Effect of Genetically Reduced Maternal Myostatin on Late Gestation Maternal, Fetal, and Placental Metabolomes in Mice

Abstract

Myostatin (gene symbol: Mstn) is an autocrine and paracrine inhibitor of muscle growth. Pregnant mice with genetically reduced levels of myostatin give birth to offspring with greater adult muscle mass and bone biomechanical strength. However, maternal myostatin is not detectable in fetal circulations. Fetal growth is dependent on the maternal environment, and the provisioning of nutrients and growth factors by the placenta. Thus, this study examined the effect of reduced maternal myostatin on maternal and fetal serum metabolomes, as well as the placental metabolome. Fetal and maternal serum metabolomes were highly distinct, which is consistent with the role of the placenta in creating a specific fetal nutrient environment. There was no effect from myostatin on maternal glucose tolerance or fasting insulin. In comparisons between pregnant control and Mstn^+/- mice, there were more significantly different metabolite concentrations in fetal serum, at 50, than in the mother's serum at 33, confirming the effect of maternal myostatin reduction on the fetal metabolic milieu. Polyamines, lysophospholipids, fatty acid oxidation, and vitamin C, in fetal serum, were all affected by maternal myostatin reduction.

Keywords: fatty acid oxidation; intrauterine growth restriction; lysophospholipids; metabolism; myostatin; placenta; polyamines; vitamin C.

Figure 1

(a) Maternal pregnancy weights in control (WT) and Mstn^+/− females. (b) Serum triglyceride concentrations in WT and Mstn^+/− mothers and in serum pooled from all the fetuses in each litter, following IPGTT. (c) Intraperitoneal glucose tolerance testing in both pregnant and virgin control and Mstn^+/− females. (d) Maternal fasting insulin concentrations in WT and Mstn^+/− females prior to IPGTT. * p < 0.05 WT pregnant vs. Mstn^+/− virgin at 15 min. (a,b,d) Each symbol represents data from an individual female, and the line represents the group means. (c) Each symbol represents the mean, and the bars represent SEM.

Figure 2

(a) Female and (b) male fetal weights on gestation d17.5, separated by maternal and fetal genotype. (c) Female and (d) male placental weights on gestation d17.5, separated by maternal and fetal genotype. There were no significant differences. Litters from females used in both the IPGTT and metabolomics experiments were used. Each symbol represents the mean weight of all fetuses of the same sex x fetal genotype combination within a single litter and the line represents the mean of all litters.

Figure 3

(a) Principal Component Analysis of metabolomic profiles of maternal and fetal sera in late pregnancy. (b) Principal Component Analysis of metabolomics profiles of wildtype, male placental tissue carried by WT and Mstn^+/− mothers on gestation d17.5. Each symbol represents an individual serum or placental sample.