Resistance and aerobic training increases genome-wide DNA methylation in women with polycystic ovary syndrome

Abstract

Physical activity is a first-line treatment for polycystic ovary syndrome (PCOS). Resistance or aerobic exercise improves metabolic complications, reproductive outcomes, and quality of life in PCOS. DNA methylation reprogramming during exercise may be the major modifier behind these changes. We sought to evaluate genome-wide DNA methylation changes after supervised resistance and aerobic exercise in women with PCOS. Exercises were performed in 56 women with PCOS (resistance, n = 30; aerobic, n = 26), for 16 weeks (wks), three times per week, in 50-minute to one-hour sessions. Anthropometric indices and hormonal and metabolic parameters were measured before and after training. Genome-wide leukocyte DNA methylation was analysed by Infinium Human MethylationEPIC 850K BeadChip microarrays (Illumina). Both resistance and aerobic exercise improved anthropometric indices, metabolic dysfunction, and hyperandrogenism in PCOS after the training programme, but no differences were observed between the two exercises. Resistance and aerobic exercise increased genome-wide DNA methylation, although resistance changed every category in the CpG island context (islands, shores, shelve, and open sea), whereas aerobic exercise altered CpG shores and the open sea. Using a stringent FDR (>40), 6 significantly differentially methylated regions (DMRs) were observed in the resistance exercise cohort and 14 DRMs in the aerobic cohort, all of which were hypermethylated. The increase in genome-wide DNA methylation may be related to the metabolic and hormonal changes observed in PCOS after resistance and aerobic exercise. Since the mammalian genome is hypermethylated globally to prevent genomic instability and ageing, resistance and aerobic exercise may promote health and longevity through environmentally induced epigenetic changes.

Keywords: DNA methylation; Polycystic ovary syndrome; aerobic training; physical activity; resistance training.

Figure 1.

Average beta values for all probes on the array were compared before and after the implementation of the protocols evidencing an increasing in global DNA before both aerobic exercise (a) and resistance exercise (c). Differential methylation was assessed using paired t-tests for each respective region of the genome. The aerobic exercise (b) increased DNA methylation in global, shores and open sea genomic context, while the resistance exercise (d) increased DNA methylation in all genomic context, including global, islands, shores, shelves and open sea. *designates a p-value of < 0.05, **designates a p-value of < 0.01, and ***designates a p-value of < 0.001. This figure was made with R program version 4.2.2.

Figure 2.

Circos plots display all significantly differentially methylated regions that passed a threshold of FDR > 13 for both aerobic (a) and resistance (c) exercise cohorts. The outer track represents the chromosomes, and the inner track represents the log2 ratio of all differentially methylated regions for both differences that increase following exercise (orange) and decreased following exercise (blue). Additionally, box plots depict the results from the paired sliding window analysis at all sites that were differentially methylated with an FDR > 40 for both the aerobic (b) and the resistance (d) cohorts. The specific location of these regions can be found in Table 3. Circular plots were made with RCircos (a package in R version 4.2.2).

Figure 3.

Scatter plots depict the accuracy of the Horvath ageing calculator in our cohort of samples for both aerobic (a) and resistance (c) exercise. Boxplots depict the change in predicted age following the exercise regimen for both aerobic (b) and resistance (d). No significant difference was identified for either aerobic (p-value = 0.14) or resistance (p-value = 0.34). This figure was made with R program version 4.2.2.

Figure 4.

Resistance and aerobic training have different effects on the metabolic, hormonal and body composition of women with PCOS after 16 weeks of intervention [10,11]. The resistance exercise reduces waist circumference, testosterone levels and HDL, while the aerobic exercises reduced waist circumference and testosterone levels. These changes are reflected in epigenetic reprogramming through different exercises, in which the resistance exercises increased average DNA methylation in all CpG island contexts, including global, islands, shores, shelves and open sea and the aerobic exercise increased average DNA methylation across all probes (global), as well as at shores and open sea. This figure was made in part using BioRender (https://biorender.com).