Skip to main content
SpringerLink
Log in

DNA Methylation in the Adaptive Response to Exercise

  • Review Article
  • Published:
Sports Medicine Aims and scope Submit manuscript

Abstract

Emerging evidence published over the past decade has highlighted the role of DNA methylation in skeletal muscle function and health, including as an epigenetic transducer of the adaptive response to exercise. In this review, we aim to synthesize the latest findings in this field to highlight: (1) the shifting understanding of the genomic localization of altered DNA methylation in response to acute and chronic aerobic and resistance exercise in skeletal muscle (e.g., promoter, gene bodies, enhancers, intergenic regions, un-annotated regions, and genome-wide methylation); (2) how these global/regional methylation changes relate to transcriptional activity following exercise; and (3) the factors (e.g., individual demographic or genetic features, dietary, training history, exercise parameters, local epigenetic characteristics, circulating hormones) demonstrated to alter both the pattern of DNA methylation after exercise, and the relationship between DNA methylation and gene expression. Finally, we discuss the changes in non-CpG methylation and 5-hydroxymethylation after exercise, as well as the importance of emerging single-cell analyses to future studies—areas of increasing focus in the field of epigenetics. We anticipate that this review will help generate a framework for clinicians and researchers to begin developing and testing exercise interventions designed to generate targeted changes in DNA methylation as part of a personalized exercise regimen.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ehrlich M, Wang R. 5-Methylcytosine in eukaryotic DNA. Science. 1981;212(4501):1350–7. https://doi.org/10.1126/science.6262918.

    Article  CAS  PubMed  Google Scholar 

  2. Lister R, Pelizzola M, Dowen RH, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462(7271):315–22. https://doi.org/10.1038/nature08514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ehrlich M, Gama-Sosa MA, Huang LH, et al. Amount and distribution of 5-methylcytosine in human DNA from different types of tissues or cells. Nucl Acids Res. 1982;10(8):2709–21. https://doi.org/10.1093/nar/10.8.2709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Illingworth RS, Gruenewald-Schneider U, Webb S, et al. Orphan CpG islands identify numerous conserved promoters in the mammalian genome. PLoS Genet. 2010;6(9):e1001134. https://doi.org/10.1371/journal.pgen.1001134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Begue G, Raue U, Jemiolo B, Trappe S. DNA methylation assessment from human slow- and fast-twitch skeletal muscle fibers. J Appl Physiol. 2017;122(4):952–67. https://doi.org/10.1152/japplphysiol.00867.2016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liu Y, Sun L, Jost J-P. In differentiating mouse myoblasts dna methyltransferase is posttranscriptionally and posttranslationally regulated. Nucleic Acids Res. 1996;24(14):2718–22. https://doi.org/10.1093/nar/24.14.2718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Saccone V, Consalvi S, Giordani L, et al. HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibro-adipogenic progenitors in dystrophic muscles. Genes Dev. 2014;28(8):841–57. https://doi.org/10.1101/gad.234468.113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shani M, Admon S, Yaffe D. The methylation state of 2 muscle-specific genes: restriction enzyme analysis did not detect a correlation with expression. Nucl Acids Res. 1984;12(18):7225–34. https://doi.org/10.1093/nar/12.18.7225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Turner DC, Gorski PP, Maasar MF, et al. DNA methylation across the genome in aged human skeletal muscle tissue and muscle-derived cells: the role of HOX genes and physical activity. Sci Rep. 2020;10(1):15360. https://doi.org/10.1038/s41598-020-72730-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Coppedè F. Epigenetics of neuromuscular disorders. Epigenomics. 2020;12(23):2125–39. https://doi.org/10.2217/epi-2020-0282.

    Article  CAS  PubMed  Google Scholar 

  11. Nitert MD, Dayeh T, Volkov P, et al. Impact of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of patients with type 2 diabetes. Diabetes. 2012;61(12):3322–32. https://doi.org/10.2337/db11-1653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Roche S, Dion C, Broucqsault N, et al. Methylation hotspots evidenced by deep sequencing in patients with facioscapulohumeral dystrophy and mosaicism. Neurol Genet. 2019;5(6):e372. https://doi.org/10.1212/NXG.0000000000000372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Otani J, Nankumo T, Arita K, Inamoto S, Ariyoshi M, Shirakawa M. Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX–DNMT3–DNMT3L domain. EMBO Rep. 2009;10(11):1235–41. https://doi.org/10.1038/embor.2009.218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. He YF, Li BZ, Li Z, et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011;333(6047):1303–7. https://doi.org/10.1126/science.1210944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930–5. https://doi.org/10.1126/science.1170116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cai Y, Tsai HC, Yen RWC, et al. Critical threshold levels of DNA methyltransferase 1 are required to maintain DNA methylation across the genome in human cancer cells. Genome Res. 2017;27(4):533–44. https://doi.org/10.1101/gr.208108.116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fujiki K, Shinoda A, Kano F, Sato R, Shirahige K, Murata M. PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine. Nat Commun. 2013;4(1):2262. https://doi.org/10.1038/ncomms3262.

    Article  CAS  PubMed  Google Scholar 

  18. Ginno PA, Gaidatzis D, Feldmann A, et al. A genome-scale map of DNA methylation turnover identifies site-specific dependencies of DNMT and TET activity. Nat Commun. 2020;11(1):2680. https://doi.org/10.1038/s41467-020-16354-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ooi SKT, Qiu C, Bernstein E, et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature. 2007;448(7154):714–7. https://doi.org/10.1038/nature05987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Di Ruscio A, Ebralidze AK, Benoukraf T, et al. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature. 2013;503(7476):371–6. https://doi.org/10.1038/nature12598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mao S-Q, Cuesta SM, Tannahill D, Balasubramanian S. Genome-wide DNA methylation signatures are determined by DNMT3A/B sequence preferences. Biochemistry. 2020;59(27):2541–50. https://doi.org/10.1021/acs.biochem.0c00339.

    Article  CAS  PubMed  Google Scholar 

  22. Bao X, Wu H, Zhu X, et al. The p53-induced lincRNA-p21 derails somatic cell reprogramming by sustaining H3K9me3 and CpG methylation at pluripotency gene promoters. Cell Res. 2015;25(1):80–92. https://doi.org/10.1038/cr.2014.165.

    Article  CAS  PubMed  Google Scholar 

  23. Choi JK. Contrasting chromatin organization of CpG islands and exons in the human genome. Genome Biol. 2010;11(7):R70. https://doi.org/10.1186/gb-2010-11-7-r70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Collings CK, Waddell PJ, Anderson JN. Effects of DNA methylation on nucleosome stability. Nucleic Acids Res. 2013;41(5):2918–31. https://doi.org/10.1093/nar/gks893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Leighton G, Williams DC. The methyl-CpG-binding domain 2 and 3 proteins and formation of the nucleosome remodeling and deacetylase complex. J Mol Biol. 2020;432(6):1624–39. https://doi.org/10.1016/j.jmb.2019.10.007.

    Article  CAS  PubMed  Google Scholar 

  26. Rao S, Chiu T-P, Kribelbauer JF, Mann RS, Bussemaker HJ, Rohs R. Systematic prediction of DNA shape changes due to CpG methylation explains epigenetic effects on protein-DNA binding. Epigenet Chromatin. 2018;11(1):6. https://doi.org/10.1186/s13072-018-0174-4.

    Article  CAS  Google Scholar 

  27. Geahigan KB, Meints GA, Hatcher ME, Orban J, Drobny GP. The dynamic impact of CpG methylation in DNA. Biochemistry. 2000;39(16):4939–46. https://doi.org/10.1021/bi9917636.

    Article  CAS  PubMed  Google Scholar 

  28. Ashburner BP, Westerheide SD, Baldwin AS. The p65 (RelA) subunit of NF-κB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 To negatively regulate gene expression. Mol Cell Biol. 2001;21(20):7065–77. https://doi.org/10.1128/MCB.21.20.7065-7077.2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bornelöv S, Reynolds N, Xenophontos M, et al. The nucleosome remodeling and deacetylation complex modulates chromatin structure at sites of active transcription to fine-tune gene expression. Mol Cell. 2018;71(1):56-72.e4. https://doi.org/10.1016/j.molcel.2018.06.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Héberlé É, Bardet AF. Sensitivity of transcription factors to DNA methylation. Essays Biochem. 2019;63(6):727–41. https://doi.org/10.1042/EBC20190033.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lambert SA, Jolma A, Campitelli LF, et al. The human transcription factors. Cell. 2018;172(4):650–65. https://doi.org/10.1016/j.cell.2018.01.029.

    Article  CAS  PubMed  Google Scholar 

  32. Spruijt CG, Gnerlich F, Smits AH, et al. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell. 2013;152(5):1146–59. https://doi.org/10.1016/j.cell.2013.02.004.

    Article  CAS  PubMed  Google Scholar 

  33. Xin B, Rohs R. Relationship between histone modifications and transcription factor binding is protein family specific. Genome Res. 2018;28(3):321–33. https://doi.org/10.1101/gr.220079.116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yin Y, Morgunova E, Jolma A, et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science. 2017;356(6337):eaaj2239. https://doi.org/10.1126/science.aaj2239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shayevitch R, Askayo D, Keydar I, Ast G. The importance of DNA methylation of exons on alternative splicing. RNA. 2018;24(10):1351–62. https://doi.org/10.1261/rna.064865.117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Barrès R, Yan J, Egan B, et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab. 2012;15(3):405–11. https://doi.org/10.1016/j.cmet.2012.01.001.

    Article  CAS  PubMed  Google Scholar 

  37. Egan B, Carson BP, Garcia-Roves PM, et al. Exercise intensity-dependent regulation of peroxisome proliferator-activated receptor γ coactivator-1α mRNA abundance is associated with differential activation of upstream signalling kinases in human skeletal muscle: exercise intensity and PGC-1α regulation. J Physiol. 2010;588(10):1779–90. https://doi.org/10.1113/jphysiol.2010.188011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lindholm ME, Marabita F, Gomez-Cabrero D, et al. An integrative analysis reveals coordinated reprogramming of the epigenome and the transcriptome in human skeletal muscle after training. Epigenetics. 2014;9(12):1557–69. https://doi.org/10.4161/15592294.2014.982445.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Bajpeyi S, Covington JD, Taylor EM, Stewart LK, Galgani JE, Henagan TM. Skeletal muscle PGC1α −1 nucleosome position and −260 nt DNA methylation determine exercise response and prevent ectopic lipid accumulation in men. Endocrinology. 2017;158(7):2190–9. https://doi.org/10.1210/en.2017-00051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Alibegovic AC, Sonne MP, Højbjerre L, et al. Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men. Am J Physiol Endocrinol Metab. 2010;299(5):E752–63. https://doi.org/10.1152/ajpendo.00590.2009.

    Article  CAS  PubMed  Google Scholar 

  41. Robinson MM, Dasari S, Konopka AR, et al. Enhanced protein translation underlies improved metabolic and physical adaptations to different exercise training modes in young and old humans. Cell Metab. 2017;25(3):581–92. https://doi.org/10.1016/j.cmet.2017.02.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lane SC, Camera DM, Lassiter DG, et al. Effects of sleeping with reduced carbohydrate availability on acute training responses. J Appl Physiol. 2015;119(6):643–55. https://doi.org/10.1152/japplphysiol.00857.2014.

    Article  CAS  PubMed  Google Scholar 

  43. King-Himmelreich TS, Schramm S, Wolters MC, et al. The impact of endurance exercise on global and AMPK gene-specific DNA methylation. Biochem Biophys Res Commun. 2016;474(2):284–90. https://doi.org/10.1016/j.bbrc.2016.04.078.

    Article  CAS  PubMed  Google Scholar 

  44. Rowlands DS, Page RA, Sukala WR, et al. Multi-omic integrated networks connect DNA methylation and miRNA with skeletal muscle plasticity to chronic exercise in type 2 diabetic obesity. Physiol Genomics. 2014;46(20):747–65. https://doi.org/10.1152/physiolgenomics.00024.2014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lochmann TL, Thomas RR, Bennett JP, Taylor SM. Epigenetic modifications of the PGC-1α promoter during exercise induced expression in mice. PLoS ONE. 2015;10(6):e0129647. https://doi.org/10.1371/journal.pone.0129647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sailani MR, Halling JF, Møller HD, et al. Lifelong physical activity is associated with promoter hypomethylation of genes involved in metabolism, myogenesis, contractile properties and oxidative stress resistance in aged human skeletal muscle. Sci Rep. 2019;9(1):3272. https://doi.org/10.1038/s41598-018-37895-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Turner DC, Gorski PP, Seaborne RA, et al. Mechanical loading of bioengineered skeletal muscle in vitro recapitulates gene expression signatures of resistance exercise in vivo. J Cell Physiol. 2021;236(9):6534–47. https://doi.org/10.1002/jcp.30328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Maasar MF, Turner DC, Gorski PP, et al. The comparative methylome and transcriptome after change of direction compared to straight line running exercise in human skeletal muscle. Front Physiol. 2021;12:619447. https://doi.org/10.3389/fphys.2021.619447.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Romero MA, Mumford PW, Roberson PA, et al. Five months of voluntary wheel running downregulates skeletal muscle LINE-1 gene expression in rats. Am J Physiol Cell Physiol. 2019;317(6):C1313–23. https://doi.org/10.1152/ajpcell.00301.2019.

    Article  CAS  PubMed  Google Scholar 

  50. Garcia LA, Zapata-Bustos R, Day SE, et al. Can exercise training alter human skeletal muscle DNA methylation? Metabolites. 2022;12(3):222. https://doi.org/10.3390/metabo12030222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gorski PP, Turner DC, Iraki J, Morton JP, Sharples AP, Areta JL. Human skeletal muscle methylome after low carbohydrate energy balanced exercise. Am J Physiol Endocrinol Metab. 2023;324:E437–48. https://doi.org/10.1152/ajpendo.00029.2023.

    Article  CAS  PubMed  Google Scholar 

  52. Gorski PP, Raastad T, Ullrich M, et al. Aerobic exercise training resets the human skeletal muscle methylome 10 years after breast cancer treatment and survival. FASEB J. 2023;37(1):e22720. https://doi.org/10.1096/fj.202201510RR.

    Article  CAS  PubMed  Google Scholar 

  53. Telles GD, Libardi CA, Conceição MS, et al. Interrelated but not time-aligned response in myogenic regulatory factors demethylation and mRNA expression after divergent exercise bouts. Med Sci Sports Exerc. 2023;55(2):199–208. https://doi.org/10.1249/MSS.0000000000003049.

    Article  CAS  PubMed  Google Scholar 

  54. Jacques M, Landen S, Romero JA, et al. Methylome and proteome integration in human skeletal muscle uncover group and individual responses to high-intensity interval training. FASEB J. 2023;37(10):e23184. https://doi.org/10.1096/fj.202300840RR.

    Article  CAS  PubMed  Google Scholar 

  55. Landen S, Jacques M, Hiam D, et al. Sex differences in muscle protein expression and DNA methylation in response to exercise training. Biol Sex Differ. 2023;14(1):56. https://doi.org/10.1186/s13293-023-00539-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Romero MA, Mobley CB, Mumford PW, et al. Acute and chronic resistance training downregulates select LINE-1 retrotransposon activity markers in human skeletal muscle. Am J Physiol Cell Physiol. 2018;314(3):C379–88. https://doi.org/10.1152/ajpcell.00192.2017.

    Article  CAS  PubMed  Google Scholar 

  57. Lindholm ME, Rundqvist H. Skeletal muscle hypoxia-inducible factor-1 and exercise: skeletal muscle hypoxia-inducible factor-1 and exercise. Exp Physiol. 2016;101(1):28–32. https://doi.org/10.1113/EP085318.

    Article  CAS  PubMed  Google Scholar 

  58. Anastasiadi D, Esteve-Codina A, Piferrer F. Consistent inverse correlation between DNA methylation of the first intron and gene expression across tissues and species. Epigenet Chromatin. 2018;11(1):37. https://doi.org/10.1186/s13072-018-0205-1.

    Article  CAS  Google Scholar 

  59. Brenet F, Moh M, Funk P, et al. DNA methylation of the first exon is tightly linked to transcriptional silencing. PLoS ONE. 2011;6(1):e14524. https://doi.org/10.1371/journal.pone.0014524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Teissandier A, Bourc’his D. Gene body DNA methylation conspires with H3K36me3 to preclude aberrant transcription. EMBO J. 2017;36(11):1471–3. https://doi.org/10.15252/embj.201796812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Neri F, Rapelli S, Krepelova A, et al. Intragenic DNA methylation prevents spurious transcription initiation. Nature. 2017;543(7643):72–7. https://doi.org/10.1038/nature21373.

    Article  CAS  PubMed  Google Scholar 

  62. Huang T, Zhou X, Mao X, et al. Lactate-fueled oxidative metabolism drives DNA methyltransferase 1-mediated transcriptional co-activator with PDZ binding domain protein activation. Cancer Sci. 2020;111(1):186–99. https://doi.org/10.1111/cas.14246.

    Article  CAS  PubMed  Google Scholar 

  63. Mohamed A, Sun C, De Mello V, et al. The Hippo effector TAZ (WWTR1) transforms myoblasts and TAZ abundance is associated with reduced survival in embryonal rhabdomyosarcoma. J Pathol. 2016;240(1):3–14. https://doi.org/10.1002/path.4745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wu Q, Li J, Sun S, et al. YAP/TAZ-mediated activation of serine metabolism and methylation regulation is critical for LKB1-deficient breast cancer progression. Biosci Rep. 2017;37(5):BSR20171072. https://doi.org/10.1042/BSR20171072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chang Y-U, Kim J-S. The effect of uphill and downhill exercise training on myogenic mechanism of Wnt/BMP signaling in the skeletal muscle of aged rats. Exerc Sci. 2019;28(2):182–90. https://doi.org/10.15857/ksep.2019.28.2.182.

    Article  Google Scholar 

  66. Hervouet E, Vallette FM, Cartron P-F. Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation. Epigenetics. 2009;4(7):487–99. https://doi.org/10.4161/epi.4.7.9883.

    Article  CAS  PubMed  Google Scholar 

  67. Valenta T, Hausmann G, Basler K. The many faces and functions of β-catenin: β-catenin: a life by, beyond, and against the Wnt canon. EMBO J. 2012;31(12):2714–36. https://doi.org/10.1038/emboj.2012.150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gibala MJ, González-Alonso J, Saltin B. Dissociation between muscle tricarboxylic acid cycle pool size and aerobic energy provision during prolonged exercise in humans. J Physiol. 2002;545(2):705–13. https://doi.org/10.1113/jphysiol.2002.028084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Pfeifer GP, Kadam S, Jin S-G. 5-hydroxymethylcytosine and its potential roles in development and cancer. Epigenet Chromatin. 2013;6(1):10. https://doi.org/10.1186/1756-8935-6-10.

    Article  CAS  Google Scholar 

  70. White AT, Schenk S. NAD+/NADH and skeletal muscle mitochondrial adaptations to exercise. Am J Physiol Endocrinol Metab. 2012;303(3):E308–21. https://doi.org/10.1152/ajpendo.00054.2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Robertson KD. DNA methylation and human disease. Nat Rev Genet. 2005;6(8):597–610. https://doi.org/10.1038/nrg1655.

    Article  CAS  PubMed  Google Scholar 

  72. Chen C-C, Wang K-Y, Shen C-KJ. DNA 5-methylcytosine demethylation activities of the mammalian DNA methyltransferases. J Biol Chem. 2013;288(13):9084–91. https://doi.org/10.1074/jbc.M112.445585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Baylor SM, Hollingworth S. Intracellular calcium movements during excitation–contraction coupling in mammalian slow-twitch and fast-twitch muscle fibers. J Gen Physiol. 2012;139(4):261–72. https://doi.org/10.1085/jgp.201210773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Sengupta D, Deb M, Patra SK. Antagonistic activities of miR-148a and DNMT1: ectopic expression of miR-148a impairs DNMT1 mRNA and dwindle cell proliferation and survival. Gene. 2018;660:68–79. https://doi.org/10.1016/j.gene.2018.03.075.

    Article  CAS  PubMed  Google Scholar 

  75. Cai M, Huang Y, Zheng R, et al. Solution structure of the cellular factor BAF responsible for protecting retroviral DNA from autointegration. Nat Struct Mol Biol. 1998;5(10):903–9. https://doi.org/10.1038/2345.

    Article  CAS  Google Scholar 

  76. Stroud MJ, Banerjee I, Veevers J, Chen J. Linker of nucleoskeleton and cytoskeleton complex proteins in cardiac structure, function, and disease. Circ Res. 2014;114(3):538–48. https://doi.org/10.1161/CIRCRESAHA.114.301236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wang S, Stoops E, Cp U, et al. Mechanotransduction via the LINC complex regulates DNA replication in myonuclei. J Cell Biol. 2018;217(6):2005–18. https://doi.org/10.1083/jcb.201708137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Schnuck JK, Gould LM, Parry HA, et al. Metabolic effects of physiological levels of caffeine in myotubes. J Physiol Biochem. 2018;74(1):35–45. https://doi.org/10.1007/s13105-017-0601-1.

    Article  CAS  PubMed  Google Scholar 

  79. Gibala MJ, MacLean DA, Graham TE, Saltin B. Tricarboxylic acid cycle intermediate pool size and estimated cycle flux in human muscle during exercise. Am J Physiol. 1998;275(2):E235-242. https://doi.org/10.1152/ajpendo.1998.275.2.E235.

    Article  CAS  PubMed  Google Scholar 

  80. Yang Q, Liang X, Sun X, et al. AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis. Cell Metab. 2016;24(4):542–54. https://doi.org/10.1016/j.cmet.2016.08.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Green HLH, Brewer AC. Dysregulation of 2-oxoglutarate-dependent dioxygenases by hyperglycaemia: does this link diabetes and vascular disease? Clin Epigenet. 2020;12(1):59. https://doi.org/10.1186/s13148-020-00848-y.

    Article  CAS  Google Scholar 

  82. Strumilo S. Short-term regulation of the α-ketoglutarate dehydrogenase complex by energy-linked and some other effectors. Biochem (Mosc). 2005;70(7):726–9. https://doi.org/10.1007/s10541-005-0177-1.

    Article  CAS  Google Scholar 

  83. Salminen A, Kauppinen A, Hiltunen M, Kaarniranta K. Krebs cycle intermediates regulate DNA and histone methylation: epigenetic impact on the aging process. Ageing Res Rev. 2014;16:45–65. https://doi.org/10.1016/j.arr.2014.05.004.

    Article  CAS  PubMed  Google Scholar 

  84. Yuan Y, Xu P, Jiang Q, et al. Exercise-induced α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation. EMBO J. 2020;39(7):e103304. https://doi.org/10.15252/embj.2019103304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Adeva-Andany MM, Funcasta-Calderón R, Fernández-Fernández C, Castro-Quintela E, Carneiro-Freire N. Metabolic effects of glucagon in humans. J Clin Transl Endocrinol. 2019;15:45–53. https://doi.org/10.1016/j.jcte.2018.12.005.

    Article  PubMed  Google Scholar 

  86. Howlett K, Galbo H, Lorentsen J, et al. Effect of adrenaline on glucose kinetics during exercise in adrenalectomised humans. J Physiol. 1999;519(3):911–21. https://doi.org/10.1111/j.1469-7793.1999.0911n.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zouhal H, Jacob C, Delamarche P, Gratas-Delamarche A. Catecholamines and the effects of exercise, training and gender. Sports Med. 2008;38(5):401–23. https://doi.org/10.2165/00007256-200838050-00004.

    Article  PubMed  Google Scholar 

  88. Polakovičová M, Musil P, Laczo E, Hamar D, Kyselovič J. Circulating microRNAs as potential biomarkers of exercise response. IJMS. 2016;17(10):1553. https://doi.org/10.3390/ijms17101553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ficz G. New insights into mechanisms that regulate DNA methylation patterning. J Exp Biol. 2015;218(Pt 1):14–20. https://doi.org/10.1242/jeb.107961.

    Article  PubMed  Google Scholar 

  90. Song J, Du Z, Ravasz M, Dong B, Wang Z, Ewing RM. A protein interaction between β-Catenin and Dnmt1 regulates Wnt signaling and DNA methylation in colorectal cancer cells. Mol Cancer Res. 2015;13(6):969–81. https://doi.org/10.1158/1541-7786.MCR-13-0644.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Barrès R, Osler ME, Yan J, et al. Non-CpG methylation of the PGC-1α promoter through DNMT3B controls mitochondrial density. Cell Metab. 2009;10(3):189–98. https://doi.org/10.1016/j.cmet.2009.07.011.

    Article  CAS  PubMed  Google Scholar 

  92. Felle M, Hoffmeister H, Rothammer J, Fuchs A, Exler JH, Längst G. Nucleosomes protect DNA from DNA methylation in vivo and in vitro. Nucleic Acids Res. 2011;39(16):6956–69. https://doi.org/10.1093/nar/gkr263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Bagley JR, Burghardt KJ, McManus R, et al. Epigenetic responses to acute resistance exercise in trained vs. sedentary men. J Strength Cond Res. 2020;34(6):1574–80. https://doi.org/10.1519/JSC.0000000000003185.

    Article  PubMed  Google Scholar 

  94. Seaborne RA, Strauss J, Cocks M, et al. Human skeletal muscle possesses an epigenetic memory of hypertrophy. Sci Rep. 2018;8(1):1898. https://doi.org/10.1038/s41598-018-20287-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Laker RC, Garde C, Camera DM, et al. Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans. Sci Rep. 2017;7(1):15134. https://doi.org/10.1038/s41598-017-15420-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Von Walden F, Rea M, Mobley CB, et al. The myonuclear DNA methylome in response to an acute hypertrophic stimulus. Epigenetics. 2020;15(11):1151–62. https://doi.org/10.1080/15592294.2020.1755581.

    Article  Google Scholar 

  97. Turner DC, Seaborne RA, Sharples AP. Comparative transcriptome and methylome analysis in human skeletal muscle anabolism, hypertrophy and epigenetic memory. Sci Rep. 2019;9(1):4251. https://doi.org/10.1038/s41598-019-40787-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Pattamaprapanont P, Garde C, Fabre O, Barrès R. Muscle contraction induces acute hydroxymethylation of the exercise-responsive gene Nr4a3. Front Endocrinol. 2016;7:165. https://doi.org/10.3389/fendo.2016.00165.

    Article  Google Scholar 

  99. Wen Y, Dungan CM, Mobley CB, Valentino T, von Walden F, Murach KA. Nucleus type-specific DNA methylomics reveals epigenetic ‘memory’ of prior adaptation in skeletal muscle. Function. 2021;2(5):zqab038. https://doi.org/10.1093/function/zqab038.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Murach KA, Dimet‐Wiley AL, Wen Y, et al. Late-life exercise mitigates skeletal muscle epigenetic aging. Aging Cell. 2022;21(1):e13527. https://doi.org/10.1111/acel.13527.

    Article  PubMed  Google Scholar 

  101. Sexton CL, Godwin JS, McIntosh MC, et al. Skeletal muscle DNA methylation and mRNA responses to a bout of higher versus lower load resistance exercise in previously trained men. Cells. 2023;12(2):263. https://doi.org/10.3390/cells12020263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hunter DJ, James LS, Hussey B, Ferguson RA, Lindley MR, Mastana SS. Impacts of eccentric resistance exercise on DNA methylation of candidate genes for inflammatory cytokines in skeletal muscle and leukocytes of healthy males. Genes. 2023;14(2):478. https://doi.org/10.3390/genes14020478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dungan CM, Brightwell CR, Wen Y, et al. Muscle-specific cellular and molecular adaptations to late-life voluntary concurrent exercise. Function (Oxf). 2022;3(4):zqac027. https://doi.org/10.1093/function/zqac027.

    Article  PubMed  Google Scholar 

  104. Murach KA, Dungan CM, von Walden F, Wen Y. Epigenetic evidence for distinct contributions of resident and acquired myonuclei during long-term exercise adaptation using timed in vivo myonuclear labeling. Am J Physiol Cell Physiol. 2022;322(1):C86–93. https://doi.org/10.1152/ajpcell.00358.2021.

    Article  CAS  PubMed  Google Scholar 

  105. Jacobsen SC, Brøns C, Bork-Jensen J, et al. Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men. Diabetologia. 2012;55(12):3341–9. https://doi.org/10.1007/s00125-012-2717-8.

    Article  CAS  PubMed  Google Scholar 

  106. Lai CQ, Parnell LD, Smith CE, et al. Carbohydrate and fat intake associated with risk of metabolic diseases through epigenetics of CPT1A. Am J Clin Nutr. 2020;112(5):1200–11. https://doi.org/10.1093/ajcn/nqaa233.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Zeng J-D, Wu WKK, Wang H-Y, Li X-X. Serine and one-carbon metabolism, a bridge that links mTOR signaling and DNA methylation in cancer. Pharmacol Res. 2019;149: 104352. https://doi.org/10.1016/j.phrs.2019.104352.

    Article  CAS  PubMed  Google Scholar 

  108. Horsburgh S, Todryk S, Toms C, Moran CN, Ansley L. Exercise-conditioned plasma attenuates nuclear concentrations of DNA methyltransferase 3B in human peripheral blood mononuclear cells. Physiol Rep. 2015;3(12):e12621. https://doi.org/10.14814/phy2.12621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Just J, Yan Y, Farup J, et al. Blood flow-restricted resistance exercise alters the surface profile, miRNA cargo and functional impact of circulating extracellular vesicles. Sci Rep. 2020;10(1):5835. https://doi.org/10.1038/s41598-020-62456-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tsai YP, Chen HF, Chen SY, et al. TET1 regulates hypoxia-induced epithelial-mesenchymal transition by acting as a co-activator. Genome Biol. 2014;15(12):513. https://doi.org/10.1186/s13059-014-0513-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Gates LA, Shi J, Rohira AD, et al. Acetylation on histone H3 lysine 9 mediates a switch from transcription initiation to elongation. J Biol Chem. 2017;292(35):14456–72. https://doi.org/10.1074/jbc.M117.802074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Morral N, Liu S, Conteh AM, et al. Aberrant gene expression induced by a high-fat diet is linked to H3K9 acetylation in the promoter-proximal region. Biochim Biophys Acta (BBA) Gene Regul Mech. 2021;1864(3):194691. https://doi.org/10.1016/j.bbagrm.2021.194691.

    Article  CAS  Google Scholar 

  113. Maeder ML, Angstman JF, Richardson ME, et al. Targeted DNA demethylation and activation of endogenous genes using programmable TALE-TET1 fusion proteins. Nat Biotechnol. 2013;31(12):1137–42. https://doi.org/10.1038/nbt.2726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Barrès R, Zierath JR. The role of diet and exercise in the transgenerational epigenetic landscape of T2DM. Nat Rev Endocrinol. 2016;12(8):441–51. https://doi.org/10.1038/nrendo.2016.87.

    Article  CAS  PubMed  Google Scholar 

  115. Rubenstein AB, Smith GR, Raue U, et al. Single-cell transcriptional profiles in human skeletal muscle. Sci Rep. 2020;10(1):229. https://doi.org/10.1038/s41598-019-57110-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Jang H, Shin W, Lee J, Do J. CpG and non-CpG methylation in epigenetic gene regulation and brain function. Genes. 2017;8(6):148. https://doi.org/10.3390/genes8060148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Taylor DL, Jackson AU, Narisu N, et al. Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle. Proc Natl Acad Sci USA. 2019;116(22):10883–8. https://doi.org/10.1073/pnas.1814263116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Giordani L, He GJ, Negroni E, et al. High-dimensional single-cell cartography reveals novel skeletal muscle-resident cell populations. Mol Cell. 2019;74(3):609-621.e6. https://doi.org/10.1016/j.molcel.2019.02.026.

    Article  CAS  PubMed  Google Scholar 

  119. Hunter DJ, James L, Hussey B, Wadley AJ, Lindley MR, Mastana SS. Impact of aerobic exercise and fatty acid supplementation on global and gene-specific DNA methylation. Epigenetics. 2019;14(3):294–309. https://doi.org/10.1080/15592294.2019.1582276.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Schenk A, Koliamitra C, Bauer CJ, et al. Impact of acute aerobic exercise on genome-wide DNA-methylation in natural killer cells—a pilot study. Genes. 2019;10(5):380. https://doi.org/10.3390/genes10050380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Denham J, Marques FZ, Bruns EL, O’Brien BJ, Charchar FJ. Epigenetic changes in leukocytes after 8 weeks of resistance exercise training. Eur J Appl Physiol. 2016;116(6):1245–53. https://doi.org/10.1007/s00421-016-3382-2.

    Article  CAS  PubMed  Google Scholar 

  122. Sotiropoulos A, Ohanna M, Kedzia C, et al. Growth hormone promotes skeletal muscle cell fusion independent of insulin-like growth factor 1 up-regulation. Proc Natl Acad Sci. 2006;103(19):7315–20. https://doi.org/10.1073/pnas.0510033103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Yablonka-Reuveni Z, Seger R, Rivera AJ. Fibroblast growth factor promotes recruitment of skeletal muscle satellite cells in young and old rats. J Histochem Cytochem. 1999;47(1):23–42. https://doi.org/10.1177/002215549904700104.

    Article  CAS  PubMed  Google Scholar 

  124. Ramsahoye BH, Biniszkiewicz D, Lyko F, Clark V, Bird AP, Jaenisch R. Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci. 2000;97(10):5237–42. https://doi.org/10.1073/pnas.97.10.5237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Sendžikaitė G, Hanna CW, Stewart-Morgan KR, Ivanova E, Kelsey G. A DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice. Nat Commun. 2019;10(1):1884. https://doi.org/10.1038/s41467-019-09713-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lee J-H, Saito Y, Park S-J, Nakai K. Existence and possible roles of independent non-CpG methylation in the mammalian brain. DNA Res. 2020;27(4):dsaa020. https://doi.org/10.1093/dnares/dsaa020.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Lin I-H, Chen Y-F, Hsu M-T. Correlated 5-hydroxymethylcytosine (5hmC) and gene expression profiles underpin gene and organ-specific epigenetic regulation in adult mouse brain and liver. PLoS ONE. 2017;12(1):e0170779. https://doi.org/10.1371/journal.pone.0170779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Nestor CE, Ottaviano R, Reddington J, et al. Tissue type is a major modifier of the 5-hydroxymethylcytosine content of human genes. Genome Res. 2012;22(3):467–77. https://doi.org/10.1101/gr.126417.111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Rauluseviciute I, Drabløs F, Rye MB. DNA methylation data by sequencing: experimental approaches and recommendations for tools and pipelines for data analysis. Clin Epigenet. 2019;11(1):193. https://doi.org/10.1186/s13148-019-0795-x.

    Article  CAS  Google Scholar 

  130. Huang Y, Pastor WA, Shen Y, Tahiliani M, Liu DR, Rao A. The behaviour of 5-hydroxymethylcytosine in bisulfite sequencing. PLoS ONE. 2010;5(1):e8888. https://doi.org/10.1371/journal.pone.0008888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Silva AM, Shen W, Heo M, et al. Ethnicity-related skeletal muscle differences across the lifespan. Am J Hum Biol. 2010;22(1):76–82. https://doi.org/10.1002/ajhb.20956.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Spanakis EK, Golden SH. Race/ethnic difference in diabetes and diabetic complications. Curr Diab Rep. 2013;13(6):814–23. https://doi.org/10.1007/s11892-013-0421-9.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Center for Genetic Medicine, Children’s National Hospital, 111 Michigan Ave NW, Washington, DC, 20010, USA

    Adam J. Bittel & Yi-Wen Chen

  2. Department of Genomics and Precision Medicine, The George Washington University School of Medicine and Health Science, 111 Michigan Ave NW, Washington, DC, 20010, USA

    Yi-Wen Chen

  3. Department of Integrative Systems Biology, Institute for Biomedical Sciences, The George Washington University, 2121 I St NW, Washington, DC, 20052, USA

    Yi-Wen Chen

Authors
  1. Adam J. Bittel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi-Wen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AJB and YWC contributed to the idea for the article. AJB performed the literature search and synthesis, and drafted the first draft of the manuscript. YWC and AJB critically revised subsequent drafts. Both authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Adam J. Bittel.

Ethics declarations

Funding

This research was supported by the National Institutes of Health T32 AR056993-06 (PI: Partridge) and 1R21HD103993-01 (PI: Chen), as well as the Muscular Dystrophy Association—Strength, Science, and Stories of Inspiration Fellowship (PI: A. Bittel), FSHD Canada (PI: Chen), an FSHD Society Grant Award (PI: A. Bittel), and the American Physical Therapy Association New Investigator Fellowship Training Initiative (PI: A. Bittel).

Conflicts of Interest

AJB and YWC declare no conflicts of interest or significant financial support for this work that could have influenced its outcome.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 21 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bittel, A.J., Chen, YW. DNA Methylation in the Adaptive Response to Exercise. Sports Med (2024). https://doi.org/10.1007/s40279-024-02011-6

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s40279-024-02011-6

Search

Navigation