Multi-omic integrated networks connect DNA methylation and miRNA with skeletal muscle plasticity to chronic exercise in Type 2 diabetic obesity

David S Rowlands, Rachel A Page, William R Sukala, Mamta Giri, Svetlana D Ghimbovschi, Irum Hayat, Birinder S Cheema, Isabelle Lys, Murray Leikis, Phillip W Sheard, St John Wakefield, Bernhard Breier, Yetrib Hathout, Kristy Brown, Ramya Marathi, Funda E Orkunoglu-Suer, Joseph M Devaney, Benjamin Leiken, Gina Many, Jeremy Krebs, Will G Hopkins, Eric P Hoffman

Epigenomic regulation of the transcriptome by DNA methylation and post-transcriptional gene silencing by miRNAs are potential environmental modulators of skeletal muscle plasticity to chronic exercise in healthy and diseased populations. We utilised transcriptome networks to connect exercise-induced differential methylation and miRNA with functional skeletal muscle plasticity. Biopsies of the Vastus lateralis were collected from middle aged Polynesian men and women with morbid obesity (44 kg/m(2) ± 10) and Type-2 diabetes before and following 16 weeks of resistance (n=9) or endurance training (n=8). Longitudinal transcriptome, methylome, and miRNA responses were obtained via microarray, filtered by novel effect-size based false discovery rate probe selection preceding bioinformatic interrogation. Metabolic and microvascular transcriptome topology dominated the network landscape following endurance exercise. Lipid and glucose metabolism modules were connected to: miR-29a; promoter region hypomethylation of nuclear receptor factor (NRF1) and fatty-acid transporter (SLC27A4), and hypermethylation of fatty acid synthase, and to exon hypomethylation of 6-phosphofructo-2-kinase and Ser/Thr protein kinase. Directional change in the endurance networks was validated by lower intramyocellular lipid, increased capillarity, GLUT4, hexokinase and mitochondrial enzyme activity and proteome. Resistance training also lowered lipid, increased enzyme activity, and caused GLUT4-promoter hypomethylation; however, training was inconsequential to GLUT4, capillarity, and metabolic transcriptome. miR-195 connected to negative regulation of vascular development. To conclude, integrated molecular network modelling revealed differential DNA methylation and miRNA expression changes occur in skeletal muscle in response to chronic exercise training that are most pronounced with endurance training and topographically associated with functional metabolic and microvascular plasticity relevant to diabetes rehabilitation.