Disruption of mitochondrial malate-aspartate shuttle activity in mouse blastocysts impairs viability and fetal growth.
The nutrient requirements and metabolic pathways used by the developing embryo transition from predominantly pyruvate during early cleavage stages to glucose at the blastocyst; however, the complexities involved in the regulation of metabolism at different developmental stages are not clear. The aims of this study were to examine the role of the malate-aspartate shuttle (MAS) in nutrient metabolism pathways in the developing mouse blastocyst and the consequences of impaired metabolism on embryo viability and fetal and placental growth. Eight-cell-stage mouse embryos were cultured in the presence of the MAS inhibitor amino-oxyacetate, with or without pyruvate as an energy substrate in the media. When the MAS was inhibited, the rate of glycolysis and lactate production was significantly elevated and glucose uptake reduced, relative to control cultured embryos in the presence of pyruvate. Despite these changes in embryo metabolism, this did not influence development to the blastocyst stage, but it did reduce the number of inner cell mass and trophectoderm cells. When these embryos were transferred to psuedopregnant females, inhibition of the MAS significantly reduced the proportion of embryos that implanted and developed into fetuses on Day 18 of pregnancy. Finally, fetal growth was reduced while placental weight was maintained, leading to a decreased fetal:placental weight ratio relative to control embryos. These results suggest that impaired metabolism of glucose in the blastocyst via the MAS alters the ability of the embryos to implant and form a pregnancy and leads to reduced fetal weight, likely via altered placental development and function.
Mitchell
Megan
M
Research Centre for Reproductive Health, University of Adelaide, Adelaide, South Australia 5005, Australia. megan.mitchell@adelaide.edu.au
Cashman
Kara S
KS
Gardner
David K
DK
Thompson
Jeremy G
JG
Lane
Michelle
M
D000625:Aminooxyacetic Acid / Q000494:pharmacology*; D000818:Animals; D024443:Aspartate Aminotransferase, Cytoplasmic / Q000037:antagonists & inhibitors / Q000378:metabolism; D001224:Aspartic Acid / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001755:Blastocyst / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005328:Fetal Viability / Q000187:drug effects*; D008291:Malate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008293:Malates / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy
D004791:Enzyme Inhibitors; D008293:Malates; D000625:Aminooxyacetic Acid; D001224:Aspartic Acid; C030298:malic acid; D008291:Malate Dehydrogenase; D024443:Aspartate Aminotransferase, Cytoplasmic