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      Whole Blood Transcriptomics and Urinary Metabolomics to Define Adaptive Biochemical Pathways of High-Intensity Exercise in 50-60 Year Old Masters Athletes

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          Abstract

          Exercise is beneficial for a variety of age-related disorders. However, the molecular mechanisms mediating the beneficial adaptations to exercise in older adults are not well understood. The aim of the current study was to utilize a dual approach to characterize the genetic and metabolic adaptive pathways altered by exercise in veteran athletes and age-matched untrained individuals. Two groups of 50–60 year old males: competitive cyclists (athletes, n = 9; VO 2peak 59.1±5.2 ml·kg −1·min −1; peak aerobic power 383±39 W) and untrained, minimally active individuals (controls, n = 8; VO 2peak 35.9±9.7 ml·kg −1·min −1; peak aerobic power 230±57 W) were examined. All participants completed an acute bout of submaximal endurance exercise, and blood and urine samples pre- and post-exercise were analyzed for gene expression and metabolic changes utilizing genome-wide DNA microarray analysis and NMR spectroscopy-based metabolomics, respectively. Our results indicate distinct differences in gene and metabolite expression involving energy metabolism, lipids, insulin signaling and cardiovascular function between the two groups. These findings may lead to new insights into beneficial signaling pathways of healthy aging and help identify surrogate markers for monitoring exercise and training load.

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          Most cited references51

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          Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans.

          A low maximal oxygen consumption (VO2max) is a strong risk factor for premature mortality. Supervised endurance exercise training increases VO2max with a very wide range of effectiveness in humans. Discovering the DNA variants that contribute to this heterogeneity typically requires substantial sample sizes. In the present study, we first use RNA expression profiling to produce a molecular classifier that predicts VO2max training response. We then hypothesized that the classifier genes would harbor DNA variants that contributed to the heterogeneous VO2max response. Two independent preintervention RNA expression data sets were generated (n=41 gene chips) from subjects that underwent supervised endurance training: one identified and the second blindly validated an RNA expression signature that predicted change in VO2max ("predictor" genes). The HERITAGE Family Study (n=473) was used for genotyping. We discovered a 29-RNA signature that predicted VO2max training response on a continuous scale; these genes contained approximately 6 new single-nucleotide polymorphisms associated with gains in VO2max in the HERITAGE Family Study. Three of four novel candidate genes from the HERITAGE Family Study were confirmed as RNA predictor genes (i.e., "reciprocal" RNA validation of a quantitative trait locus genotype), enhancing the performance of the 29-RNA-based predictor. Notably, RNA abundance for the predictor genes was unchanged by exercise training, supporting the idea that expression was preset by genetic variation. Regression analysis yielded a model where 11 single-nucleotide polymorphisms explained 23% of the variance in gains in VO2max, corresponding to approximately 50% of the estimated genetic variance for VO2max. In conclusion, combining RNA profiling with single-gene DNA marker association analysis yields a strongly validated molecular predictor with meaningful explanatory power. VO2max responses to endurance training can be predicted by measuring a approximately 30-gene RNA expression signature in muscle prior to training. The general approach taken could accelerate the discovery of genetic biomarkers, sufficiently discrete for diagnostic purposes, for a range of physiological and pharmacological phenotypes in humans.
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            Occludin: structure, function and regulation.

            Epithelial and/or endothelial barriers play a critical role in animal, including human, life forms. The tight junction (TJ) is an essential component of these barriers. Occludin is a major component of the TJ. The structure of occludin, including its gene splice variants and protein essential components have been elucidated. Phosphorylation/dephosphorylation plays a major role in regulation of occludin and TJ. Disruption of occludin regulation is an important aspect of a number of diseases. Strategies to prevent and/or reverse occludin downregulation may be an important therapeutic target.
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              Age-associated remodeling of the intestinal epithelial barrier.

              Disorders of the gastrointestinal tract are common in the elderly people; however, the precise trait(s) of aging that contribute to the vulnerability of the gastrointestinal tract are poorly understood. Recent evidence suggests that patients with gastrointestinal disorders have increased intestinal permeability. Here, we address the hypothesis that disruption of the intestinal barrier is associated with aging. Our results demonstrated that permeability was significantly higher in colonic biopsies collected from old baboons compared with young baboons. Additionally, colonic tissue from the older animals had decreased zonula occluden-1, occludin, and junctional adhesion molecule-A tight junction protein expression and increased claudin-2 expression. Upregulation of miR-29a and inflammatory cytokines IFN-γ, IL-6, and IL-1β was also found in colonic biopsies from old baboons relative to young baboons. These results show for the first time that a pivotal contributing factor to geriatric vulnerability to gastrointestinal dysfunction may be increased colonic permeability via age-associated remodeling of intestinal epithelial tight junction proteins.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                18 March 2014
                : 9
                : 3
                : e92031
                Affiliations
                [1 ]Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
                [2 ]School of Kinesiology and Health Studies, Queen's University, Kingston, Ontario, Canada
                [3 ]Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom
                [4 ]Division of Cardiology, McGill University Health Centre, Montreal, Quebec, Canada
                Instituto de Investigación Sanitaria INCLIVA, Spain
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: BJG CDF KM BAE. Performed the experiments: KM BAE CC AGS. Analyzed the data: KM BAE HWB CC BJG JLG CDF. Contributed reagents/materials/analysis tools: AGS. Wrote the paper: KM BJG HWB CDF JLG.

                Article
                PONE-D-13-46726
                10.1371/journal.pone.0092031
                3958411
                24643011
                ac23dc5c-3732-491c-9475-eb9548041f67
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 7 November 2013
                : 18 February 2014
                Page count
                Pages: 16
                Funding
                CDF holds a Tier 1 Canada Research Chair in Molecular, Cellular, and Physiological Medicine and is recipient of a Career Investigator Award from the Heart and Stroke Foundation of Ontario. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Blood Chemistry
                Computational Biology
                Genome Analysis
                Transcriptome Analysis
                Genome Expression Analysis
                Developmental Biology
                Organism Development
                Aging
                Genetics
                Genomics
                Physiogenomics
                Systems Biology
                Integrative Physiology
                Medicine and Health Sciences
                Sports and Exercise Medicine
                Physical Sciences
                Physics
                Condensed Matter Physics
                Magnetism
                Nuclear Magnetic Resonance
                Research and Analysis Methods
                Bioassays and Physiological Analysis
                Microarrays

                Uncategorized
                Uncategorized

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