The Role of Inflammatory Pathways in Development, Growth, and Metabolism of Skeletal Muscle in IUGR Offspring; Blood Gene Expression of Inflammatory Factors as Novel Biomarkers for Assessing Stress and Wellbeing in Exotic Species.
Professor Dustin T. Yates
Date of this Version
Our first study identified the effects of maternal inflammation-induced intrauterine growth restriction (MI-IUGR) on growth and muscle glucose metabolism in offspring supplemented with curcumin. MI-IUGR lambs exhibited asymmetric growth restriction at birth and 30d of age, but normal glucose-stimulated insulin secretion. Hindlimb glucose oxidation was reduced by MI-IUGR and not improved by curcumin supplementation. Ex vivo muscle glucose oxidation was reduced by MI-IUGR but improved somewhat by curcumin. These finding indicate that fetal programming responses to MI contribute to neonatal growth and metabolic deficits. Neonatal curcumin supplementation had minimal effect on growth deficits but may improve glucose metabolism.
Our second study identified programmed mechanistic changes that explain intrinsic functional deficits in myoblasts from maternal hyperthermia-induced IUGR fetal sheep. Myoblasts were incubated with TNF⍺, TNFα with IKK inhibitor (IKKi), or IL6. Proliferation in IUGR myoblasts was less than controls in basal and IL6-spiked media. IKKi decreased proliferation in all myoblasts, but more in IUGR myoblasts. IUGR myoblasts differentiated less than controls, and TNF⍺ further reduced their differentiation. TNFα increased TLR4 mRNA in all myoblasts, but more in IUGR myoblasts. TNFR1 and ULK2 mRNA was greater in IUGR myoblasts. IL6 and TNFR1 mRNA and c-Fos protein were greater in IUGR semitendinosus muscle, but I𝜿B content was reduced. These results demonstrate intrinsic enhancement of inflammatory signaling and IKK pathways in IUGR myoblasts, which coincided with reduced functional capacity.
A final study assessed stress-responsive mRNA biomarkers in blood. MI at mid-gestation altered blood mRNA expression in pregnant rats and fetuses. Blood TNFR1 was increased in IUGR fetuses, but not when dams received meloxicam. Fetal IL6R and maternal TNFR1 were reduced by IUGR with or without meloxicam. We also designed ddPCR probes/primers to assess stress-responsive transcripts including cytokines/receptors in blood from elephants, cheetahs, and giraffes. These studies demonstrate stress-induced changes in blood transcriptomes of animals, which represent novel stress biomarkers.
Advisor: Dustin Yates