Epigenetic networks and skeletal muscle plasticity to resistance and endurance exercise in type-II diabetic obesity

Epigenomic modification of the transcriptome by DNA methylation and post-transcriptional gene silencing by microRNAs are potential environmental modulators skeletal muscle plasticity to exercise rehabilitation in people with obesity and type-2 diabetes. PURPOSE: Identify novel methylation and microRNA associations with leading processes directing adaptation to chronic exercise in type-2 diabetic skeletal muscle. METHODS: Biopsies of the Vastus Lateralis were collected from middle-aged (49 y ± 5) Polynesians with metabolic syndrome and morbid obesity (44 kg/m2 ± 10) before and following 16- wk supervised progressive resistance (n=9) or endurance training (n=8). The transcriptome, methylome (Infinium 450k), and global microRNA expression were determined from microarray. Ingenuity Pathway Analysis was used to construct networks connecting methylation and microRNA into disease and functional modules. Network outcomes were evaluated against select protein phenotype outcomes. RESULTS: Reductions in intramyocellular lipid and increased mitochondrial β-hydroyxlacyl-CoA-dehydrogenase and cytochrome-C-oxidase activity were associated with lipid metabolic and antifibrosis networks with both forms of training; however, only with endurance were functional networks and protein phenotype (increased hexokinase, GLUT4, capillary density) associated with decreased glucose metabolic disorder and vasculogenesis. MicroRNAs connected with glucose metabolism disorder, vasculogenesis, and antifibrosis modules altered in response to endurance exercise included miR29b-3p, miR30c-5p, miR-301a-3p, miR-302d-3p; while fatty-acid metabolism and insulin resistance networks connected miR-222-3p, miR-137, miR-1305, miR-181a-5p, and let-7a-5p. Hypomethylated hub genes included NOTCH4, EPAS1, DLC1, CNTFR, and ACTN4. In response to resistance exercise: antifibrosis overlapped with leukocyte migration and muscle development, with miR-26a-5p, miR-16-5p, and miR-208b-3p, miR-544-3p, miR-377-3p, and hypomethylated genes PAX7, COL4A1, PRKCB, PDGFB, LAMA4, APOE, connected as candidate epigenetic regulators. Conclusions: An integrated network approach yields new potential epigenomic regulators of skeletal muscle plasticity to chronic exercise training in obese type-2 diabetes.