title: Multi-omic integrated networks connect DNA methylation and miRNA with skeletal muscle plasticity to chronic exercise in Type 2 diabetic obesity.
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/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.
authors.affiliation: School of Sport and Exercise, Massey University, Wellington, New Zealand; D.S.Rowlands@massey.ac.nz.
authors.forename: David S
authors.initials: DS
authors.lastname: Rowlands
authors.affiliation: Institute of Food, Nutrition & Human Health, Massey University, New Zealand;
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Page
authors.affiliation: Institute of Food, Nutrition & Human Health, Massey University, New Zealand;
authors.forename: William R
authors.initials: WR
authors.lastname: Sukala
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research (CGMR), Washington, District of Columbia;
authors.forename: Mamta
authors.initials: M
authors.lastname: Giri
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research (CGMR), Washington, District of Columbia;
authors.forename: Svetlana D
authors.initials: SD
authors.lastname: Ghimbovschi
authors.affiliation: Institute of Food, Nutrition & Human Health, Massey University, New Zealand;
authors.forename: Irum
authors.initials: I
authors.lastname: Hayat
authors.affiliation: School of Science and Health, University of Western Sydney, Campbelltown, Australia;
authors.forename: Birinder S
authors.initials: BS
authors.lastname: Cheema
authors.affiliation: Faculty of Engineering, Health, Science and the Environment, Charles Darwin University, Australia;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lys
authors.affiliation: Wellington Hospital, Capital and Coast District Health Board, Wellington, New Zealand;
authors.forename: Murray
authors.initials: M
authors.lastname: Leikis
authors.affiliation: Department of Physiology, University of Otago, Dunedin, New Zealand;
authors.forename: Phillip W
authors.initials: PW
authors.lastname: Sheard
authors.affiliation: Department of Pathology, University of Otago, Wellington, New Zealand; and.
authors.forename: St John
authors.initials: SJ
authors.lastname: Wakefield
authors.affiliation: Institute of Food, Nutrition & Human Health, Massey University, New Zealand;
authors.forename: Bernhard
authors.initials: B
authors.lastname: Breier
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research (CGMR), Washington, District of Columbia;
authors.forename: Yetrib
authors.initials: Y
authors.lastname: Hathout
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research (CGMR), Washington, District of Columbia;
authors.forename: Kristy
authors.initials: K
authors.lastname: Brown
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research (CGMR), Washington, District of Columbia;
authors.forename: Ramya
authors.initials: R
authors.lastname: Marathi
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research (CGMR), Washington, District of Columbia;
authors.forename: Funda E
authors.initials: FE
authors.lastname: Orkunoglu-Suer
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research (CGMR), Washington, District of Columbia;
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Devaney
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research (CGMR), Washington, District of Columbia;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Leiken
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research (CGMR), Washington, District of Columbia;
authors.forename: Gina
authors.initials: G
authors.lastname: Many
authors.affiliation: Endocrine and Diabetes Unit, Capital and Coast District Health Board, Wellington, New Zealand;
authors.forename: Jeremy
authors.initials: J
authors.lastname: Krebs
authors.affiliation: Health Science/Sport and Recreation, Auckland University of Technology, Auckland, New Zealand.
authors.forename: Will G
authors.initials: WG
authors.lastname: Hopkins
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research (CGMR), Washington, District of Columbia;
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D019175:DNA Methylation / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D044127:Epigenesis, Genetic; D015444:Exercise; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D005947:Glucose / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply / Q000473:pathology* / Q000648:ultrastructure; D009765:Obesity / Q000150:complications / Q000235:genetics*; D010641:Phenotype; D010807:Physical Endurance / Q000235:genetics; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055070:Resistance Training; D059467:Transcriptome / Q000235:genetics
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D005947:Glucose
keywords: diabetes rehabilitation; epigenomic; intramyocellular lipid; myomiRs; network medicine