Journal
JOURNAL OF ENDOCRINOLOGY
Volume 232, Issue 3, Pages 475-491Publisher
BIOSCIENTIFICA LTD
DOI: 10.1530/JOE-16-0123
Keywords
skeletal muscle; myogenesis; muscle growth; fetal programming
Categories
Funding
- NIH Building Interdisciplinary Careers in Women's Health Scholar Award [K12 HD057022, R01 HD079404]
- Center for Women's Health Research, University of Colorado School of Medicine
- NIH [T32 HD007186, R01 DK088139, K08 HD060688, T32 HL007822, T32007186-32, K12HD068372, 2R24DK090964, GM29090]
- AHA [13POST14410014]
- Bill and Melinda Gates Foundation [OPP1061082]
- Genomics and Microarray Shared Resource of Colorado's NIH/NCI Cancer Center Support [P30CA046934]
- Colorado Clinical and Translational Sciences Institute NIH/NCATS [UL1-TR001082]
- [K01 DK090199]
- Bill and Melinda Gates Foundation [OPP1061082] Funding Source: Bill and Melinda Gates Foundation
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Adults who were affected by intrauterine growth restriction (IUGR) suffer from reductions in muscle mass and insulin resistance, suggesting muscle growth may be restricted by molecular events that occur during fetal development. To explore the basis of restricted fetal muscle growth, we used a sheep model of progressive placental insufficiency-induced IUGR to assess myoblast proliferation within intact skeletal muscle in vivo and isolated myoblasts stimulated with insulin in vitro. Gastrocnemius and soleus muscle weights were reduced by 25% in IUGR fetuses compared to those in controls (CON). The ratio of PAX7+ nuclei (a marker of myoblasts) to total nuclei was maintained in IUGR muscle compared to CON, but the fraction of PAX7+ myoblasts that also expressed Ki-67 (a marker of cellular proliferation) was reduced by 23%. Despite reduced proliferation in vivo, fetal myoblasts isolated from IUGR biceps femoris and cultured in enriched media in vitro responded robustly to insulin in a dose-and time-dependent manner to increase proliferation. Similarly, insulin stimulation of IUGR myoblasts upregulated key cell cycle genes and DNA replication. There were no differences in the expression of myogenic regulatory transcription factors that drive commitment to muscle differentiation between CON and IUGR groups. These results demonstrate that the molecular machinery necessary for transcriptional control of proliferation remains intact in IUGR fetal myoblasts, indicating that in vivo factors such as reduced insulin and IGF1, hypoxia and/or elevated counter-regulatory hormones may be inhibiting muscle growth in IUGR fetuses.
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