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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054163-03
Application #
6177838
Study Section
AIDS and Related Research Study Section 2 (ARRB)
Program Officer
Jones, Teresa L Z
Project Start
1998-05-15
Project End
2003-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
3
Fiscal Year
2000
Total Cost
$349,903
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Bhasin, Shalender; He, E Jiaxiu; Kawakubo, Miwa et al. (2009) N-terminal propeptide of type III procollagen as a biomarker of anabolic response to recombinant human GH and testosterone. J Clin Endocrinol Metab 94:4224-33
Cade, W T; Reeds, D N; Lassa-Claxton, S et al. (2008) Post-exercise heart rate recovery in HIV-positive individuals on highly active antiretroviral therapy. Early indicator of cardiovascular disease? HIV Med 9:96-100
Cade, W Todd; Reeds, Dominic N; Mittendorfer, Bettina et al. (2007) Blunted lipolysis and fatty acid oxidation during moderate exercise in HIV-infected subjects taking HAART. Am J Physiol Endocrinol Metab 292:E812-9
Reeds, Dominic N; Cade, W Todd; Patterson, Bruce W et al. (2006) Whole-body proteolysis rate is elevated in HIV-associated insulin resistance. Diabetes 55:2849-55
Reeds, D N; Yarasheski, K E; Fontana, L et al. (2006) Alterations in liver, muscle, and adipose tissue insulin sensitivity in men with HIV infection and dyslipidemia. Am J Physiol Endocrinol Metab 290:E47-E53
Yarasheski, Kevin E; Smith, Samuel R; Powderly, William G (2005) Reducing plasma HIV RNA improves muscle amino acid metabolism. Am J Physiol Endocrinol Metab 288:E278-84
Chaparro, Juan; Reeds, Dominic N; Wen, Weidong et al. (2005) Alterations in thigh subcutaneous adipose tissue gene expression in protease inhibitor-based highly active antiretroviral therapy. Metabolism 54:561-7
Gerber, Marisa T; Mondy, Kristin E; Yarasheski, Kevin E et al. (2004) Niacin in HIV-infected individuals with hyperlipidemia receiving potent antiretroviral therapy. Clin Infect Dis 39:419-25
Yarasheski, Kevin E; Tebas, Pablo; Claxton, Sherry et al. (2003) Visceral adiposity, C-peptide levels, and low lipase activities predict HIV-dyslipidemia. Am J Physiol Endocrinol Metab 285:E899-905
Yarasheski, Kevin E (2003) Exercise, aging, and muscle protein metabolism. J Gerontol A Biol Sci Med Sci 58:M918-22

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