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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040606-03
Application #
6656244
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Program Officer
Chen, Daofen
Project Start
2001-09-30
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
3
Fiscal Year
2003
Total Cost
$1,136,135
Indirect Cost
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
Bruneau Jr, Michael; Walsh, Sean; Selinsky, Eric et al. (2018) A genetic variant in IL-15R? correlates with physical activity among European-American adults. Mol Genet Genomic Med 6:401-408
Bruneau Jr, Michael; Angelopoulos, Theodore J; Gordon, Paul et al. (2017) The angiotensin-converting enzyme insertion/deletion polymorphism rs4340 associates with habitual physical activity among European American adults. Mol Genet Genomic Med 5:524-530
Ash, Garrett I; Kostek, Matthew A; Lee, Harold et al. (2016) Glucocorticoid Receptor (NR3C1) Variants Associate with the Muscle Strength and Size Response to Resistance Training. PLoS One 11:e0148112
Lee, Harold; Ash, Garrett I; Angelopoulos, Theodore J et al. (2015) Obesity-Related Genetic Variants and their Associations with Physical Activity. Sports Med Open 1:34
Liu, Dongmei; Sartor, Maureen A; Nader, Gustavo A et al. (2013) Microarray analysis reveals novel features of the muscle aging process in men and women. J Gerontol A Biol Sci Med Sci 68:1035-44
Pescatello, Linda S; Devaney, Joseph M; Hubal, Monica J et al. (2013) Highlights from the functional single nucleotide polymorphisms associated with human muscle size and strength or FAMuSS study. Biomed Res Int 2013:643575
Hoffman, Eric P; Gordish-Dressman, Heather; McLane, Virginia D et al. (2013) Alterations in osteopontin modify muscle size in females in both humans and mice. Med Sci Sports Exerc 45:1060-8
Gordon, Paul M; Liu, Dongmei; Sartor, Maureen A et al. (2012) Resistance exercise training influences skeletal muscle immune activation: a microarray analysis. J Appl Physiol 112:443-53
Van Deveire, Katherine N; Scranton, Sarah K; Kostek, Mathew A et al. (2012) Variants of the ankyrin repeat domain 6 gene (ANKRD6) and muscle and physical activity phenotypes among European-derived American adults. J Strength Cond Res 26:1740-8
Walsh, S; Haddad, C J; Kostek, M A et al. (2012) Leptin and leptin receptor genetic variants associate with habitual physical activity and the arm body composition response to resistance training. Gene 510:66-70

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