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Cited by 135Epigenetics and DNA MethylationGenetics and Physical PerformanceMetabolism, Diabetes, and Cancer

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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

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Sailani, M. Reza, Halling, Jens Frey, Møller, Henrik Devitt, Lee, Hayan, Plomgaard, Peter, Pilegaard, Henriette, Snyder, Michael P., Regenberg, Birgitte·2019·Scientific Reports
DOI 10.1038/s41598-018-37895-8PMC PMC6397284
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Abstract

Lifelong regular physical activity is associated with reduced risk of type 2 diabetes (T2D), maintenance of muscle mass and increased metabolic capacity. However, little is known about epigenetic mechanisms that might contribute to these beneficial effects in aged individuals. We investigated the effect of lifelong physical activity on global DNA methylation patterns in skeletal muscle of healthy aged men, who had either performed regular exercise or remained sedentary their entire lives (average age 62 years). DNA methylation was significantly lower in 714 promoters of the physically active than inactive men while methylation of introns, exons and CpG islands was similar in the two groups. Promoters for genes encoding critical insulin-responsive enzymes in glycogen metabolism, glycolysis and TCA cycle were hypomethylated in active relative to inactive men. Hypomethylation was also found in promoters of myosin light chain, dystrophin, actin polymerization, PAK regulatory genes and oxidative stress response genes. A cluster of genes regulated by GSK3β-TCF7L2 also displayed promoter hypomethylation. Together, our results suggest that lifelong physical activity is associated with DNA methylation patterns that potentially allow for increased insulin sensitivity and a higher expression of genes in energy metabolism, myogenesis, contractile properties and oxidative stress resistance in skeletal muscle of aged individuals.

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Figures

Figure 1 DNA methylation patterns in men with a physically active lifestyle and physically inactive lifestyle. (A) PCA analysis based on methylation profile of 26 CpG loci from muscle tissue. The 60–65 year old men with a lifelong physically active lifestyle are presented in blue color (n = 8) and those with a lifelong physically inactive lifestyle are presented in red (n = 8). (B–E) Cumulative distribution of the average DNA methylation level in active and inactive men for (B) promoters, (C) introns, (D) CpG islands, (E) exons in the human genome. (F) Model of methylation patterns (represented by dots) in DNA (represented by lines) of men with a physically active and inactive lifestyle.
Figure 1 DNA methylation patterns in men with a physically active lifestyle and physically inactive lifestyle. (A) PCA analysis based on methylation profile of 26 CpG loci from muscle tissue. The 60–65 year old men with a lifelong physically active lifestyle are presented in blue color (n = 8) and those with a lifelong physically inactive lifestyle are presented in red (n = 8). (B–E) Cumulative distribution of the average DNA methylation level in active and inactive men for (B) promoters, (C) introns, (D) CpG islands, (E) exons in the human genome. (F) Model of methylation patterns (represented by dots) in DNA (represented by lines) of men with a physically active and inactive lifestyle.CC BY · PubMed Central
Figure 2 Regulation of key enzymes in the central carbon and energy metabolism at the level of promoter DNA methylation and protein level. (A) Genes with significant and >30% hypomethylated promoters are shown in bold. Corresponding substrates and products for the affected steps in glycolysis, glycogen metabolism and TCA cycle are shown in red, insulin sensitive steps are shown as broad grey arrows. Protein levels of (B) pyruvate dehydrogenase, (D) OXPHOS subunits, (E) and mitochondrial ATP-transporters are shown as average of the level in eight physically active men (grey bars) and eight physically inactive men (black bars). *Indicates p < 0.05. (F) Representative Western blots for four men. (C) Citrate synthase activity measured as enzymatic activity. See Supplementary Figs 1 and 2A–C for full-length western blots and scatter plots showing individual data points for all presented proteins.
Figure 2 Regulation of key enzymes in the central carbon and energy metabolism at the level of promoter DNA methylation and protein level. (A) Genes with significant and >30% hypomethylated promoters are shown in bold. Corresponding substrates and products for the affected steps in glycolysis, glycogen metabolism and TCA cycle are shown in red, insulin sensitive steps are shown as broad grey arrows. Protein levels of (B) pyruvate dehydrogenase, (D) OXPHOS subunits, (E) and mitochondrial ATP-transporters are shown as average of the level in eight physically active men (grey bars) and eight physically inactive men (black bars). *Indicates p < 0.05. (F) Representative Western blots for four men. (C) Citrate synthase activity measured as enzymatic activity. See Supplementary Figs 1 and 2A–C for full-length western blots and scatter plots showing individual data points for all presented proteins.CC BY · PubMed Central
Figure 3 Hypomethylation of 73 GSK3β /TCF7L2 targets. (A) Model of 73 promoters known to bind TCF7L2. These promoters were hypomethylated (represented by dots) in men with a physically active lifestyle (blue) compared to men with an inactive lifestyle (red). (B) Protein levels of GSK3β are shown as average of the level in eight physically active men (grey bars) and eight physically inactive men (black bars). *Indicates p < 0.05. (C) Representative Western blots for four men. See Supplementary Figs 1 and 2D for full-length western blot and scatter plots showing individual data points for GSK3β.
Figure 3 Hypomethylation of 73 GSK3β /TCF7L2 targets. (A) Model of 73 promoters known to bind TCF7L2. These promoters were hypomethylated (represented by dots) in men with a physically active lifestyle (blue) compared to men with an inactive lifestyle (red). (B) Protein levels of GSK3β are shown as average of the level in eight physically active men (grey bars) and eight physically inactive men (black bars). *Indicates p < 0.05. (C) Representative Western blots for four men. See Supplementary Figs 1 and 2D for full-length western blot and scatter plots showing individual data points for GSK3β.CC BY · PubMed Central
Figure 4 Promoter hypomethylation of genes involved in myogenesis, structural dynamics of muscles and CDC42 signaling. Shown in black are gene products with significant and >30% hypomethylated promoters in the physically active men compared with inactive men. A grey box indicates the pathway position of CDC42. Pathway steps are indicated with black arrows. Pathway end products and inducers are show in red text. The model is based on map 04810, http://www.genome.jp/kegg/pathway.html.
Figure 4 Promoter hypomethylation of genes involved in myogenesis, structural dynamics of muscles and CDC42 signaling. Shown in black are gene products with significant and >30% hypomethylated promoters in the physically active men compared with inactive men. A grey box indicates the pathway position of CDC42. Pathway steps are indicated with black arrows. Pathway end products and inducers are show in red text. The model is based on map 04810, http://www.genome.jp/kegg/pathway.html.CC BY · PubMed Central
Figure 5 Protein levels of catalase and super oxide dismutase, SOD2, in men with a physically active lifestyle and physically inactive lifestyle. (A) Protein levels of catalase and SOD2 are shown as average of the level in eight physically active men (grey bars) and eight physically inactive men (black bars). *Indicates p < 0.05. (B) Representative Western blots for four men. See Supplementary Figs 1 and 2E for full-length western blot and scatter plots showing individual data points for SOD2 and catalase.
Figure 5 Protein levels of catalase and super oxide dismutase, SOD2, in men with a physically active lifestyle and physically inactive lifestyle. (A) Protein levels of catalase and SOD2 are shown as average of the level in eight physically active men (grey bars) and eight physically inactive men (black bars). *Indicates p < 0.05. (B) Representative Western blots for four men. See Supplementary Figs 1 and 2E for full-length western blot and scatter plots showing individual data points for SOD2 and catalase.CC BY · PubMed Central

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Metadata

Authors
Sailani, M. R., Halling, J. F., Møller, H. D., Lee, H., Plomgaard, P., Pilegaard, H., Snyder, M. P., & Regenberg, B.
Affiliations
  • Stanford Medicine (US)
  • University of Copenhagen (DK)
  • Copenhagen University Hospital (DK)
Corresponding author
Regenberg, Birgitte
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2019-03-01
Volume
9
Issue
1
Pages
3272-3272
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-018-37895-8
PMC
PMC6397284
OpenAlex
W2920732619
Cited by
129
References
40
Citations by year
2026: 9 · 2025: 24 · 2024: 24 · 2023: 18 · 2022: 23 · 2021: 13 · 2020: 9 · 2019: 8
FWCI
4.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Science Foundation
  • Villum Fonden (VKR023513)
  • Danish Diabetes Academy
  • National Research Foundation
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (161005, 151825)
  • Danmarks Grundforskningsfond (DNRF55)
  • Danmarks Frie Forskningsfond
  • TrygFonden
  • National Heart, Lung, and Blood Institute (R01HL122887)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
lifelong physical activity, DNA methylation, promoter hypomethylation, skeletal muscle aging, epigenetics, sedentary lifestyle, insulin sensitivity, glycogen metabolism, myogenesis, oxidative stress resistance, myosin light chain, dystrophin, actin polymerization, PAK, type 2 diabetes risk, muscle contractile properties
MeSH terms
Aging, Humans, Male, Middle Aged, Muscle Contraction, Muscle Proteins, Promoter Regions, Genetic, Exercise, Oxidative Stress, Muscle, Skeletal, DNA Methylation, Muscle Development

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