FAT DISTRIBUTION AND INSULIN RESISTANCE IN HIV

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Myostatin, uncoupling proteins, and ACE polymorphisms are recently discovered regulators of skeletal muscle growth, metabolism, and function. Skeletal muscle, the largest body compartment in normal weight humans, is increasingly a research focus of molecular genetic, and clinical investigations. Despite this intense research interest, methods of non-invasively characterizing regional and total body skeletal muscle distribution, mass, and composition remain remarkably limited. The first phase of this study in Program Project II developed and refined skeletal muscle evaluation methods and models in a cross-sectional cohort of normal and overweight ethnically-mixed adults. In progressing towards this aim in adults we observed and reported, using reference body composition methods, that; older adults have less relative skeletal muscle mass than young subjects; that skeletal muscle mass than young subjects; that skeletal muscle mass and distribution are functions of gender, age, and body mass; and that at all adult ages, African Americans have a larger skeletal muscle and related bone compartment than Caucasians, even after controlling for other known skeletal muscle determinants. With these biological observations as a basis, we validated, improved older, or developed new skeletal muscle mass measurement methods including those based on magnetic resonance imaging, or developed new skeletal muscle mass measurement methods including those based on magnetic resonance imaging, dual-energy x-ray absorptiometry, 40K counting, bioimpedance analysis, anthropometry, and urinary metabolite markers. These efforts led to important collaborations with members of the other projects, development of new laboratory resources in the core units, and outreach to engineers with modeling experience in the new Columbia Department of Biomedical Engineering. Important gaps, however, remain: our method and models are applicable only in adults; models were developed in normal and overweight adults and not at body mass extremes; and our methods were validated only in cross-sectional samples and not in longitudinal cohorts with skeletal muscle changes secondary to growth in children or interventions. The clinical and research importance of all 3 of these areas led us to advance 6 new hypotheses and related aims divided into 3 separate human and animal studies.: Study 1 proposes to advance method development in 240 African American and Caucasian males & females in Tanner Stages 1-5; 48 will be followed up at 2-3 years with growth; Study 2 proposes to cross-validate models in adult patients with underweight (anorexia nervosa) and obesity, in Projects 2 and 3, before and during treatments designed to produce weight change; Study 3 is designed to non-invasively evaluate aspects of muscle composition across the human lifespan in subjects from all four projects; and to establish, for the first time, relevant electrical properties of isolated rodent skeletal muscle before and following specific hypothesis-based interventions. In addition, to interact projects, this study will also provide important new information on adiposity and energy expenditure-related issues in children. The composite developed methods and the biological issues that they touch upon would provide a foundation for human skeletal muscle studies anticipated in the near future, particularly in children.