Investigations in humans and animals over the last several years have shown exercise is a potent inhibitor of skeletal muscle wasting associated with diseases and experimental conditions resulting in glucocorticoid excess The mechanism of exercise is conserving muscle mass remains as yet unidentified. By examining hormone-responsive proteins as models for understanding protein regulation, the long-term objectives are to elucidate the molecular basis by which exercise prevents muscle atrophy from this state.
The specific aims are: (a) to determine whether exercise inhibits the up-regulation of glutamine synthetase enzyme induction and gene expression. (b) To evaluate whether exercise reverses the down-regulation of myosin and specifically myosin heavy chains. The parameters to be studied are myosin heavy chain synthesis and MRNA content, native isomyosin characterization, and the synthesis rates of each isoform. (c) Pathologic changes produced by glucocorticoids, besides those in myofibrillar proteins, are also found in the mitochondria. The use of CDNA probes for both a nuclear genome and a mitochondrial genome for the multisubunit cytochrome c oxidase, a mitochondrial marker enzyme, will allow us to identify whether there is a coordinated transcriptional response by exercise in preventing the mitochondrial alterations associated with muscle wasting, and will also provide evidence as to whether there is a predilection for myofibrillar or mitochondrial sparing in the prevention of atrophy by exercise. (d) Myofibrillar protein degradation will also be measured to fully comprehend the overall contributions of exercise in altering synthesis, degradation, or both in protein sparing. By comparing individual proteins, which are hormonally-regulated in opposing directions, basic knowledge can be obtained into whether the exercise-related interference of muscle atrophy is mediated preferentially through up-regulated or down-regulated proteins or both. By quantifying protein synthesis, enzyme induction, and gene expression, we will be able to assess the roles of transcriptional or translational control to these processes.
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