Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects

BMC Medicine

Research Article

Emma Nilsson¹  Petr Volkov¹  Cajsa Davegårdh¹  Sonia García-Calzón¹  Charlotte Ling¹  Alexander Perfilyev¹  Christa Broholm²  Ninna Schiøler Hansen²  Allan Vaag³  Rasmus Kjøbsted⁴  Jørgen F. P. Wojtaszewski⁴  Dov B. Ballak⁵  Bas Heinhuis⁶  Leo A. B. Joosten⁶  Charles A. Dinarello⁷  Tora Henriksen⁸  Lone Peijs⁸  Maria Pedersen⁸  Bente Klarlund Pedersen⁸  Camilla Scheele⁹ 

[1] Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, 205 02, Malmö, Sweden;Department of Endocrinology, Rigshospitalet, 2100, Copenhagen, Denmark;Department of Endocrinology, Rigshospitalet, 2100, Copenhagen, Denmark;Early Clinical Development, Translational Medical Unit, AstraZeneca, 431 83, Mölndal, Sweden;Department of Exercise and Sports Sciences, Faculty of Health, University of Copenhagen, Copenhagen, Denmark;Department of Integrative Physiology, University of Colorado Boulder, 80309, Boulder, CO, USA;Department of Medicine, University of Colorado, 80045, Aurora, CO, USA;Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;Department of Medicine, University of Colorado, 80045, Aurora, CO, USA;Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark;

关键词: DNA methylation;    Myogenesis;    Obesity;    IL-32;    Epigenetics;    ARPP21;    TGF-β3;    PSG;    CGB;    MT;    Insulin resistance;   

DOI  :  10.1186/s12916-017-0792-x

 received in 2016-10-12, accepted in 2017-01-11,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundHuman skeletal muscle stem cells are important for muscle regeneration. However, the combined genome-wide DNA methylation and expression changes taking place during adult myogenesis have not been described in detail and novel myogenic factors may be discovered. Additionally, obesity is associated with low relative muscle mass and diminished metabolism. Epigenetic alterations taking place during myogenesis might contribute to these defects.MethodsWe used Infinium HumanMethylation450 BeadChip Kit (Illumina) and HumanHT-12 Expression BeadChip (Illumina) to analyze genome-wide DNA methylation and transcription before versus after differentiation of primary human myoblasts from 14 non-obese and 14 obese individuals. Functional follow-up experiments were performed using siRNA mediated gene silencing in primary human myoblasts and a transgenic mouse model.ResultsWe observed genome-wide changes in DNA methylation and expression patterns during differentiation of primary human muscle stem cells (myoblasts). We identified epigenetic and transcriptional changes of myogenic transcription factors (MYOD1, MYOG, MYF5, MYF6, PAX7, MEF2A, MEF2C, and MEF2D), cell cycle regulators, metabolic enzymes and genes previously not linked to myogenesis, including IL32, metallothioneins, and pregnancy-specific beta-1-glycoproteins. Functional studies demonstrated IL-32 as a novel target that regulates human myogenesis, insulin sensitivity and ATP levels in muscle cells. Furthermore, IL32 transgenic mice had reduced insulin response and muscle weight. Remarkably, approximately 3.7 times more methylation changes (147,161 versus 39,572) were observed during differentiation of myoblasts from obese versus non-obese subjects. In accordance, DNMT1 expression increased during myogenesis only in obese subjects. Interestingly, numerous genes implicated in metabolic diseases and epigenetic regulation showed differential methylation and expression during differentiation only in obese subjects.ConclusionsOur study identifies IL-32 as a novel myogenic regulator, provides a comprehensive map of the dynamic epigenome during differentiation of human muscle stem cells and reveals abnormal epigenetic changes in obesity.

【 授权许可】

CC BY   
© The Author(s). 2017