TY - JOUR

T1 - Epigenome- and transcriptome-wide changes in muscle stem cells from low birth weight men

AU - Broholm, Christa

AU - Ribel-Madsen, Rasmus

AU - Hjort, Line

AU - Olsson, Anders Henrik

AU - Ahlers, Juliane Maria Dorothee

AU - Hansen, Ninna Schiøler

AU - Schrölkamp, Maren

AU - Gillberg, Linn

AU - Perfilyev, Alexander

AU - Volkov, Petr

AU - Ling, Charlotte

AU - Jørgensen, Sine W

AU - Mortensen, Brynjulf

AU - Hingst, Janne Rasmuss

AU - Wojtaszewski, Jørgen

AU - Scheele, Camilla

AU - Brøns, Charlotte

AU - Pedersen, Bente Klarlund

AU - Vaag, Allan

N1 - CURIS 2019 NEXS 314

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Faculty of Science

KW - Low birth weight

KW - Myogenesis

KW - Epigenetics

KW - Skeletal muscle

KW - FYN

KW - HDAC7

KW - FAM8A1

U2 - 10.1080/07435800.2019.1669160

DO - 10.1080/07435800.2019.1669160

M3 - Journal article

C2 - 31566019

VL - 45

SP - 58

EP - 71

JO - Endocrine Research Communications

JF - Endocrine Research Communications

SN - 0743-5800

IS - 1

ER -