMEG was harvested from the omohyoid (OH) muscle and then transplanted to the experimentally paralyzed sternomastoid (SM) muscle. Meanwhile, nerve- muscle pedicle (NMP) and end-to-end anastomosis (EEA) reinnervation procedures were also carried out for comparison. Our pilot studies using immediate reinnervation model showed that NMEG resulted in successful neuroregeneration and better functional recovery than the NMP and EEA. This research is to determine the efficacy of the NMEG for the immediate and delayed reinnervation of paralyzed cervical strap muscles as compared with the classic EEA technique. Studies designed in this proposal will document the fundamental neural basis of the functional recovery and other major factors influencing outcomes. We hypothesized that the extent of functional recovery of a reinnervated muscle is largely dependent on both the quantity of the reestablished nerve-muscle contacts and the denervation induced muscular alterations and that the NMEG would be a better option for muscle reinnervation than the commonly used EEA and other methods. These hypotheses will be tested with the following 3 specific aims.
Specific Aim 1 is to evaluate functional recovery of the reinnervated muscles by analyzing electromyographic (EMG) recordings, muscle force and movement measurements, and distribution of the glycogen depleted muscle fibers.
Specific Aim 2 is to demonstrate the neural basis of the functional restoration of the reinnervated muscles by quantifying the retrograde horseradish peroxidase (HRP) labeled motoneurons, regenerating axons and sprouts, and newly formed motor endplates.
Specific Aim 3 is to explore procedure-related and time-dependent morphological, immunocytochemical, and biochemical changes in the reinnervated muscles by analyzing muscle mass, fiber size, fiber type grouping, and fiber type and myosin heavy chain (MHC) composition. The results will allow the reliable documentation of the efficacy of the NMEG in rehabilitation of muscle paralysis. The significance of the proposed work extends far beyond what is currently understood. Once the advantages of the NMEG are fully documented by extensive animal studies, the impact of this research on science and health care could be substantial as the data obtained from this research are useful for ultimate clinical application in the near future to the treatment of patients with paralytic neuromuscular disorders. As an entirely satisfactory solution to restoration of the paralyzed skeletal muscles has not yet been found, we developed a new technique (nerve-muscle-endplate band grafting) to reinnervate paralyzed cervical strap muscles in a rat model. Our preliminary work showed that this technique results in better outcomes than currently used methods. The data obtained from this research is useful for future clinical application to treat muscle paralysis.
