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. 2012 Dec;61(12):3322-32.
doi: 10.2337/db11-1653. Epub 2012 Oct 1.

Impact of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of patients with type 2 diabetes

Marloes Dekker Nitert  1 , Tasnim Dayeh, Peter Volkov, Targ Elgzyri, Elin Hall, Emma Nilsson, Beatrice T Yang, Stefan Lang, Hemang Parikh, Ylva Wessman, Holger Weishaupt, Joanne Attema, Mia Abels, Nils Wierup, Peter Almgren, Per-Anders Jansson, Tina Rönn, Ola Hansson, Karl-Fredrik Eriksson, Leif Groop, Charlotte Ling
Affiliations

Impact of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of patients with type 2 diabetes

Marloes Dekker Nitert et al. Diabetes. 2012 Dec.

Abstract

To identify epigenetic patterns, which may predispose to type 2 diabetes (T2D) due to a family history (FH) of the disease, we analyzed DNA methylation genome-wide in skeletal muscle from individuals with (FH(+)) or without (FH(-)) an FH of T2D. We found differential DNA methylation of genes in biological pathways including mitogen-activated protein kinase (MAPK), insulin, and calcium signaling (P ≤ 0.007) and of individual genes with known function in muscle, including MAPK1, MYO18B, HOXC6, and the AMP-activated protein kinase subunit PRKAB1 in skeletal muscle of FH(+) compared with FH(-) men. We further validated our findings from FH(+) men in monozygotic twin pairs discordant for T2D, and 40% of 65 analyzed genes exhibited differential DNA methylation in muscle of both FH(+) men and diabetic twins. We further examined if a 6-month exercise intervention modifies the genome-wide DNA methylation pattern in skeletal muscle of the FH(+) and FH(-) individuals. DNA methylation of genes in retinol metabolism and calcium signaling pathways (P < 3 × 10(-6)) and with known functions in muscle and T2D including MEF2A, RUNX1, NDUFC2, and THADA decreased after exercise. Methylation of these human promoter regions suppressed reporter gene expression in vitro. In addition, both expression and methylation of several genes, i.e., ADIPOR1, BDKRB2, and TRIB1, changed after exercise. These findings provide new insights into how genetic background and environment can alter the human epigenome.

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Figures

FIG. 1.
FIG. 1.
Comparison of DNA methylation in skeletal muscle of men with (FH+) vs. men without (FH−) a family history of T2D. The top KEGG pathways of genes, which exhibit decreased (A) and increased (B) methylation in skeletal muscle of FH+ (n = 15) vs. FH− (n = 13) men, respectively, with the expected number of genes (white), the observed number of genes (black), and the total number of genes in the pathway in parentheses. The P values were adjusted for multiple testing.
FIG. 2.
FIG. 2.
Impact of a 6-month exercise intervention on DNA methylation in human skeletal muscle. A: Exercise-induced changes in DNA methylation of THADA, MEF2A, RUNX1, and NDUFC2. Data are presented as mean ± SEM, and P values were corrected for multiple testing using Bonferroni corrections. Gene expression of THADA (B), MEF2A (C), RUNX1 (D), and NDUFC2 (E) correlates negatively with DNA methylation of respective gene. F: A diagram of the four luciferase reporter plasmids used to test the effect of DNA methylation on THADA, MEF2A, RUNX1, and NDUFC2 promoter activity and the empty vector are visualized. The four plasmids contain either 2,580 bp of the human THADA promoter, 2,460 bp of the human MEF2A promoter, 2,700 bp of the human RUNX1 promoter, or 2,500 bp of the human NDUFC2 promoter region inserted into a pCpGL-basic vector. Methylated (gray and black bars) or mock-methylated (white bars) promoter constructs were transfected into HEK293 cells for 48 h prior to luciferase assay. The data were normalized with cotransfected renilla luciferase control vector and are the average from three separate experiments of five replicates each. In each experiment, cells were transfected with an empty pCpGL-vector as a background control. A Student t test was used for statistical comparisons, and data are presented as relative expression compared with the nonmethylated construct including the promoter regions. G: Mitochondrial density, lipid content, and IL-7 mRNA expression in skeletal muscle as well as serum levels of IL-7 before and after exercise. Results are expressed as mean ± SEM. The analyses of mitochondrial density and lipid content were performed in 10 images covering at least 50 muscle fiber profiles. *P < 0.05.
FIG. 3.
FIG. 3.
The top KEGG pathways of genes, which are differentially methylated in skeletal muscle after exercise. KEGG pathways of genes, which exhibit decreased (A) and increased (B) methylation in skeletal muscle of all men (n = 28) after a 6-month exercise intervention with the expected number of genes (white), the observed number of genes (black), and the total number of genes in the pathway in parentheses. The P values were adjusted for multiple testing. C: Diagram showing the genes in the starch and sucrose metabolism pathway with decreased DNA methylation in skeletal muscle of all men (n = 28) after a 6-month exercise intervention. P, phosphate.
FIG. 4.
FIG. 4.
Comparison of DNA methylation in skeletal muscle of men with (FH+) vs. men without (FH−) a family history of T2D after a 6-month exercise intervention. The top KEGG pathways of genes, which exhibit decreased (A) and increased (B) methylation in skeletal muscle of FH+ (n = 15) vs. FH− (n = 13) men after exercise, with the expected number of genes (white), the observed number of genes (black), and the total number of genes in the pathway in parentheses. The P values were adjusted for multiple testing.
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