Acute Exercise Remodels Promoter Methylation in Human Skeletal Muscle
Open accessAbstract
DNA methylation is a covalent biochemical modification controlling chromatin structure and gene expression. Exercise elicits gene expression changes that trigger structural and metabolic adaptations in skeletal muscle. We determined whether DNA methylation plays a role in exercise-induced gene expression. Whole genome methylation was decreased in skeletal muscle biopsies obtained from healthy sedentary men and women after acute exercise. Exercise induced a dose-dependent expression of PGC-1α, PDK4, and PPAR-δ, together with a marked hypomethylation on each respective promoter. Similarly, promoter methylation of PGC-1α, PDK4, and PPAR-δ was markedly decreased in mouse soleus muscles 45 min after ex vivo contraction. In L6 myotubes, caffeine exposure induced gene hypomethylation in parallel with an increase in the respective mRNA content. Collectively, our results provide evidence that acute gene activation is associated with a dynamic change in DNA methylation in skeletal muscle and suggest that DNA hypomethylation is an early event in contraction-induced gene activation.
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From Fear and the Defense Cascade (2015) · cites this paper as [121]
Muscle contraction during exercise causes intracellular perturbations that disturb metabolic homeostasis, promoting adaptive responses and increasing overall resilience to stress.
“The muscle contraction that occurs during exercise also causes intracellular perturbations that disturb metabolic homeostasis, thereby promoting a broad range of adaptive responses and increasing overall resilience in response to stress.157,158”
From Fear and the Defense Cascade (2015) · cites this paper as [157]
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MethodInfluentialRaising Ca2+ in L6 myotubes mimics effects of exercise on mitochondrial biogenesis in muscle
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“The CXXC domain-containing enzyme TET1 has been described to participate in DNA demethylation through modifying 50-hydroxylase activity (Zhang et al., 2010).”
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“In one study, a single bout of endurance-type exercise was shown to affect methylation at a few promoter CpG sites.(12) In the context of diabetes, exercise training has been shown to affect genome-wide methylation pattern in skeletal muscle,(13) as well as in adipose tissue.”
BackgroundPhysical Activity and Brain Health
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“In human and mouse muscles, the mitochondrial transcription factor (TFAM), PGC-1a methylation, citrate synthase, MEF2A, gene promoters, and pyruvate dehydrogenase kinase isozyme (PDK4) decrease after acute aerobic exercise (80).”
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Exercise and bone health across the lifespan
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“DNA was hypomethylated in skeletal muscle, in a dose-responsive fashion, with similar findings in mouse muscles 45 min after ex vivo contraction, both suggesting a putative role of exercise in epigenetic modification through DNA methylation (Barrès et al. 2012).”
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“The lack of significant findings may also be due to the assessment of chromatin states in the basal state, which may not reflect the dynamic changes that occur when cells are perturbed by PA [23].”
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“the period between conception and reproductive maturity [8]) and in adulthood can both have potent effects on the epigenome [118, 120, 140].”
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“Although PPARd is known to be activated by high intensity exercise [44], Catoire et al.”
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“Accordingly, PGC-1α promoter methylation is reduced by physical exercise, a classical inducer of PGC-1α expression in skeletal muscle [17].”
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“Dietary intervention [17,18] and exercise [19,20] have been demonstrated to provoke epigenetic modulation in humans.”
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“DNA methylation of gene promoters and promoter-interacting enhancers is one epigenetic mechanism involved in the control of gene expression (9) and is a malleable process following acute lifestyle interventions (10).”
BackgroundInfluentialSelf-citationThe evidence for functional non-CpG methylation in mammalian cells
Patil, V., Ward, R. L., & Hesson, L. B. (2014) · Epigenetics · doi:10.4161/epi.28741 · Cited by 203 · see citing works
“Also, acute bouts of exercise cause transient reductions in the levels of nonCpG methylation at the PGC-1α promoter, concomitant with increased PGC-1α expression.(40) Interestingly, a study of mitochondrial DNA methylation has also reported that ~50% of methylcytosine within the D-loop region, which contributes to the…”
BackgroundMaximizing Cellular Adaptation to Endurance Exercise in Skeletal Muscle
Hawley, J. A., Lundby, C., Cotter, J. D., & Burke, L. M. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.04.014 · Cited by 182 · see citing works
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“High-intensity exercise is a powerful stimulus affecting the content, location, and/or activity of nuclear proteins, and genes encoding mitochondrial proteins, leading to an increase in mitoPS (5, 30, 44, 49, 54).”
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“…acute aerobic exercise at 80% of maximal aerobic capacity (until 1674 KJ was expended) and a reduction in PPARd methylation 3 h post exercise, corresponding with reductions in their own gene expression (3 h post exercise for PGC-1a, PDK4 and PPAR-d, immediately post for TFAM) (Barres et al., 2012).”
BackgroundInfluentialExercise adaptations: molecular mechanisms and potential targets for therapeutic benefit
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“[78] focused on the possible link between epigenetic modification, T2D and the effects of PA.”
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“Hypermethylation and reduced expression of PGC1α is associated with decreased mitochondrial number and function in muscle (Barrès et al., 2009; 2012).”
BackgroundAn Overview of Epigenetics in Obesity: The Role of Lifestyle and Therapeutic Interventions
Mahmoud, A. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031341 · Cited by 202 · see citing works
“These genes play essential roles in mitochondrial activity, insulin sensitivity, and energy expenditure [92].”
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“One such modification is DNA cytosine methylation, which was found to be decreased overall in skeletal muscle samples from sedentary men and women following acute exercise (Barres et al. 2012).”
BackgroundPhysical exercise and epigenetic modifications in skeletal muscle
Widmann, M., Nieß, A. M., & Munz, B. (2019) · Sports Medicine · doi:10.1007/s40279-019-01070-4 · Cited by 165 · see citing works
DNA methylation in the pathogenesis of type 2 diabetes in humans
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“Several studies have examined the effect of exercise on the epigenome in skeletal muscle of healthy, obese, or individuals with T2D [78,93].”
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“Epigenetics A single muscle contraction is sufficient to induce hypomethylation of the promoter regions of key substrate metabolism genes, resulting in upregulated transcription and subsequent protein translation and action [31].”
BackgroundGenome-wide sperm DNA methylation changes after 3 months of exercise training in humans.
Denham, J., O'Brien, B., Harvey, J., & Charchar, F. (2015) · Epigenomics · doi:10.2217/epi.15.29 · Cited by 158 · see citing works
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“exercise induces gene activation producing DNA hypomethylation on each respective promoter [50].”
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Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs
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“It can be speculated that a change in DNA methylation might not result in altered expression levels when relevant A B C 0.0 0.2 0.4 0.6 0.8 1.0 T S S 15 00 T S S 15 00 T S S 15 00 T S S 20 0 B od y 3' U T R Probe position C WY14,643 F A B P 4 D N A m et h yl at io n ( B v al u e) 0 2 4 6 8 10 12 D -3 0 D -3 1 D -3 4 D…”
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“3,68 71 Physical activity also bolsters mediating immune proteins and gene expression 72,73 and more distal biologic aging end points, such as mitochondrial health and telomerase levels, 74 – 77 which are closely related to telomere maintenance.”
Role of DNA Methylation in the Resistance to Therapy in Solid Tumors
Romero‐Garcia, S., Prado-Garcı́a, H., & Carlos‐Reyes, Á. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01152 · Cited by 176 · see citing works
“Each cell type possesses its own gene expression pattern, driven by a specific epigenetic signature, which may also produce cell heritable characteristics (5).”
BackgroundInfluentialEpigenetic flexibility in metabolic regulation: disease cause and prevention
Kirchner, H., Osler, M. E., Krook, A., & Zierath, J. R. (2013) · Trends in Cell Biology · doi:10.1016/j.tcb.2012.11.008 · Cited by 143 · see citing works
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Self-citationGenetic and epigenetic control of metabolic health
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“PDK4 expression has been shown to be regulated by various metabolic stimuli (such as starvation, exercise, and diabetes), the transcription factors FOXO and E2F1 [20], and epigenetic mechanisms such as promoter methylation and histone acetylation [37,38].”
BackgroundAcute exercise remodels mitochondrial membrane interactions in mouse skeletal muscle
Picard, M. A., Gentil, B. J., McManus, M. J., White, K., Louis, K. S., Gartside, S. E., Wallace, D. C., & Turnbull, D. M. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00819.2013 · Cited by 145 · see citing works
Physical Exercise as Therapy for Type 2 Diabetes Mellitus: From Mechanism to Orientation
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Genes to predict VO2max trainability: a systematic review
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“DNA methylation and histone acetylation) that can influence gene expression, molecular function and thereby influence VO2max training response [61, 66].”
BackgroundEpigenetic programming, early life nutrition and the risk of metabolic disease
Block, T., & El-Osta, A. (2017) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2017.09.003 · Cited by 130 · see citing works
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Exercise: Putting Action into Our Epigenome
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“Furthermore, the quantification of DNA methylation at CpG sites related to genes involved in metabolism—peroxisome proliferator-activated receptor-c, coactivator 1-a (PPARGC1A), peroxisome proliferator-activated receptord (PPARD) and mitochondrial transcription factor-a (TFAM) revealed decreased DNA methylation with p…”
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“A number of attractive possibilities may explain this phenomenon; for instance, changes in DNA methylation (3) may silence/activate gene expression, and this may vary according to the training state.”
BackgroundNoone, J., Mucinski, J. M., DeLany, J. P., Sparks, L. M., & Goodpaster, B. H. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.12.025 · Cited by 128 · see citing works
Kirchner, H., Sinha, I., Gao, H., Ruby, M. A., Schönke, M., Lindvall, J. M., Barrès, R., Krook, A., Näslund, E. B., Dahlman‐Wright, K., et al. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2015.12.004 · Cited by 135 · see citing works
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Genome-wide quantification of the effects of DNA methylation on human gene regulation
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“term (Barrès et al., 2012; Pacis et al., 2015) and long-term (Dominguez-Salas et al.”
BackgroundInfluence of vitamin C and vitamin E on redox signaling: implications for exercise adaptations
Cobley, J. N., McHardy, H., Morton, J. P., Nikolaidis, M. G., & Close, G. L. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.03.018 · Cited by 118 · see citing works
“Of interest, ascorbate can regulate the activ ity of enzymes implicated in the regulation 515 of histone methylation [194-195], an epigenetic pro cess that regulates exercise adaptations 516 [196].”
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Epigenetics of type 2 diabetes mellitus and weight change — a tool for precision medicine?
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Epigenetic changes in healthy human skeletal muscle following exercise– a systematic review
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“Interestingly, 3-hour post-exercise, these promoters became re-methylated, demonstrating the dynamic epigenetic response to exercise in skeletal muscle [38].”
BackgroundInfluentialSelf-citationDnmt3a is an epigenetic mediator of adipose insulin resistance
You, D., Nilsson, E., Tenen, D. E., Lyubetskaya, A., Lo, J. C., Jiang, R., Deng, J., Dawes, B. A., Vaag, A. A., Ling, C., et al. (2017) · eLife · doi:10.7554/elife.30766 · Cited by 124 · see citing works
“As an example, a bout of intense exercise can induce DNA hypomethylation at the PPARGC1a locus in human skeletal muscle within hours, followed by increased gene expression; these effects were reversed after resting (Barrès et al., 2012).”
BackgroundAn Epigenetic Role of Mitochondria in Cancer
Liu, Y., Chen, C., Wang, X., Sun, Y., Zhang, J., Chen, J., & Shi, Y. (2022) · Cells · doi:10.3390/cells11162518 · Cited by 125 · see citing works
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Na,K-ATPase regulation in skeletal muscle
Pirkmajer, S., & Chibalin, A. (2016) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00539.2015 · Cited by 121 · see citing works
“However, while these mechanisms have emerged as regulators 467 of skeletal muscle adaptations to various physiological stimuli, such as exercise (21), epigenetic 468”
Background
- Authors
- Barrès, R., Yan, J., Egan, B., Treebak, J. T., Rasmussen, M., Fritz, T., Caidahl, K., Krook, A., O'Gorman, D. J., & Zierath, J. R.
- Affiliations
- University of Copenhagen (DK)
- Karolinska University Hospital (SE)
- Corresponding author
- Zierath, Juleen R.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 15
- Issue
- 3
- Pages
- 405-411
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2113728034
- Cited by
- 965
- References
- 32
- Citations by year
- 2026: 65 · 2025: 64 · 2024: 61 · 2023: 39 · 2022: 67 · 2021: 73 · 2020: 53 · 2019: 67 · 2018: 75 · 2017: 79 · 2016: 65 · 2015: 77 · 2014: 76 · 2013: 75 · 2012: 28
- FWCI
- 32.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- DNA methylation, promoter hypomethylation, acute exercise, skeletal muscle, PGC-1α, PDK4, PPARδ, gene expression regulation, muscle contraction, caffeine, soleus muscle, L6 myotubes, epigenetic regulation
- MeSH terms
- Adult, Animals, Female, Humans, Male, Mice, Inbred C57BL, Exercise, Muscle, Skeletal, DNA Methylation, Mice, Young Adult
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