The mechanisms of skeletal muscle atrophy, and the associated functional deficits, produced by a chronic decrease in the levels of neuromuscular activity are not well defined. Similarly, the most efficacious type or quantity of electro-mechanical activation to use as a countermeasure for these detrimental effects are undefined. We are proposing to use a model of virtually complete inactivity while preserving neurotrophic support, i.e., spinal cord isolation (SI), to address these issues. SI involves complete spinal cord transections at a mid-thoracic and high sacral level and bilateral dorsal rhizotomy between the two transection sites. SI, therefore, provides a baseline for determining the effects of chronic inactivity on skeletal muscle. We have successfully used a battery of molecular markers for protein metabolism to identify some of the major pathways involved in the skeletal muscle hypertrophic response associated with the functional overloading of a muscle by removal of its major synergists. These results have provided a framework for identifying the major pathways associated with muscle atrophy. Our overall working hypothesis is that the elimination of the normal activation/loading parameters on a muscle will down-regulate the pathways that have been shown to be up-regulated with increased activation/loading. We then will use high resistance isometric regimes to counteract the detrimental effects of inactivity on muscle function and phenotype. A unique BION stimulation implant system will be used to impose a known amount of electro-mechanical stimulation on the otherwise """"""""silent"""""""" plantarflexor muscles. Our approach will be to begin to identify the optimum stimulation paradigms for maximum maintenance of the properties of both a slow and a fast plantarflexor. We will vary the patterns of stimulation to optimize the normal contractile dynamics of each of these muscle types and will determine the effectiveness of imposing these electro-mechanical regimes once vs. twice per day. We will identify molecular mechanisms which can be used to counter the atrophic response. From a clinical perspective, understanding how critical molecular events can be modulated by known quantities of electro-mechanical stimulation will provide a clear direction for designing exercise and programmed mechanical stimulation paradigms to be used as preventive and/or rehabilitative tools for patients with muscle atrophy associated with spinal and neuromuscular maladies, aging, etc.
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