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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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“A review of available data suggests that tonic immobility, peritraumatic dissociation, and dissociative PTSD may be mediated by a shared neural network involving amygdala deactivation, absence of sympathetically mediated arousal symptoms (decreased skin conductance and an absence of heart rate increases), parasympathetic activation (a decrease in heart rate in some studies, presumably reflecting a”
From Fear and the Defense Cascade (2015) · cites this paper as [121]
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“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]
Citations
Cites
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Items 201–300 of 851
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Carrió, E. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00019 · Cited by 67
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Fuller, O. K., Whitham, M., Mathivanan, S., & Febbraio, M. A. (2020) · Cells · doi:10.3390/cells9102182 · Cited by 60
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“…region of genes including peroxisome proliferator activated receptor 𝛾 ( Pparg ) coactivator-1 𝛼 ( Ppargc1a ), pyruvate dehydrogenase kinase 4 ( Pdk4 ), and Ppard in skeletal muscle, which corresponded to transient induction of gene expression in a time and intensity dependent manner [73].”
Environmental enrichment modulates 5-hydroxymethylcytosine dynamics in hippocampus
Irier, H. A., Street, R. C., Dave, R., Lin, L., Cai, C. W., Davis, T., Yao, B., Cheng, Y., & Jin, P. (2014) · Genomics · doi:10.1016/j.ygeno.2014.08.019 · Cited by 59
“In addition to improving health and cognitive function in humans, voluntary physical exercise can also delay the cognitive deficits associated with aging and related neurodegenerative disorders, such as Alzheimer's disease (AD) [9,10], mitigate the disease phenotype of fatal neurodegenerative diseases, such as spinoce…”
BackgroundMitochondrial and skeletal muscle health with advancing age
Konopka, A. R., & Nair, K. S. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.05.008 · Cited by 57
“An eloquent study (Barres et al., 2012) recently revealed that acute aerobic exercise of sufficient intensity can alter global and promoter specific methylation leading to changes in mRNA expression related to mitochondrial and substrate regulation in young adults.”
Mudry, J. M., Alm, P. S., Erhardt, S., Goiny, M., Fritz, T., Caidahl, K., Zierath, J. R., Krook, A., & Wallberg‐Henriksson, H. (2016) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2798 · Cited by 62
“port acute exercise increased skeletal muscle PGC-1α1 mRNA expression during recovery in people with normal glucose tolerance or type 2 diabetes, consistent with healthy untrained young men and women [15].”
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Molecular control of endurance training adaptation in male mouse skeletal muscle
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“Although PPAR mRNA expression is exercise-inducible in human skeletal muscle (Watt et al. 2004; Perry et al. 2010; Barrès et al. 2012), the upstream events that regulate PPAR gene expression are not well-understood.”
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Kanzleiter, T., Jähnert, M., Schulze, G., Selbig, J., Hallahan, N., Schwenk, R., & Schürmann, A. (2015) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.00289.2014 · Cited by 57
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“Besides PGC1α, exercise induces a whole genome hypomethylation in human skeletal muscle and dose-dependent expression of the pyruvate dehydrogenase kinase isozyme 4, of the peroxisome proliferator activator receptor delta and of the glucose transporter GLUT4 [30,31].”
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“In addition, caffeine exposure decreased promoter methylation in L6 rat myotubes that was paralleled by an increase in the respective gene expression [56].”
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“In another study measuring DNA methylation and gene expression in skeletal muscle biopsies from sedentary adults who underwent acute exercise, whole genome methylation and methylation of promoters of specific genes—PPARG, PGC-1a, and PDK4—decreased in an exercise intensity–dependent manner, accompanied by increased ex…”
Gestational diabetes mellitus, programing and epigenetics
Yan, J., & Yang, H. (2013) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.3109/14767058.2013.853733 · Cited by 55
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Epigenetic contribution to obesity
Ouni, M., & Schürmann, A. (2020) · Mammalian Genome · doi:10.1007/s00335-020-09835-3 · Cited by 68
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“Furthermore, our previous data suggest that even after acute catabolic stress,DNAmethylation canbe stably retained across several population doublings of muscle cells in vitro (24); however,wedemonstrate here thatDNA methylation does respond at a rate that allows for its participation in the adaptive control of gene e…”
The impact of endurance exercise on global and AMPK gene-specific DNA methylation
King-Himmelreich, T. S., Schramm, S., Wolters, M. C., Schmetzer, J., Möser, C. V., Knothe, C., Resch, E., Peil, J., Geißlinger, G., & Niederberger, E. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.04.078 · Cited by 59
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Towards ageing well: Use it or lose it: Exercise, epigenetics and cognition
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“In their study of healthy-exercising men, compared to healthy-butinactive men, Barres et al. (2012) found that genes involved in energy metabolism-PGC-1a, PPAR-c and PDK4-showed a changed methylation pattern, dependent on the exercise intensity.”
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BackgroundSkeletal Muscle Nucleo-Mitochondrial Crosstalk in Obesity and Type 2 Diabetes
Devarshi, P. P., McNabney, S. M., & Henagan, T. M. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18040831 · Cited by 55
“These data are compelling given that retrograde communication that determines NEMG expression may occur through an epigenetic mechanism involving acyl-coAs, as several NEMG have recently been shown to be epigenetically regulated by HFD, fatty acids, and exercise [76,166,167].”
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“(176) 1 wk of acute exercise Changes in global DNA”
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Endurance exercise training-responsive miR-19b-3p improves skeletal muscle glucose metabolism
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Self-citationAge-Related DNA Methylation Changes: Potential Impact on Skeletal Muscle Aging in Humans
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“Additionally, Barres et al have shown non-CpG methylation near promoter A [41, 42].”
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“This finding is consistent with a recent study demonstrating that acute exercise induces epigenomic changes in human skeletal muscle (20).”
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da Silva, F. C., Iop, R. D. R., Andrade, A., Costa, V. P., Filho, P. J. B. G., & da Silva, R. (2019) · The Journal of Strength and Conditioning Research · doi:10.1519/jsc.0000000000003103 · Cited by 68
“Many of these changes have been attributed to exerciseinduced epigenetic alterations that alter the expression profile of several genes (8).”
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“(2012) [105] Global DNA methylation of candidate genes (MeDIP assay and bisulfite sequencing) Sedentary cohort under an acute bout of exercise (n = 14) Skeletal muscle Marked hypomethylation of PPARGC1A, PDK4, and PPAR-δ promoter and dose-dependent increase of PPARGC1A (−2337/−139 bp from TSS), PDK4, and PPAR-δ mRNA e…”
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“L6 myotubes Exercise-like treatment 15–60 min 2 mM [6]”
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“DNA Methylation Analysis Reduced representation bisulfite sequencing (RRBS) and methylated DNA capture sequencing were performed as described (21,22) on satellite cells (N = 6).”
MethodSelf-citationAssociations between whole peripheral blood fatty acids and DNA methylation in humans
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“work now indicates that these mechanisms also occur in humans [34].”
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“It has been shown that DNA methylation is influenced by age, gender, genetic background, lifestyle and body weight [16-18].”
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“Furthermore, exercise exerts short-term transient effects on epigenetic targets [330,331] and seems to have a wider epigenetic impact in the long term during exercise training [332–334].”
BackgroundEffects of skeletal muscle energy availability on protein turnover responses to exercise
Smiles, W. J., Hawley, J. A., & Camera, D. M. (2016) · Journal of Experimental Biology · doi:10.1242/jeb.125104 · Cited by 48
“Recent evidence also suggests that acute gene activation is associated with a dynamic change in DNA methylation in skeletal muscle and that DNA hypomethylation is an early event in contraction-induced gene activation (Barres̀ et al., 2012).”
Li, J., Wang, Z., Li, C., Song, Y., Wang, Y., Hai, B., & Zhang, Y. (2022) · Cells · doi:10.3390/cells11132086 · Cited by 56
The genetics of human performance
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PGC-1α-mediated changes in phospholipid profiles of exercise-trained skeletal muscle
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Psoriasis and sport: a new ally?
Balato, N., Megna, M., Palmisano, F., Patruno, C., Napolitano, M., Scalvenzi, M., & Ayala, F. (2015) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/jdv.12607 · Cited by 48
Genome-wide DNA methylation analysis of heavy cannabis exposure in a New Zealand longitudinal cohort
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Cell environment shapes TDP-43 function with implications in neuronal and muscle disease
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Genetic Markers Associated with Power Athlete Status
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“It has been shown that exercise-induced acute gene activation was associated with a dynamic change in DNA methylation in skeletal muscle and it has been suggested that DNA hypomethylation is an early event in contraction-induced gene activation (Barrès et al., 2012).”
BackgroundDNA methylation assessment from human slow- and fast-twitch skeletal muscle fibers
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“tion changes in both healthy and nonhealthy human populations (2, 4, 40, 52, 63, 91).”
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Resistance training rejuvenates the mitochondrial methylome in aged human skeletal muscle
Ruple, B. A., Godwin, J. S., Mesquita, P. H. C., Osburn, S. C., Vann, C. G., Lamb, D. A., Sexton, C. L., Candow, D. G., Forbes, S. C., Frugé, A. D., et al. (2021) · The FASEB Journal · doi:10.1096/fj.202100873rr · Cited by 59
The role of exercise-induced peripheral factors in sleep regulation
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“PGC-1a increases in skeletal muscle in an exercise intensity-dependent manner [59] and can simultaneously induce transcription of a broad set of genes, most of which are involved in energy metabolism [60].”
BackgroundStephens, N. A., Brouwers, B., Eroshkin, A. M., Yi, F., Cornnell, H. H., Meyer, C., Goodpaster, B. H., Pratley, R. E., Smith, S. R., & Sparks, L. M. (2018) · Diabetes Care · doi:10.2337/dc18-0296 · Cited by 48
“olism, highlighting the potential epigenomic control of exercise training responses (14).”
BackgroundExercise and the Skeletal Muscle EpigenomePreprint
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“For example, Barres et al. (2012) showed that high-intensity exercise (80% VO2 max) caused an immediate reduction in the methylation levels in the promoter regions of PGC1a, PDK4, and PPARd in human skeletal muscle, which was associated with increased transcription of these genes.”
BackgroundKeller, M., Kralisch, S., Rohde, K., Schleinitz, D., Dietrich, A., Schön, M., Gärtner, D., Lohmann, T., Dressler, M., Tönjes, A., et al. (2014) · Diabetologia · doi:10.1007/s00125-014-3356-z · Cited by 46
“Furthermore, DNA methylation in both skeletal muscle and SAT varies significantly following acute [9] or long-term [10] exercise intervention.”
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“Later, it was demonstrated that acute exercise [119] and weight loss restored the methylation of promotors of PGC1α and several other genes [120].”
BackgroundRoles of physical exercise in neurodegeneration: reversal of epigenetic clock
Xu, M., Zhu, J., Liu, X.-D., Luo, M.-Y., & Xu, N.-J. (2021) · Translational Neurodegeneration · doi:10.1186/s40035-021-00254-1 · Cited by 46
The myonuclear DNA methylome in response to an acute hypertrophic stimulus
von Walden, F., Rea, M., Mobley, C. B., Fondufe‐Mittendorf, Y. N., McCarthy, J. J., Peterson, C. A., & Murach, K. A. (2020) · Epigenetics · doi:10.1080/15592294.2020.1755581 · Cited by 57
“Widespread promoter hypomethylation in myonuclei after 3 d of overload in mice is congruent with the acute and chronic methylation response to exercise reported in human muscle biopsy samples [16,42–45], as is the relative uncoupling of promoter methylation and gene expression early after exercise [16,45,46]; however,…”
BackgroundDNA methylation associated with healthy aging of elderly twins
Kim, S., Wyckoff, J., Morris, A.-T., Succop, A., Avery, A. R., Duncan, G. E., & Jazwinski, S. M. (2018) · GeroScience · doi:10.1007/s11357-018-0040-0 · Cited by 47
Emerging concepts on the role of epigenetics in the relationships between nutrition and health
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Self-citationDNA methylation landscapes in the pathogenesis of type 2 diabetes mellitus
Zhou, Z. G., Sun, B., Li, X., & Zhu, C. (2018) · Nutrition & Metabolism · doi:10.1186/s12986-018-0283-x · Cited by 56
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Oxidative stress and metabolism meet epigenetic modulation in physical exercise
García‐Giménez, J. L., Cánovas‐Cervera, I., & Pallardó, F. V. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.01.008 · Cited by 50
Social environmental effects on gene regulation
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“consistent with evidence from other environmental exposures [103–106]).”
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Mechanisms of aerobic exercise impairment in diabetes: a narrative review
Wahl, M. P., Scalzo, R. L., Regensteiner, J. G., & Reusch, J. E. B. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00181 · Cited by 44
“Epigenetic modifications have been noted in T2D (63) and research also shows that acute exercise results in DNA hypomethylation in promoter regions in human skeletal muscle (64).”
BackgroundA necessary role of DNMT3A in endurance exercise by suppressing ALDH1L1‐mediated oxidative stress
Villivalam, S. D., Ebert, S. M., Lim, H., Kim, J., You, D., Jung, B. C., Palacios, H. H., Tcheau, T., Adams, C. M., & Kang, S. (2021) · The EMBO Journal · doi:10.15252/embj.2020106491 · Cited by 46
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Maasar, M. F., Turner, D. C., Gorski, P. P., Seaborne, R. A. E., Strauss, J. A., Shepherd, S. O., Cocks, M. S., Pillon, N. J., Zierath, J. R., Hulton, A. T., et al. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.619447 · Cited by 54
Self-citationContraction influences Per2 gene expression in skeletal muscle through a calcium‐dependent pathway
Small, L., Altıntaş, A., Laker, R. C., Ehrlich, A. M., Pattamaprapanont, P., Villarroel, J., Pillon, N. J., Zierath, J. R., & Barrès, R. (2020) · The Journal of Physiology · doi:10.1113/jp280428 · Cited by 57
“aerobic intervals and, in a similar protocol, increased the expression of exercise responsive genes (Barrès et al. 2012).”
BackgroundSelf-citationCurrent advances in our understanding of exercise as medicine in metabolic disease
Sylow, L., & Richter, E. A. (2019) · Current Opinion in Physiology · doi:10.1016/j.cophys.2019.04.008 · Cited by 54
Impact of a diet and activity health promotion intervention on regional patterns of DNA methylation
Hibler, E. A., Huang, L., Andrade, J., & Spring, B. J. (2019) · Clinical Epigenetics · doi:10.1186/s13148-019-0707-0 · Cited by 60
Bryan, K. R., McGivney, B. A., Farries, G., McGettigan, P., McGivney, C. L., Gough, K. F., MacHugh, D. E., Katz, L. M., & Hill, E. W. (2017) · BMC Genomics · doi:10.1186/s12864-017-4007-9 · Cited by 50
“For example, four of the five genes reported by Barrès and colleagues to be hypomethylated and expressed in human skeletal muscle in response to acute exercise, namely PPARD (peroxisome proliferator activated receptor delta), PPARGC1A (PPARG coactivator 1 alpha), PDK4 (pyruvate dehydrogenase kinase 4) and CS (citrate…”
BackgroundThe effect of exercise on epigenetic modifications of PGC1: The impact on type 2 diabetes
dos Santos, J. M., Tewari, S., & Benite‐Ribeiro, S. A. (2014) · Medical Hypotheses · doi:10.1016/j.mehy.2014.03.018 · Cited by 45
Genetic determinants of voluntary exercise
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“Another group [70] found dose-dependent expression and promoter hypomethylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), pyruvate dehydrogenase kinase, isoenzyme 4 (PDK4), and peroxisome proliferator-activated receptor δ (PPAR-δ) in human skeletal muscle in response to acute ex…”
BackgroundNair, V. D., Pinças, H., Smith, G. R., Zaslavsky, E., Ge, Y., Amper, M. A. S., Vasoya, M., Chikina, M. D., Sun, Y., Raja, A. N., et al. (2024) · Cell Genomics · doi:10.1016/j.xgen.2023.100421 · Cited by 45
“31,84,85 Exercise has been re-ported to remodel DNAme in SKM-GN and adipose tissue both acutely and in the long-term, 21–23, 25, 29, 31, 33, 37, 39 thereby modifying gene Inter-organ crosstalk has been shown to mediate the bene-ficial effects of exercise training in various tissues at cellular and…”
Joint Location–Specific JAK ‐ STAT Signaling in Rheumatoid Arthritis Fibroblast‐like Synoviocytes
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“Stress from high-intensity muscle contractions, for instance, can induce changes in DNA methylation and histone modifications (25,26).”
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Exercise in vivo marks human myotubes in vitro: Training-induced increase in lipid metabolism
Lund, J., Rustan, A. C., Løvsletten, N. G., Mudry, J. M., Langleite, T. M., Feng, Y., Stensrud, C., Brubak, M. G., Drevon, C. A., Birkeland, K. I., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0175441 · Cited by 44
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“Methylation of DNA and histone modifications have been shown to be affected by, for example, body mass index (BMI) [24], age [25], intrauterine environment [26-28], glucose exposure [29,30], and exercise [31].”
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Coffee Consumption Is Associated with DNA Methylation Levels of Human Blood
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“Alternatively, MitoQ may augment acute exercise-induced increases in PGC1α mRNA expression through a mechanism involving hypomethylation of the PGC1α promotor region [47] as ROS derived from mitochondria can affect DNA methylation by acting on the activity and expression of DNA methyltransferases [48].”
BackgroundEpigenetics and Type 2 Diabetes Risk
Dhawan, S., & Natarajan, R. D. (2019) · Current Diabetes Reports · doi:10.1007/s11892-019-1168-8 · Cited by 46
Muscle Contraction Induces Acute Hydroxymethylation of the Exercise-Responsive Gene Nr4a3
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“Environmental factors may affect not only the somatic cells but also the gametes, which means that metabolic states that are experienced by the parents may influence the health of the next generation [1,9,10].”
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Metadata
- 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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