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
AU - Wojtaszewski, Jørgen
AU - Scheele, Camilla
AU - Brøns, Charlotte
AU - Pedersen, Bente Klarlund
AU - Vaag, Allan
PY - 2020/1/2
Y1 - 2020/1/2
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 - epigenetics
KW - FAM8A1
KW - FYN
KW - HDAC7
KW - Low birth weight
KW - myogenesis
KW - skeletal muscle
KW - Infant, Low Birth Weight
KW - Humans
KW - Male
KW - Transcriptome/genetics
KW - Young Adult
KW - Epigenome/genetics
KW - Myoblasts/metabolism
KW - Adult
KW - Down-Regulation/genetics
KW - Muscle Fibers, Skeletal/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85073995464&partnerID=8YFLogxK
U2 - 10.1080/07435800.2019.1669160
DO - 10.1080/07435800.2019.1669160
M3 - Journal article
C2 - 31566019
SN - 0743-5800
VL - 45
SP - 58
EP - 71
JO - Endocrine Research
JF - Endocrine Research
IS - 1
ER -