Our long-term objective is to provide an alternative source of motoneurons to reinnervate denervated muscles. Reinnervation would minimize and/or reverse the denervation-induced muscle wasting and dysfunction that is characteristic of many neuromuscular disorders and after central or peripheral nervous system trauma. We have shown that embryonic day 15 ventral spinal cord cells transplanted into peripheral nerve produce axons that form functional neuromuscular junctions with denervated muscles. In this proposal we aim to improve the strength of the reinnervated muscles by manipulation of the cells that are transplanted and the local neuromuscular environment. In adult Fischer rats, our Specific aims are to evaluate whether muscle reinnervation and function are improved by: 1) long-term delivery of pharmacological inhibitors to the transplant or muscles; 2) transplantation of embryonic cells of different ages; 3) long-term addition of trophic factors to the transplant; 4) combinations of these 3 treatments; 5) cell transplantation, then after a delay, the reintroduction of peripheral axons, a chronic denervation situation typical of peripheral nerve injuries. Outcomes measures will include survival of specific cell types by immunohistological characterization of the transplant; the number and diameter of myelinated axons in peripheral nerve; muscle reinnervation by retrograde fluorescent tracing, silver and acetylcholine esterase staining of axons and neuromuscular junctions; the number of reinnervated motor units judged by evoking distinct electromyographic steps in response to electrical stimulation of the transplant; muscle strength, fatigue resistance, fiber size and weight. These data will provide insights into the in vivo potential of embryonic ventral spinal cord cells to reinnervate adult muscle. Muscles with functional reinnervation can be excited artificially by electrical stimulation to potentially produce simple behaviors. This may improve the independence and quality of life of compromised individuals. Equally important, reinnervation may maintain muscle tissue, making it more receptive to renewed neural activity established by regeneration of peripheral or central axons.
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