Cited by 199Muscle Physiology and DisordersGenetics and Physical PerformanceNutrition and Health in Aging

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Molecular Networks of Human Muscle Adaptation to Exercise and Age

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Phillips, Bethan E., Williams, John P., Gustafsson, Thomas, Bouchard, Claude, Rankinen, Tuomo, Knudsen, Steen, Smith, Kenneth, Timmons, James A., Atherton, Philip J.·2013·PLoS Genetics

DOI 10.1371/journal.pgen.1003389PMC PMC3605101

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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.

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Authors: Phillips, B. E., Williams, J. P., Gustafsson, T., Bouchard, C., Rankinen, T., Knudsen, S., Smith, K., Timmons, J. A., & Atherton, P. J.
Affiliations: Royal Derby Hospital (GB)
Karolinska Institutet (SE)
Pennington Biomedical Research Center (US)
Medical Prognosis Institute (Denmark) (DK)
Loughborough University (GB)
Corresponding author: Timmons, James A.
ORCID: Phillips, Bethan E.
Williams, John P.
Gustafsson, Thomas
Bouchard, Claude
Knudsen, Steen
Smith, Kenneth
Timmons, James A.
Atherton, Philip J.
Venue: PLoS Genetics
Publisher: Public Library of Science (PLoS)
Published: 2013-03-21
Volume: 9
Issue: 3
Pages: e1003389
ISSN: 1553-7390 (ISSN-L)
1553-7404
DOI: 10.1371/journal.pgen.1003389
PMC: PMC3605101
OpenAlex: W2094388228
Cited by: 199
References: 90
Citations by year: 2026: 6 · 2025: 6 · 2024: 14 · 2023: 13 · 2022: 18 · 2021: 22 · 2020: 13 · 2019: 17 · 2018: 17 · 2017: 9 · 2016: 16 · 2015: 23 · 2014: 18 · 2013: 6
FWCI: 9.41
Type: journal article
Language: en
Update notices: correction (2013-04-25)
correction (2013-04-03)
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS Genetics (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Nottingham ePrints (University of Nottingham) (submittedVersion)
Figshare (submittedVersion, cc-by)
Funders: University of Stirling
National Institutes of Health (HL- 47317, HL- 47327, HL- 47323)
Directorate for Biological Sciences
Medical Research Council (MR/K00414X/1)
Biotechnology and Biological Sciences Research Council (BB/X5106971, BB/C516779/1)
National Heart, Lung, and Blood Institute (R01HL047327, HL 47321, HL 45670, HL47323, R01HL047317, HL 47327, R01HL047323, HL47317, R01HL045670, R01HL047321)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
Health Sciences › Medicine › Physiology (medical) › Nutrition and Health in Aging
Keywords: muscle aging, resistance training, endurance training, sarcopenia, mTOR signaling, rapamycin, muscle hypertrophy, lean body mass, all-trans retinoic acid, aryl hydrocarbon receptor signaling, age-related gene expression, post-transcriptional regulation, ribosomal genes, gene regulatory networks
MeSH terms: Adaptation, Physiological, Adolescent, Adult, Aged, Aging, Female, Humans, Male, Middle Aged, Signal Transduction, Exercise, Down-Regulation, Muscle, Skeletal, Gene Expression Profiling, Gene Regulatory Networks, Ribosome Subunits, TOR Serine-Threonine Kinases

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