The Principal Investigator proposes to test five objectives based on his preliminary observations. He and his associates have published that increased muscle proteolysis and failure to sustain muscle protein synthesis exists in AIDS-cachexia.
The first aim of this project, therefore, is to determine if the increased mediators of muscle proteolysis in this population is due to contractile muscle protein breakdown by way of the ubiquitin-proteasome pathway or whether increased proteolysis is due to the overproduction of cytotoxic nitric oxide/NO reactive intermediates in skeletal muscle. These researchers have demonstrated that not only is the rate of appearance (Ra) of glutamine (70% derived from muscle) in the circulation increased but serum glutamine concentrations are low in patients with HIV-associated wasting. The Investigator hypothesizes that the overproduction of glutamine serves to provide nitrogen to other important biochemical processes. Hence, he plans to determine (1) if glutamine is used at a more rapid rate by for CD4 and CD8 lymphocytes (approximately 10~9 cells are produced each day to combat HIV); (2) if excess glutamine nitrogen is transported to the liver for urea synthesis; and (3) if excess glutamine is used by the liver for antioxidant activity (i.e., glutathione synthesis). Finally, the researchers have preliminary data suggesting that serum levels of HIV RNA are associated with greater rates of muscle proteolysis. The Investigator hypothesizes that reducing HIV viral burden will reduce muscle wasting. In this phase of the project, he proposes to assess whether a reduction of HIV with highly active antiviral drugs will be associated with significant reductions in muscle proteolysis, reduced plasma glutamine Ra, increased muscle protein synthetic rate and increased muscle mass in patients with wasting.
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