title: Specific deletion of AMP-activated protein kinase (α1AMPK) in murine oocytes alters junctional protein expression and mitochondrial physiology.
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.
authors.affiliation: UMR 7247 INRA CNRS Université de Tours Haras Nationaux Physiologie de la Reproduction et des Comportements, 37380, Nouzilly, France; School of Women's and Children's Health, Discipline of Obstetrics and Gynaecology, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bertoldo
authors.affiliation: UMR 7247 INRA CNRS Université de Tours Haras Nationaux Physiologie de la Reproduction et des Comportements, 37380, Nouzilly, France.
authors.forename: Edith
authors.initials: E
authors.lastname: Guibert
authors.affiliation: UMR 7247 INRA CNRS Université de Tours Haras Nationaux Physiologie de la Reproduction et des Comportements, 37380, Nouzilly, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Faure
authors.affiliation: UMR 7247 INRA CNRS Université de Tours Haras Nationaux Physiologie de la Reproduction et des Comportements, 37380, Nouzilly, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Ramé
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: UMR 7247 INRA CNRS Université de Tours Haras Nationaux Physiologie de la Reproduction et des Comportements, 37380, Nouzilly, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dupont
authors.affiliation: UMR 7247 INRA CNRS Université de Tours Haras Nationaux Physiologie de la Reproduction et des Comportements, 37380, Nouzilly, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Froment
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D017630:Connexins / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D005260:Female; D017629:Gap Junctions / Q000378:metabolism*; D006107:Granulosa Cells / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology*; D009865:Oocytes / Q000378:metabolism* / Q000502:physiology; D009866:Oogenesis / Q000502:physiology; D006080:Ovarian Follicle / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D000097006:Gap Junction alpha-4 Protein
chemical_list: D055372:AMP-Activated Protein Kinases; D015820:Cadherins; D017630:Connexins; D000097006:Gap Junction alpha-4 Protein; C548179:Prkaa1 protein, mouse