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.
