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

doi:10.1152/physiolgenomics.00024.2014

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 journal › Article › peer-review

97 Citations (Scopus)

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 language	English
Pages (from-to)	747-765
Number of pages	19
Journal	Physiological Genomics
Volume	46
Issue number	20
DOIs	https://doi.org/10.1152/physiolgenomics.00024.2014
Publication status	Published - 2014

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10.1152/physiolgenomics.00024.2014

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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

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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/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.",

keywords = "6 phosphofructo 2 kinase, cell nucleus receptor, DNA, fatty acid synthase, fatty acid transporter, glucose transporter 4, hexokinase, microRNA, mitochondrial enzyme, transcriptome, glucose, messenger RNA, adult, Article, clinical article, controlled study, diabetic obesity, DNA methylation, endurance training, enzyme activity, female, glucose metabolism, human, human tissue, immunohistochemistry, lipid metabolism, male, morbid obesity, muscle biopsy, non insulin dependent diabetes mellitus, phenotype, plasticity, posttranscriptional gene silencing, promoter region, randomized controlled trial, resistance training, skeletal muscle, complication, endurance, exercise, gene expression regulation, gene regulatory network, genetic epigenesis, genetics, metabolism, middle aged, obesity, pathology, proteomics, ultrastructure, vascularization, Diabetes Mellitus, Type 2, DNA Methylation, Epigenesis, Genetic, Exercise, Female, Gene Expression Regulation, Gene Regulatory Networks, Glucose, Humans, Lipid Metabolism, Male, MicroRNAs, Middle Aged, Muscle, Skeletal, Obesity, Phenotype, Physical Endurance, Proteomics, Resistance Training, RNA, Messenger, Transcriptome",

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

year = "2014",

doi = "10.1152/physiolgenomics.00024.2014",

language = "English",

volume = "46",

pages = "747--765",

journal = "Physiological Genomics",

issn = "1094-8341",

publisher = "American Physiological Society",

number = "20",

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Rowlands, DS, Page, RA, Sukala, WR, Giri, M, Ghimbovschi, SD, Hayat, I, Cheema, BS, Lys, I, Leikis, M, Sheard, PW, Wakefield, SJ, Breier, B, Hathout, Y, Brown, K, Marathi, R, Orkunoglu-Suer, FE, Devaney, JM, Leiken, B, Many, G, Krebs, J, Hopkins, WG & Hoffman, EP 2014, 'Multi-Omic integrated networks connect DNA methylation and miRNA with skeletal muscle plasticity to chronic exercise in type 2 diabetic obesity', Physiological Genomics, vol. 46, no. 20, pp. 747-765. https://doi.org/10.1152/physiolgenomics.00024.2014

TY - JOUR

T1 - Multi-Omic integrated networks connect DNA methylation and miRNA with skeletal muscle plasticity to chronic exercise in type 2 diabetic obesity

AU - Rowlands, David S.

AU - Page, Rachel A.

AU - Sukala, William R.

AU - Giri, Mamta

AU - Ghimbovschi, Svetlana D.

AU - Hayat, Irum

AU - Cheema, Birinder S.

AU - Lys, Isabelle

AU - Leikis, Murray

AU - Sheard, Phillip W.

AU - Wakefield, St John

AU - Breier, Bernhard

AU - Hathout, Yetrib

AU - Brown, Kristy

AU - Marathi, Ramya

AU - Orkunoglu-Suer, Funda E.

AU - Devaney, Joseph M.

AU - Leiken, Benjamin

AU - Many, Gina

AU - Krebs, Jeremy

AU - Hopkins, Will G.

AU - Hoffman, Eric P.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - 6 phosphofructo 2 kinase

KW - cell nucleus receptor

KW - DNA

KW - fatty acid synthase

KW - fatty acid transporter

KW - glucose transporter 4

KW - hexokinase

KW - microRNA

KW - mitochondrial enzyme

KW - transcriptome

KW - glucose

KW - messenger RNA

KW - adult

KW - Article

KW - clinical article

KW - controlled study

KW - diabetic obesity

KW - DNA methylation

KW - endurance training

KW - enzyme activity

KW - female

KW - glucose metabolism

KW - human

KW - human tissue

KW - immunohistochemistry

KW - lipid metabolism

KW - male

KW - morbid obesity

KW - muscle biopsy

KW - non insulin dependent diabetes mellitus

KW - phenotype

KW - plasticity

KW - posttranscriptional gene silencing

KW - promoter region

KW - randomized controlled trial

KW - resistance training

KW - skeletal muscle

KW - complication

KW - endurance

KW - exercise

KW - gene expression regulation

KW - gene regulatory network

KW - genetic epigenesis

KW - genetics

KW - metabolism

KW - middle aged

KW - obesity

KW - pathology

KW - proteomics

KW - ultrastructure

KW - vascularization

KW - Diabetes Mellitus, Type 2

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Exercise

KW - Female

KW - Gene Expression Regulation

KW - Gene Regulatory Networks

KW - Glucose

KW - Humans

KW - Lipid Metabolism

KW - Male

KW - MicroRNAs

KW - Middle Aged

KW - Muscle, Skeletal

KW - Obesity

KW - Phenotype

KW - Physical Endurance

KW - Proteomics

KW - Resistance Training

KW - RNA, Messenger

KW - Transcriptome

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U2 - 10.1152/physiolgenomics.00024.2014

DO - 10.1152/physiolgenomics.00024.2014

M3 - Article

C2 - 25138607

SN - 1094-8341

VL - 46

SP - 747

EP - 765

JO - Physiological Genomics

JF - Physiological Genomics

IS - 20

ER -

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

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