Murine blastocysts generated by in vitro fertilization show increased Warburg metabolism and altered lactate production

Abstract

In vitro fertilization (IVF) has resulted in the birth of over 8 million children. Although most of IVF-conceived children are healthy, several studies suggest an increased risk of altered growth rate, cardiovascular dysfunction, and glucose intolerance in this population compared to naturally conceived children. However, a clear understanding of how embryonic metabolism is affected by culture condition and how embryos reprogram their metabolism is unknown. Here, we studied oxidative stress and metabolic alteration in blastocysts conceived by natural mating or by IVF and culture in physiologic (5%) or atmospheric (20%) oxygen. We found that IVF-generated blastocyst manifest increased reactive oxygen species, oxidative damage to DNA/lipid/proteins, and reduction in glutathione. Metabolic analysis revealed IVF-generated blastocysts display decreased mitochondria respiration and increased glycolytic activity suggestive of enhanced Warburg metabolism. These findings were corroborated by altered intracellular and extracellular pH and increased intracellular lactate levels in IVF-generated embryos. Comprehensive proteomic analysis and targeted immunofluorescence showed reduction of LDH-B and MCT1, enzymes involved in lactate metabolism. Importantly, these enzymes remained downregulated in tissues of adult IVF-conceived mice, suggesting that metabolic alterations in IVF-generated embryos may result in alteration in lactate metabolism. These findings suggest that alterations in lactate metabolism is a likely mechanism involved in genomic reprogramming and could be involved in the developmental origin of health and disease.

A prospective study of the proteome of equine pre‐implantation embryo

“…Additionally, Lee et al. (2022) shed light on the metabolic alterations in murine blastocysts produced through in vitro fertilization, demonstrating changed lactate synthesis and increased Warburg metabolism. Future research on equine embryo culture media should prioritize optimizing mitochondrial metabolism by adjusting sugar and lipid levels.…”

Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism

“…Lactate fuels the spiral mitochondrial reticulum at the base of the sperm head. The event of conception is followed by the influence of lactate on embryonic development ( 17 , 242 ), and subsequently over the lifespan ( 238 ).…”

“…In contrast, neither glucose nor glutamine was able to advance development and ZGA beyond 2C ( 17 ). Of particular interest is histone lactylation, not only for the effects of gene expression in adults, but also in early stages of development ( 242 ).…”