The wasting syndrome that occurs in patients with AIDS is a significant cause of the morbidity and mortality in this patient population. The underlying metabolic disturbances that accompany this syndrome are not well defined. However, the wasting syndrome that occurs is unlike simple malnutrition, in that body fat appears to be relatively conserved at the expense of muscle mass. Preliminary data from our laboratories have identified marked decreases in the circulating levels of the insulin-like growth factors (IFGs) and significant post-translational modifications of the IGF binding proteins (BPs), BP-1 and BP-3, in patients with AIDS who have lost 10-20% of ideal body weight. Therefore, it is the hypothesis of this proposal that alterations in the growth hormone (GH)/IGF axis resulting from HIV infection impairs IGF stimulation of anabolic processes, including muscle protein synthesis, and is a contributing factor to the muscle wasting that occurs in patients with AIDS. This hypothesis will be addressed by the following specific aims: (1) measurement of rates of skeletal muscle protein synthesis and degradation throughout the course of the disease; (2) assessment of changes in the GH/IGF axis in patients from the period of initial diagnosis of HIV infection through end stage of AIDS; and (3) to determine at what stage of AIDS acute nutritional and hormonal intervention fails to modulate muscle protein synthesis and breakdown and the IGF system. In vivo muscle protein synthesis will be measured by the flooding technique using stable (non-radioactive) isotopes. The GH/IGF axis will be assessed by specific radiometric assays for GH, IGF-I, IGF-II,BP-3; an ELISA has been developed to measure BP-1; the post-translational modification of the BPs will be assessed by Western and ligand blotting as well as by non-denaturing gel electrophoresis. GH plus a high protein diet will be used as acute intervention to determine the responsiveness of muscle protein synthesis and degradation, as well as the IGF system at different stages of AIDS. These studies will be the first to measure in vivo muscle protein balance directly and detail the defects in the IGF system. This information will aid in our understanding of the pathophysiology involved in muscle wasting and provide a scientific rationale upon which to base future therapeutics for this disease.
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