Accepted manuscript
A functional role for AMPK in female fertility and endometrial regeneration
Reproduction (Cambridge, England), Vol.156(6), pp.501-513
12/2018
Handle:
https://hdl.handle.net/2376/108815
PMCID: PMC6414284
PMID: 30328345
Abstract
Adenosine monophosphate-activated protein kinase (AMPK) is a highly conserved heterotrimeric complex that acts as an intracellular energy sensor. Based on recent observations of AMPK expression in all structures of the female reproductive system, we hypothesized that AMPK is functionally required for maintaining fertility in the female. This hypothesis was tested by conditionally ablating the two catalytic alpha subunits of AMPK, Prkaa1 and Prkaa2, using Pgr-cre mice. After confirming the presence of PRKAA1, PRKAA2 and the active phospho-PRKAA1/2 in the gravid uterus by immunohistochemistry, control (Prkaa1/2 fl/fl ) and double conditional knockout mice (Prkaa1/2 d/d ) were placed into a six-month breeding trial. While the first litter size was comparable between Prkaa1/2 fl/fl and Prkaa1/2 d/d female mice (P = 0.8619), the size of all subsequent litters was dramatically reduced in Prkaa1/2 d/d female mice (P = 0.0015). All Prkaa1/2 d/d female mice experienced premature reproductive senescence or dystocia by the fourth parity. This phenotype manifested despite no difference in estrous cycle length, ovarian histology in young and old nulliparous or multiparous animals, mid-gestation serum progesterone levels or uterine expression of Esr1 or Pgr between Prkaa1/2 fl/fl and Prkaa1/2 d/d female mice suggesting that the hypothalamic-pituitary-ovary axis remained unaffected by PRKAA1/2 deficiency. However, an evaluation of uterine histology from multiparous animals identified extensive endometrial fibrosis and disorganized stromal-glandular architecture indicative of endometritis, a condition that causes subfertility or infertility in most mammals. Interestingly, Prkaa1/2 d/d female mice failed to undergo artificial decidualization. Collectively, these findings suggest that AMPK plays an essential role in endometrial regeneration following parturition and tissue remodeling that accompanies decidualization.
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Details
- Title
- A functional role for AMPK in female fertility and endometrial regeneration
- Creators
- Melissa L McCallum - Department of Animal Sciences, Center for Reproductive Biology, Washington State University, Pullman, Washington, USACindy A Pru - Department of Animal Sciences, Center for Reproductive Biology, Washington State University, Pullman, Washington, USAAndrea R Smith - Department of Animal Sciences, Center for Reproductive Biology, Washington State University, Pullman, Washington, USANicole C Kelp - Department of Animal Sciences, Center for Reproductive Biology, Washington State University, Pullman, Washington, USAMarc Foretz - Université Paris Descartes, Sorbonne Paris Cité, Paris, FranceBenoit Viollet - Université Paris Descartes, Sorbonne Paris Cité, Paris, FranceMin Du - Department of Animal Sciences, Center for Reproductive Biology, Washington State University, Pullman, Washington, USAJames K Pru - Department of Animal Sciences, Center for Reproductive Biology, Washington State University, Pullman, Washington, USA
- Publication Details
- Reproduction (Cambridge, England), Vol.156(6), pp.501-513
- Academic Unit
- School of Molecular Biosciences; Department of Animal Sciences
- Publisher
- England
- Grant note
- P50 HD028934 / NICHD NIH HHS R21 HD086402 / NICHD NIH HHS U54 HD028934 / NICHD NIH HHS R21 OD016564 / NIH HHS P30 HD028934 / NICHD NIH HHS
- Identifiers
- 99900547798401842
- Language
- English
- Resource Type
- Accepted manuscript