Abstract
Oogenesis and folliculogenesis are dynamic processes that are regulated by endocrine, paracrine and autocrine signals. These signals are exchanged between the oocyte and the somatic cells of the follicle. Here we analyzed the role of AMP-activated protein kinase (AMPK), an important regulator of cellular energy homeostasis, by using transgenic mice deficient in α1AMPK specifically in the oocyte. We found a decrease of 27% in litter size was observed in ZP3-α1AMPK-/- (ZP3-KO) female mice. Following in vitro fertilization, where conditions are stressful for the oocyte and embryo, ZP3-KO oocytes were 68% less likely to pass the 2-cell stage. In vivo and in cumulus-oocyte complexes, several proteins involved in junctional communication, such as connexin37 and N-cadherin were down-regulated in the absence of α1AMPK. While the two signalling pathways (PKA and MAPK) involved in the junctional communication between the cumulus/granulosa cells and the oocyte were stimulated in control oocytes, ZP3-KO oocytes exhibited only low phosphorylation of MAPK or CREB proteins. In addition, MII oocytes deficient in α1AMPK had a 3-fold lower ATP concentration, an increase in abnormal mitochondria, and a decrease in cytochrome C and PGC1α levels, suggesting perturbed energy production by mitochondria. The absence of α1AMPK also induced a reduction in histone deacetylase activity, which was associated with an increase in histone H3 acetylation (K9/K14 residues). Together, the results of the present study suggest that absence of AMPK, modifies oocyte quality through energy processes and oocyte/somatic cell communication. The limited effect observed in vivo could be partly due to a favourable follicle microenvironment where nutrients, growth factors, and adequate cell interaction were present. Whereas in a challenging environment such as that of in vitro culture following IVF, the phenotype is revealed.
Highlights
Numerous studies have emphasized the importance of adequate nutritional status in maintaining reproductive function
Several dynamic processes that are regulated by endocrine, paracrine and autocrine signals have been shown to be linked with energetic status
We observed that the absence of α1AMPK can directly affect the oocyte and its maternally-derived mitochondria
Summary
Numerous studies have emphasized the importance of adequate nutritional status in maintaining reproductive function. Mitochondria play a key role in cellular energy generation, the control of cell death [5] and the dynamic process of meiosis including DNA reorganization [2]. In the case of diabetes, mitochondria are abnormally distributed around the spindle or in the oocyte cytoplasm [2] For these crucial activities in oocyte maturation, mitochondrial redistribution, activity or dysfunction have been suggested as markers of oocyte quality and are strongly related to fertilization rates and embryo development [2,6]. A protein kinase called AMP-activated protein kinase (AMPK), plays an important role in cellular energy homeostasis and mitochondrial function. We have focused on the consequences on cell communication between oocytes and cumulus cells [20], mitochondrial function [21] and early embryo development following in vitro fertilization. One AMPK activator, called metformin, is currently used as an antidiabetic drug and to treat female infertility associated with insulin resistance
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