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

被引：109

作者：

Rowlands, David S. ^{[1
]}

Page, Rachel A. ^{[2
]}

Sukala, William R. ^{[2
]}

Giri, Mamta ^{[3
]}

Ghimbovschi, Svetlana D. ^{[3
]}

Hayat, Irum ^{[2
]}

Cheema, Birinder S. ^{[4
]}

Lys, Isabelle ^{[5
]}

Leikis, Murray ^{[6
]}

Sheard, Phillip W. ^{[8
]}

Wakefield, St. John ^{[9
]}

Breier, Bernhard ^{[2
]}

Hathout, Yetrib ^{[3
]}

Brown, Kristy ^{[3
]}

Marathi, Ramya ^{[3
]}

Orkunoglu-Suer, Funda E. ^{[3
]}

Devaney, Joseph M. ^{[3
]}

Leiken, Benjamin ^{[3
]}

Many, Gina ^{[3
]}

Krebs, Jeremy ^{[7
]}

Hopkins, Will G. ^{[10
]}

Hoffman, Eric P. ^{[3
]}

机构：

[1] Massey Univ, Sch Sport & Exercise, Wellington 6011, New Zealand

[2] Massey Univ, Inst Food Nutr & Human Hlth, Wellington 6011, New Zealand

[3] Med Genet Res Ctr, Childrens Natl Med Ctr, Washington, DC USA

[4] Univ Western Sydney, Sch Sci & Hlth, Campbelltown, NSW, Australia

[5] Charles Darwin Univ, Fac Engn Hlth Sci & Environm, Darwin, NT 0909, Australia

[6] Capital & Coast Dist Hlth Board, Wellington Hosp, Wellington, New Zealand

[7] Capital & Coast Dist Hlth Board, Endocrine & Diabet Unit, Wellington, New Zealand

[8] Univ Otago, Dept Physiol, Dunedin, New Zealand

[9] Univ Otago, Dept Pathol, Wellington, New Zealand

[10] Auckland Univ Technol, Auckland, New Zealand

来源：

PHYSIOLOGICAL GENOMICS | 2014年 / 46卷 / 20期

关键词：

diabetes rehabilitation; epigenomic; intramyocellular lipid; network medicine; myomiRs; INSULIN-RESISTANCE; ENDURANCE EXERCISE; EXTRACELLULAR-MATRIX; GENE-EXPRESSION; IMMUNE-SYSTEM; GROWTH-FACTOR; PROTEIN; DIFFERENTIATION; MICRORNAS; CELL;

D O I：

10.1152/physiolgenomics.00024.2014

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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/m(2) +/- 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 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 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.

引用

页码：747 / 765

页数：19

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