The mechanism of muscle wasting in AIDS is not known. It is the hypothesis of this proposal that wasting in AIDS is associated with increased production of glutamine by muscle. Glucocorticoids, by stimulating muscle proteolysis and glutamine synthetase activity, are a key contributing factor to wasting. Therefore, pharmacological blockade of glucocorticoid receptors might prevent or alleviate a significant component of the wasting syndrome. The proposed studies will employ muscle biopsy specimens from human AIDS patients, as well as mice with a persistent retrovirus infection (LP-BM5), the manifestations of which simulate many features of human AIDS. The specific objectives are: (1) to characterize muscle wasting in AIDS; (2) to evaluate the mechanism of changes in glutamine synthetase and glutaminase activities and glutamine production in muscle from human AIDS patients and LP-BM5- infected mice; (3) to determine alterations in glucocorticoid receptors in muscle from human AIDS patients and from LP-BM5- infected mice and the mechanisms underlying such changes; and, (4) to assess antiglucocorticoid therapy for muscle wasting in LP-BM5- infected mice. The proposed studies are expected to contribute to a better understanding of biochemical mechanisms underlying muscle wasting in AIDS, provide useful biochemical markers for clinical assessment of early wasting, and lead to the development of specific treatments for this devastating conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041022-03
Application #
3241580
Study Section
Special Emphasis Panel (ARR (V1))
Project Start
1989-08-01
Project End
1992-07-31
Budget Start
1991-08-01
Budget End
1992-07-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Feng, B; Konagaya, M; Konagaya, Y et al. (1990) Neural control of glutamine synthetase activity in rat skeletal muscles. Am J Physiol 258:E757-61
Feng, B; Hilt, D C; Max, S R (1990) Transcriptional regulation of glutamine synthetase gene expression by dexamethasone in L6 muscle cells. J Biol Chem 265:18702-6
Zielke, H R; Tildon, J T; Landry, M E et al. (1990) Effect of 8-bromo-cAMP and dexamethasone on glutamate metabolism in rat astrocytes. Neurochem Res 15:1115-22
Feng, B; Shiber, S K; Max, S R (1990) Glutamine regulates glutamine synthetase expression in skeletal muscle cells in culture. J Cell Physiol 145:376-80
Max, S R; Landry, M E; Zielke, H R (1990) Induction of glutamine synthetase by 8-bromo cyclic AMP in primary cultures of rat brain astrocytes. Neurochem Res 15:583-6
Feng, B; Banner, C; Max, S R (1990) Effect of diabetes on glutamine synthetase expression in rat skeletal muscles. Am J Physiol 258:E762-6
Max, S R (1990) Glucocorticoid-mediated induction of glutamine synthetase in skeletal muscle. Med Sci Sports Exerc 22:325-30
Kelso, T B; Shear, C R; Max, S R (1989) Enzymes of glutamine metabolism in inflammation associated with skeletal muscle hypertrophy. Am J Physiol 257:E885-94