AMPK is required for uterine receptivity and normal responses to steroid hormones. Issue 6 (May 2020)

• Record Type: Journal Article
• Authors: Griffiths, Richard M; Pru, Cindy A; Behura, Susanta K; Cronrath, Andrea R; McCallum, Melissa L; Kelp, Nicole C; Winuthayanon, Wipawee; Spencer, Thomas E; Pru, James K
• Is Part Of: Reproduction. Volume 159:Issue 6(2020)
• Page Start: 707
• Page End: 717
• Publication Date: 2020-05
• Subjects: Reproduction -- Periodicals; Reproduction -- Molecular aspects -- Periodicals; Reproduction -- Immunological aspects -- Periodicals; Reproduction -- Endocrine aspects -- Periodicals; Fertility -- Periodicals; Human reproduction -- Periodicals; 571.805
• DOI: 10.1530/REP-19-0402
• Languages: English
• ISSNs: 1470-1626

Abstract

Abstract : We previously demonstrated that 5′-AMP-activated protein kinase (AMPK) is essential for normal reproductive functions in female mice. Conditional ablation of Prkaa1 and Prkaa2, genes that encode the α1 and α2 catalytic domains of AMPK, resulted in early reproductive senescence, faulty artificial decidualization, uterine inflammation and fibrotic postparturient endometrial regeneration. We also noted a delay in the timing of embryo implantation in Prkaa1/2 d/d female mice, suggesting a role for AMPK in establishing uterine receptivity. As outlined in new studies here, conditional uterine ablation of Prkaa1/2 led to an increase in ESR1 in the uteri of Prkaa1/2 d/d mice, resulting in prolonged epithelial cell proliferation and retention of E2 -induced gene expression (e.g. Msx1, Muc1, Ltf ) through the implantation window. Within the stromal compartment, stromal cell proliferation was reduced by five-fold in Prkaa1/2 d/d mice, and this was accompanied by a significant decrease in cell cycle regulatory genes and aberrant expression of decidualization marker genes such as Hand2, Bmp2, Fst and Inhbb . This phenotype is consistent with our prior study, demonstrating a failure of the Prkaa1/2 d/d uterus to undergo decidualization. Despite these uterine defects, ovarian function seemed to be normal following ablation of Prkaa1/2 from peri-ovulatory follicles in which ovulation, luteinization and serum progesterone levels were not different on day 5 of pregnancy or pseudopregnancy between Prkaa1/2 fl/fl and Prkaa1/2 d/d mice. These cumulative findings demonstrate that AMPK activity plays a prominent role in mediating several steroid hormone-dependent events such as epithelial cell proliferation, uterine receptivity and decidualization as pregnancy is established.