DNA Methylation Response to Exercise Training Is Lower in Insulin Resistant Skeletal Muscle

Background: There is evidence that suggests insulin resistant muscle exhibits characteristics of exercise resistance, in that there are differences in gene expression responses to exercise. It remains elusive whether there are altered DNA methylation responses to exercise in insulin resistant muscle. The aim of this study was to determine (1) whether exercise training changes skeletal muscle global DNA methylation, and (2) if so, identify whether the methylation response to exercise is reduced in insulin resistance.Methods: Nine obese insulin-resistant participants (4M/5F; age 34.9 ± 3.6 years; M value 4.3 ± 0.8 mg/kg/min) and 5 lean insulin sensitive (1M/4F; age 32.9 ± 5.8 years; M value 7.8 ± 1.1 mg/kg/min) participants were studied before and after 8-weeks of supervised exercise training (60% of VO2peak for 20 minutes, 3 times per week; gradually increased to 70% of VO2peak for 45 minutes, 4 times per week). Vastus lateralis muscle biopsies were obtained before and after training. Global DNA methylation was performed using Illumina's Methylation EPIC 850K BeadChip.Results: Training increased VO2peak from 30.5 ± 1.2 to 35.4 ± 1.9 ml·min-l·kg FFM-1 (P = 0.00074) in the obese insulin-resistant participants. VO2peak increased from 34.3 ± 1.4 to 38.4 ± 1.9 ml·minl·kg FFM-1 (P = 0.040) in the lean insulin-sensitive participants. Methylation analysis showed that 651 differentially methylated cytosines (DMCs) were significantly altered in the obese participants post versus pre-exercise training (P < 0.05). The lean participants had 2,283 DMCs significantly changing post versus pre-training (P < 0.05).Conclusions: In conclusion, we showed that 8-weeks of exercise training alters skeletal muscle DNA methylation, and that the lean participants had more differentially methylated responses to the exercise compared to the obese group. Our findings provide additional evidence that insulin resistant muscle exhibits characteristics of "exercise resistance".