Effect of Epidermal Growth Factor-Like Peptides on the Metabolism of In Vitro- Matured Mouse Oocytes and Cumulus Cells1

Oocyte in vitro maturation (IVM) is an assisted reproductive technology that involves the maturation of cumulus-oocyte-complexes (COCs) that are then capable of normal development. We have shown that epidermal growth factor (EGF)-like peptide signalling is perturbed in mouse COCs undergoing IVM when matured with FSH and/or EGF, but supplementation of IVM with EGF-like peptides amphiregulin or epiregulin improves oocyte developmental competence. Here we aimed to determine whether EGF-like peptides regulate COC metabolism. Immature 129/Sv mouse COCs underwent IVM with FSH, EGF, amphiregulin, epiregulin, betacellulin, or no treatment (control). Epiregulin significantly increased intra-oocyte FAD++ and REDOX ratio compared to FSH and control. Amphiregulin and epiregulin significantly increased the proportion of J-aggregates (from JC-1) in oocyte mitochondria compared to control, FSH or EGF, and this coupled with FAD++ and REDOX measures indicates greater mitochondrial activity. There were no differences in glucose consumption, lactate production, or glycolysis between COCs matured with FSH, EGF and EGF-like peptides. COCs matured with EGF or EGF-like peptides exhibited significantly higher mRNA expression of the hexosamine biosynthesis pathway (HBP) rate-limiting enzyme gene Gfpt2, Has2 expression, and global beta-O-linked glycosylation of proteins, compared to control or FSH, suggesting greater HBP activity. Our findings suggest that; (i) EGF-like peptides, particularly epiregulin, induce more oocyte mitochondrial activity than EGF or FSH, and (ii) EGF-like peptides and EGF induce greater HBP activity, enabling more hyaluronic acid synthesis and protein beta-O-linked glycosylation. These metabolic alterations may be a mechanism by which EGF-like peptides increase oocyte developmental competence.Dulama Richani, Melanie L. Sutton-McDowall, Laura A. Frank, Robert B. Gilchrist, and Jeremy G. Thompso