Exercise Training Alters Sorbin and SH3 Domain Containing 3 DNA Methylation in Human Skeletal Muscle

The physiological changes observed in skeletal muscle following exercise training may be due to epigenetic modifications. Previously, we have shown increased methylation of cytosines (5.0 to 24.4%) in sorbin and SH3 domain containing 3 (SORBS3) in obesity. In another study, we showed decreased methylation (-5.6 to -24.2%) of SORBS3 following weight loss induced by bariatric surgery. The aim of this study was to determine whether an exercise training regimen alters DNA methylation of SORBS3. Skeletal muscle biopsies were obtained basally from five insulin-resistant obese (BMI: 32.3±0.8 kg/m2) participants (41.8±3.3 years) before and after 8-weeks of supervised exercise training. After training, BMI and total body weight were unchanged. Training increased peak aerobic capacity (VO2peak) from 20.2±1.9 to 24.3±2.7 mL/kg/min. We performed next generation methylation reduced representation bisulfite sequencing on DNA isolated from the vastus lateralis muscle biopsies. MethylSig analysis revealed 4 cytosines that were decreased in methylation following the exercise training (chr8.22423199: -19.3%, chr8.22423207: -14.6%; chr8.22423252: -27.5% and chr8.22423257: -12.3%, all Benjamini Hochberg q<0.05). All 4 differentially methylated sites fell within the 5’ untranslated region of SORBS3 variant 2. Our results demonstrate that exercise training for 8-weeks in obese participants alters the methylation of SORBS3. To date, we have provided evidence that SORBS3 is epigenetically regulated in skeletal muscle under a number of metabolic conditions including obesity, in response to weight loss by surgical intervention and in response to an 8-week exercise training regimen.