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Molecular networks of human muscle adaptation to exercise and age

Phillips, Bethan E.; Williams, John P.; Gustafsson, Thomas; Bouchard, Claude; Rankinen, Tuomo; Knudsen, Steen; Smith, Kenneth; Timmons, James A.; Atherton, Philip J.

Authors

Bethan E. Phillips

John P. Williams

Thomas Gustafsson

Claude Bouchard

Tuomo Rankinen

Steen Knudsen

Kenneth Smith

James A. Timmons

Philip J. Atherton



Abstract

Physical activity and molecular ageing presumably interact to precipitate musculoskeletal decline in humans with age. Herein, we have delineated molecular networks for these two major components of sarcopenic risk using multiple independent clinical cohorts. We generated genome-wide transcript profiles from individuals (n = 44) who then undertook 20 weeks of supervised resistance-exercise training (RET). Expectedly, our subjects exhibited a marked range of hypertrophic responses (3% to +28%), and when applying Ingenuity Pathway Analysis (IPA) up-stream analysis to ~580 genes that co-varied with gain in lean mass, we identified rapamycin (mTOR) signaling associating with growth (P = 1.4×10−30). Paradoxically, those displaying most hypertrophy exhibited an inhibited mTOR activation signature, including the striking down-regulation of 70 rRNAs. Differential analysis found networks mimicking developmental processes (activated all-trans-retinoic acid (ATRA, Z-score = 4.5; P = 6×10−13) and inhibited aryl-hydrocarbon receptor signaling (AhR, Z-score = −2.3; P = 3×10−7)) with RET. Intriguingly, as ATRA and AhR gene-sets were also a feature of endurance exercise training (EET), they appear to represent “generic” physical activity responsive gene-networks. For age, we found that differential gene-expression methods do not produce consistent molecular differences between young versus old individuals. Instead, utilizing two independent cohorts (n = 45 and n = 52), with a continuum of subject ages (18–78 y), the first reproducible set of age-related transcripts in human muscle was identified. This analysis identified ~500 genes highly enriched in post-transcriptional processes (P = 1×10−6) and with negligible links to the aforementioned generic exercise regulated gene-sets and some overlap with ribosomal genes. The RNA signatures from multiple compounds all targeting serotonin, DNA topoisomerase antagonism, and RXR activation were significantly related to the muscle age-related genes. Finally, a number of specific chromosomal loci, including 1q12 and 13q21, contributed by more than chance to the age-related gene list (P = 0.01–0.005), implying possible epigenetic events. We conclude that human muscle age-related molecular processes appear distinct from the processes regulated by those of physical activity.

Journal Article Type Article
Publication Date Mar 21, 2013
Journal PLoS Genetics
Print ISSN 1553-7390
Electronic ISSN 1553-7390
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 9
Issue 3
Article Number e1003389
APA6 Citation Phillips, B. E., Williams, J. P., Gustafsson, T., Bouchard, C., Rankinen, T., Knudsen, S., …Atherton, P. J. (2013). Molecular networks of human muscle adaptation to exercise and age. PLoS Genetics, 9(3), doi:10.1371/journal.pgen.1003389
DOI https://doi.org/10.1371/journal.pgen.1003389
Publisher URL http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003389
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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