DNA POLYMORPHISMS IN THE MYOSTATIN GENE IN SARCOPENIA
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Sarcopenia or age-related loss of lean body mass contributes to functional decline, decreased exercise tolerance, falls, frailty, and metabolic changes in the elderly. The etiology of sarcopenia is complex, with declines in activity, hormonal and neurologic changes, age-related genes in gene expression, and variations in genes that regulate muscle mass likely all playing a role. In this pilot study, we seek to explore the role of genetic variation in the myostatin gene in the development of sarcopenia. Myostatin (GDF-8) is a member of the tissue growth factor-beta (TGF-beta) superfamily and is an important negative regulator of muscle mass maintenance in mammals. We hypothesize that variation in the human myostatin gene contributes to the development of sarcopenia. In order to test this hypothesis, we will complete the following specific aims: 1) determine the genomic structure of the human gene, 2) screen individuals with and without sarcopenia for DNA polymorphisms in the myostatin gene using sequences determined in the first specific aim, and 3) Determine the relationship of DNA polymorphisms identified in the myostatin gene to low levels of strength in the WHAS II cohort through a case-control association study, using loss of strength as a surrogate marker for sarcopenia. We have in preliminary studies determined the intron/exon structure of the myostatin gene, and will use a human genomic DNA library tp determine the 5' & 3' regulatory region sequence to complete specific aim 1. We will use single stranded conformational polymorphism analysis (SSCP) to screen-coding and regulatory regions of the gene and sequence any polymorphisms identified to complete SA2. We will test the hypothesis of whether there is association between the DNA polymorphisms and strength measures in the WHAS II cohort using unconditional logistic regression controlling for conditions known to impact mobility and strength. Elucidation of genetic contributions to the development of sarcopenia could lead to targeted preventive and treatment strategies for this disabling condition of the elderly.
