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 KrebsWill G. Hopkins, Eric P. Hoffman

    Research output: Contribution to journalArticle

    Abstract

    Epigenomic regulation of the transcriptome by DNA methylation and posttranscriptional gene silencing by miRNAs are potential environmental modulators of skeletal muscle plasticity to chronic exercise in healthy and diseased populations. We utilized 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/m2 ± 10) and Type 2 diabetes before and following 16 wk of resistance (n = 9) or endurance training (n = 8). Longitudinal transcriptome, methylome, and microRNA (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: microRNA (miR)-29a; promoter region hypomethylation of nuclear receptor factor (NRF1) and fatty acid transporter (SLC27A4), and hypermeth-ylation of fatty acid synthase, and to exon hypomethylation of 6-phos-phofructo-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 and 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.

    Original languageEnglish
    Pages (from-to)747-765
    Number of pages19
    JournalPhysiological Genomics
    Volume46
    Issue number20
    DOIs
    Publication statusPublished - 2014

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  • Cite this

    Rowlands, D. S., Page, R. A., Sukala, W. R., Giri, M., Ghimbovschi, S. D., Hayat, I., Cheema, B. S., Lys, I., Leikis, M., Sheard, P. W., Wakefield, S. J., Breier, B., Hathout, Y., Brown, K., Marathi, R., Orkunoglu-Suer, F. E., Devaney, J. M., Leiken, B., Many, G., ... Hoffman, E. P. (2014). Multi-Omic integrated networks connect DNA methylation and miRNA with skeletal muscle plasticity to chronic exercise in type 2 diabetic obesity. Physiological Genomics, 46(20), 747-765. https://doi.org/10.1152/physiolgenomics.00024.2014