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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.
Acknowledgments
We are greatly appreciative to all the young men who participated in the clinical studies for obtainment of biopsies.
Authors’ contributions
C. Broholm, L.H., C. Brøns, B.M., S.W.J. and J.F.W. designed clinical studies and/or collected clinical data. C. Broholm, J.A., C.S., N.S.H. and B.K.P. designed cell experiments. J.A., M.S., N.S.H., L.H., J.H. and C. Broholm performed cell experiments and targeted gene and protein expression analyses. L.H. and L.G. performed pyrosequencing analyses. A.H.O., A.P., P.V., C. Broholm, R.R-M. and C.L. performed microarray experiments and statistical analyses. R.R.-M., C. Broholm and A.H.O. interpreted research data and wrote the manuscript. All authors edited the manuscript and approved the final version.
C. Broholm, R.R.-M. and A.V. are guarantors of this work and take full responsibility for the work.
Availability of data and material
The datasets obtained and analyzed in the current study are available from the first authors on reasonable request.
Competing interests
Allan Vaag is employed by AstraZeneca A/S, Sweden.
Ethics approval and consent to participate
All participants were given oral and written information about the experimental procedure before giving their written informed content. The study was approved by the regional ethical committee (H-A-2009-040 and H-D-2008-127) and performed according to the Declaration of Helsinki. In all data analyses, participants were identified by number, not by name.
Supplemental material
Supplemental data for this article can be accessed on the publisher’s website.