The long-term goal of the proposed research is to define the molecular basis for polymorphic variation in muscle function in humans. Genetic variation in human muscle performance has been well documented in athletics, and in pathological situations such as sarcopenia during aging, and atrophy during space flight. Our overriding hypothesis is that muscle is an ideal tissue system in which to study both genetic variation, and response to environmental stimuli. Muscle responds quickly to strength training, with changes in both function (strength) and cell size (myofiber hypertrophy). Moreover, it is well recognized that both baseline strength, and the degree of response to exercise, are heritable. The proposed research proposes to identify all functional polymorphisms (non-synonymous SNPs) in the 500 most highly expressed muscle genes. This will be done by DHPLC analysis of muscle biopsy cDNAs from 40 ethnically diverse individuals, followed by automated sequencing of heteroduplexes. The DHPLC analysis will also permit us to directly derive preliminary allele frequencies for each polymorphism. The SNP identification aspects of the proposed research will take place at the Research Center for Genetic Medicine, where all necessary equipment for DHPLC and sequence analysis is in the Hoffman laboratory, and constitute Aim 1. In parallel to the SNP Identification project, Dr. Paul Thompson, a renowned exercise physiologist, will coordinate a 1,400-person exercise study (Aim 2). The exercise study will involve subject recruitment and training at seven universities, which includes a wide ethnic mixture, with equal numbers of males and females under study. Blood samples for DNA isolation will be taken from each subject, and pre- and post-exercise MRIs taken of both biceps. The non-dominant arm will then be subjected to a regimented 12 wk training program. The four variables to be acquired for each patient are baseline strength, baseline biceps area, and percentage change in strength and muscle area following exercise. In the third aim, statistical """"""""outliers"""""""" for each of the four muscle function variables (Aim 2) will be genotyped for each of the non-synonymous SNPs identified in Aim 1. Those SNPs showing statistical significance or trends will then be genotyped for the entire cohort In this manner, we will identify those genetic polymorphisms which predispose individuals to baseline strength and muscle bulk, and additional polymorphisms which predispose to sensitivity to an environmental influence (exercise). The proposed research takes advantage of emerging genomic technology, and the recently completed draft of the human genome. The increase in understanding of normal human variation in muscle structure and function will have implications for both health (sports performance) and disease (sarcopenia during aging, atrophy during space flight).
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