Multi-omic integrated networks connect DNA methylation and miRNA with skeletal muscle plasticity to chronic exercise in Type 2 diabetic obesity
Autor: | Jeremy D Krebs, Yetrib Hathout, Kristy J. Brown, Murray Leikis, Benjamin Leiken, St. John Wakefield, Will G. Hopkins, William R Sukala, Phillip W. Sheard, Funda E. Orkunoglu-Suer, Bernhard H. Breier, Joseph M. Devaney, Gina M. Many, David S. Rowlands, Rachel Page, Ramya Marathi, Mamta Giri, Birinder S Cheema, Svetlana Ghimbovschi, Eric P. Hoffman, Isabelle Lys, Irum Hayat |
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Jazyk: | angličtina |
Rok vydání: | 2014 |
Předmět: |
Male
Proteomics Physiology Biology Bioinformatics epigenomic Epigenesis Genetic Transcriptome intramyocellular lipid Endurance training microRNA Genetics medicine Humans Gene Regulatory Networks Obesity RNA Messenger Call for Papers: Physiological Genomics of Exercise in Health and Disease Muscle Skeletal Exercise Epigenomics network medicine Regulation of gene expression Skeletal muscle Resistance Training DNA Methylation Middle Aged Lipid Metabolism Cell biology MicroRNAs Glucose Phenotype medicine.anatomical_structure diabetes rehabilitation Diabetes Mellitus Type 2 Gene Expression Regulation myomiRs DNA methylation Physical Endurance biology.protein Female GLUT4 |
Popis: | 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 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. |
Databáze: | OpenAIRE |
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