The long-term objectives of this study are to define effective interventions to the cascade of structural, biochemical and functional alterations that occur in myofibers following a severe spinal cord injury (SCI) in the rat. Experiments are designed to evaluate the temporal sequence of changes that occur in intact muscles and myofibers after SCI in adult rats and to determine how the presence of transplanted fetal spinal cord (FSC) tissue or an exercise regimen of the hindlimbs affects these temporal changes.
The specific aims of this component are focused on testing of muscle strength and endurance (fatigability), immunocytochemical identification of myofiber type based on myosin heavy chain (MyHC) composition and determination of possible reversion to more immature MyHC types, identification of changes in expression of genes thought to regulate contractile protein content of myofibers and measurement of myofiber size. Comparison of the changes in the various parameters will establish correlations between effects on myofiber size and myofiber function, metabolic nature and possible genetic regulation. Information from these studies will provide vital knowledge about the potential use and efficient design of an interventive program(s) to alter effectively the extent of disuse atrophy and loss of mobility that occurs after SCI.
Aim I of this proposal will establish the acute and chronic effects of SCI on the hindlimbs, to provide a baseline against which all interventive approaches will be tested. Experiments will establish the pattern of changes in muscle size and function in conjunction with changes in gene expression and MyHC isoforms within myofibers.
For Aim II, using a similar transection lesion model, we will test the hypothesis that intraspinal transplants of FSC tissue can effectively disrupt the pattern of myofiber changes that occur after SCI. Animals that receive a transplant immediately after injury will be sacrificed at different stages of transplant development to demonstrate the short- and long-term effectiveness of the transplant to limit further muscle alterations. In a second experiment, a delay in transplantation after sa will test whether FSC tissue can reverse or stop progression of muscle changes that would occur without transplant intervention.
In Aim III, experiments are designed to test the hypothesis that a long duration, low intensity exercise program for hindlimb muscles following spinal cord injury can intervene in the progressive change that these muscles undergo normally. Exercise will be initiated either immediately after injury or after a short delay of less than 30 days to establish what effects intervention at different post-injury intervals might have on muscle changes. Whether reflex activation during hindlimb exercise is involved in successful intervention will be tested in separate experiments. Finally, we will determine whether there are additive effects from combined treatment of exercise and FSC tissue transplantation on characteristic changes in muscle size, metabolic capacity and muscle function after SCI. One major obstacle for the successful rehabilitation of SCI patients is the restoration of muscle strength and endurance. These experiments have direct relevance to the design and implementation of treatment programs for dealing with this aspect of the spinal cord injured individual.
