Functional Polymorphisms Associated with Human Muscle Size and Strength

Thompson, Paul D.; Moyna, Niall M.; Seip, Richard L.; Price, Thomas B.; Clarkson, Priscilla M.; Angelopoulos, Theodore J.; Gordon, Paul M.; Pescatello, Linda S.; Visich, Paul S.; Zoeller, Robert F.; Devaney, Joseph M.; Gordish, Heather; Bilbie, Stephen M.; Hoffman, Eric P.

doi:10.1249/01.mss.0000132274.26612.23

Cited by 65 publications

(115 citation statements)

References 31 publications

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“…Thus, it appears NOS3 +894 G>T may habitually influence the preference of light PA, vigorous PA and sitting and the strength gains in women that can result from an RT program. These findings suggest NOS3 +894 G>T may be important to consider for a personalized approach to exercise prescription along with a growing number of genetic variants that have been reported to be associated with muscle performance [15,[24][25][26][27] and habitual PA [21,[28][29][30][31][32]. For example, when recommending exercise to adults for its overall health benefits, the NOS3 +894 G>T and PA intensity dependent genotype differences we found could be considered when counseling people to become more physically active due to what appears to be a genetic predisposition to prefer light over vigorous intensity PA among those with the TT genotype.…”

Section: Discussionmentioning

confidence: 94%

“…We investigated the influence of NOS3 +894 G>T and −786 T>C on habitual PA and the muscle strength response to RT among a large sample of healthy, European-derived American adults from FAMuSS [15]. We found that NOS3 +894 G>T associated with habitual PA and the muscle strength response to RT.…”

Section: Discussionmentioning

confidence: 95%

“…However, the Paffenbarger PA questionnaire has been widely validated in similar populations to the present study and is considered an accurate method of leisure time PA in adults [46]. This investigation is a subset of the FAMuSS study which is the largest study that has investigated candidate genes associated with muscle performance, and the first study to specifically investigate NOS3 variant associations with PA and muscle strength in humans [15]. Furthermore, FAMuSS 6 ISRN Vascular Medicine meets the criteria outlined by Hagberg et al [14,47] that are necessary for conducting exercise genomics studies including a large sample size, a well-structured exercise intervention with stringent assessment of phenotypes, and quality control of genotyping.…”

Section: Nos3 +894 G>tmentioning

confidence: 93%

“…The experimental design of FAMuSS has been described elsewhere [6,[15][16][17][18][19][20][21]. The institutional review boards from the 10 institutions involved with the study approved the study protocol and informed consent was obtained from all individuals prior to enrollment.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, we examined the association of NOS3 −786 T>C and +894 G>T on habitual PA levels and the muscle strength response to RT among a subsample of healthy, European-derived American adults from the Functional Single Nucleotide Polymorphisms Associated with Human Muscle Size and Strength (FAMuSS) study [15]. We hypothesized that these two NOS3 SNPs would be associated with habitual PA levels and the muscle strength response to RT.…”

Section: Introductionmentioning

confidence: 99%

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Endothelial Nitric Oxide Synthase (NOS3) +894 G>T Associates with Physical Activity and Muscle Performance among Young Adults

Guidry

Kostek

Angelopoulos

et al. 2012

ISRN Vascular Medicine

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Objective. We examined the influence of missense polymorphism, endothelial nitric oxide synthase (NOS3) +894 G>T (rs1799983), on habitual physical activity (PA) and the muscle strength response to resistance training (RT). Methods. Men (n = 354) and women (n = 424; 24.3 ± 8.0 yr) were genotyped. Subjects reported hr/wk in vigorous and light intensity PA and sitting on the Paffenbarger PA questionnaire. One repetition maximum assessed muscle strength. Multivariable and repeated measures ANCOVA tested differences among NOS3 +894 G>T and PA and RT phenotypes by gender. Results. hr/wk in vigorous intensity PA (5.4 ± 1.2 versus 8.3 ± 0.4; P = 0.019), more hr/wk in light intensity PA (42.1 ± 2.4 versus 35.8 ± 0.7; P = 0.011), and less hr/wk sitting (37.6 ± 2.8 versus 45.8 ± 0.9; P = 0.006) than those with the G allele. Women with NOS3 +894 TT gained more absolute (4.4 ± 0.3 versus 3.7 ± 0.8 kg; P = 0.013) and relative (78.3 ± 5.8 versus 61.9 ± 1.8%; P = 0.007) strength than those with the G allele. Conclusions. NOS3 +894 G>T associated with PA among men and women and the muscle strength response to RT among women only. Our findings indicate the need for prospective studies examining the influence of NOS3 variants on PA and the muscle response to RT as well as elucidating underlying mechanistic pathways for the associations observed.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 95%

Section: Nos3 +894 G>tmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Endothelial Nitric Oxide Synthase (NOS3) +894 G>T Associates with Physical Activity and Muscle Performance among Young Adults

Guidry

Kostek

Angelopoulos

et al. 2012

ISRN Vascular Medicine

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N-carbamylglutamate enhancement of ureagenesis leads to discovery of a novel deleterious mutation in a newly defined enhancer of the NAGS gene and to effective therapy

et al. 2011

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NAGS catalyzes the conversion of glutamate and acetyl-CoA to N-acetylglutamate (NAG) the essential allosteric activator of carbamyl phosphate synthetase I, the first urea cycle enzyme in mammals. A 17-year-old female with recurrent hyperammonemia attacks, the cause of which remained undiagnosed for 8 years in spite of multiple molecular and biochemical investigations, showed markedly enhanced ureagenesis (measured by isotope incorporation) in response to N-carbamylglutamate (NCG). This led to sequencing of the regulatory regions of the NAG synthase (NAGS) gene and identification of a deleterious single-base substitution in the upstream enhancer. The homozygous mutation (-3063C>A), affecting a highly conserved nucleotide within the Hepatic Nuclear Factor 1 (HNF-1) binding site, was not found in SNP databases and in a screen of 1086 alleles from a diverse population. Functional assays demonstrated that this mutation decreases transcription and binding of HNF-1 to the NAGS gene, while a consensus HNF-1 binding sequence enhances binding to HNF-1 and increases transcription. Oral daily NCG therapy appears to have restored ureagenesis in this patient, normalizing her biochemical markers, and allowing discontinuation of alternate pathway therapy and normalization of her diet with no recurrence of hyperammonemia.

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Differences in fat and muscle mass associated with a functional human polymorphism in a post‐transcriptional BMP2 gene regulatory element

Devaney

Tosi

Fritz

et al. 2009

J of Cellular Biochemistry

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A classic morphogen, bone morphogenetic protein 2 (BMP2) regulates the differentiation of pluripotent mesenchymal cells. High BMP2 levels promote osteogenesis or chondrogenesis and low levels promote adipogenesis. BMP2 inhibits myogenesis. Thus, BMP2 synthesis is tightly controlled. Several hundred nucleotides within the 3′ untranslated regions of BMP2 genes are conserved from mammals to fishes indicating that the region is under stringent selective pressure. Our analyses indicate that this region controls BMP2 synthesis by post-transcriptional mechanisms. A common A to C single nucleotide polymorphism (SNP) in the BMP2 gene (rs15705, +A1123C) disrupts a putative post-transcriptional regulatory motif within the human ultra-conserved sequence. In vitro studies indicate that RNAs bearing the A or C alleles have different protein binding characteristics in extracts from mesenchymal cells. Reporter genes with the C allele of the ultra-conserved sequence were differentially expressed in mesenchymal cells. Finally, we analyzed MRI data from the upper arm of 517 healthy individuals aged 18–41 years. Individuals with the C/C genotype were associated with lower baseline subcutaneous fat volumes (P = 0.0030) and an increased gain in skeletal muscle volume (P = 0.0060) following resistance training in a cohort of young males. The rs15705 SNP explained 2–4% of inter-individual variability in the measured parameters. The rs15705 variant is one of the first genetic markers that maybe exploited to facilitate early diagnosis, treatment, and/or prevention of diseases associated with poor fitness. Furthermore, understanding the mechanisms by which regulatory polymorphisms influence BMP2 synthesis will reveal novel pharmaceutical targets for these disabling conditions.

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Functional Polymorphisms Associated with Human Muscle Size and Strength

Cited by 65 publications

References 31 publications

Endothelial Nitric Oxide Synthase (NOS3) +894 G>T Associates with Physical Activity and Muscle Performance among Young Adults

Endothelial Nitric Oxide Synthase (NOS3) +894 G>T Associates with Physical Activity and Muscle Performance among Young Adults

N-carbamylglutamate enhancement of ureagenesis leads to discovery of a novel deleterious mutation in a newly defined enhancer of the NAGS gene and to effective therapy

Differences in fat and muscle mass associated with a functional human polymorphism in a post‐transcriptional BMP2 gene regulatory element

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