Epigenome- and Transcriptome-wide Changes in Muscle Stem Cells from Low Birth Weight Men

Research output: Contribution to journalArticle

Abstract

Background: Being born with low birth weight (LBW) is a risk factor for muscle insulin resistance and type 2 diabetes (T2D), which may be mediated by epigenetic mechanisms programmed by the intrauterine environment. Epigenetic mechanisms exert their prime effects in developing cells. We hypothesized that muscle insulin resistance in LBW subjects may be due to early differential epigenomic and transcriptomic alterations in their immature muscle progenitor cells. Results: Muscle progenitor cells were obtained from 23 healthy young adult men born at term with LBW, and 15 BMI-matched normal birth weight (NBW) controls. The cells were subsequently cultured and differentiated into myotubes. DNA and RNA were harvested before and after differentiation for genome-wide DNA methylation and RNA expression measurements. After correcting for multiple comparisons (q ≤ 0.05), 56 CpG sites were found to be significantly, differentially methylated in myoblasts from LBW compared with NBW men, of which the top five gene-annotated CpG sites (SKI, ARMCX3, NR5A2, NEUROG, ESRRG) previously have been associated to regulation of cholesterol, fatty acid and glucose metabolism and muscle development or hypertrophy. LBW men displayed markedly decreased myotube gene expression levels of the AMPK-repressing tyrosine kinase gene FYN and the histone deacetylase gene HDAC7. Silencing of FYN and HDAC7 was associated with impaired myotube formation, which for HDAC7 reduced muscle glucose uptake. Conclusions: The data provides evidence of impaired muscle development predisposing LBW individuals to T2D is linked to and potentially caused by distinct DNA methylation and transcriptional changes including down regulation of HDAC7 and FYN in their immature myoblast stem cells.

Details

Authors
  • Christa Broholm
  • Rasmus Ribel-Madsen
  • Line Hjort
  • Anders Henrik Olsson
  • Juliane Maria Dorothee Ahlers
  • Ninna Schiøler Hansen
  • Maren Schrölkamp
  • Linn Gillberg
  • Alexander Perfilyev
  • Petr Volkov
  • Charlotte Ling
  • Sine W. Jørgensen
  • Brynjulf Mortensen
  • Janne Hingst
  • Jørgen Wojtaszewski
  • Camilla Scheele
  • Charlotte Brøns
  • Bente Klarlund Pedersen
  • Allan Vaag
Organisations
External organisations
  • University of Copenhagen
  • Copenhagen University Hospital
  • Steno Diabetes Center Copenhagen
  • AstraZeneca, Sweden
  • Danish Diabetes Academy
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes

Keywords

  • epigenetics, FAM8A1, FYN, HDAC7, Low birth weight, myogenesis, skeletal muscle
Original languageEnglish
JournalEndocrine Research
Publication statusE-pub ahead of print - 2019 Sep 30
Publication categoryResearch
Peer-reviewedYes