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Author Spotlight: Investigating the Mechanisms and Inducing Models of Polycystic Ovary Syndrome
Published on: July 5, 2024
Interplay between miR-21 and mTOR signaling in an experimental mouse model of polycystic ovary syndrome
Sibel Demirci Delipinar1, Hakan Ekmekci2, Zeynep Banu Gungor2
1Department of Histology and Embryology, Faculty of Medicine, Biruni University, Istanbul, Turkey. sibell.demirci@gmail.com.
Abstract:
Polycystic ovary syndrome (PCOS), one of the leading causes of anovulatory infertility, is a complex endocrinopathy influenced by environmental factors. Evidence suggests a connection between PCOS and mammalian target of rapamycin (mTOR), a serine/threonine kinase involved in cellular growth, proliferation, and metabolism. MicroRNA-21(miR-21), a key post-transcriptional regulator of ovarian function, is also implicated in follicular development, atresia, and steroidogenesis. This study aimed to investigate the relationship between miR-21 and mTOR in an experimental PCOS mouse model.Forty-two Balb/c female mice (25-day-old) were divided into six groups: Control, SO (PCOS vehicle-control), PCOS, Inhibition, PCOS+Inhibition, and DMSO (mTOR inhibition-vehicle-control. PCOS was induced via subcutaneous injection of dehydroepiandrosterone (6 mg/100 g), and mTOR inhibition was achieved with KU-0063794 (1 mg/100 g). Serum estrogen (E2) and progesterone (P4) levels were measured by ELISA. Ovarian tissues were evaluated histomorphologically and immunohistochemically.Compared with controls, PCOS mice exhibited increased body weight (p < 0.05), elevated serum E2 (p < 0.001), P4 (p < 0.01) and cystic follicles, reduced corpora lutea (p < 0.001), and enhanced mTOR/p-mTOR and PCNA immunoreactivity (p < 0.001). In the PCOS + INH group, mTOR and p-mTOR immunoreactivity were significantly reduced compared with PCOS (p < 0.001), and DHEA-induced weight gain was attenuated; however, E2 remained elevated (p < 0.001) and corpora lutea were not restored (p < 0.001). miR-21 expression was significantly upregulated in both PCOS (p < 0.05)-PCOS + INH (p < 0.001) groups, indicating persistent miR-21 activation despite mTOR inhibition.These findings demonstrate that while mTOR signaling is activated in PCOS and may be pharmacologically suppressed, mTOR inhibition alone is insufficient to normalize steroidogenesis, ovulation, or miR-21 expression, suggesting mTOR-independent regulation of miR-21 in this model.
Insights
Polycystic ovary syndrome (PCOS) involves activated mammalian target of rapamycin (mTOR) signaling. While inhibiting mTOR in a PCOS mouse model reduced some PCOS symptoms, it did not restore ovulation or normalize microRNA-21 (miR-21) levels, suggesting mTOR-independent pathways regulate miR-21.
Area of Science:
- Reproductive Endocrinology
- Molecular Biology
- Biochemistry
Background:
- Polycystic ovary syndrome (PCOS) is a leading cause of anovulatory infertility, characterized by complex endocrine and metabolic dysregulation.
- Mammalian target of rapamycin (mTOR) signaling, crucial for cellular processes, is implicated in PCOS pathogenesis.
- MicroRNA-21 (miR-21) plays a significant role in ovarian function, including follicular development and steroidogenesis, and is linked to PCOS.
Purpose of the Study:
- To investigate the relationship between miR-21 and mTOR signaling in an experimental mouse model of PCOS.
- To evaluate the effects of mTOR inhibition on PCOS-related physiological and molecular changes.
Main Methods:
- A PCOS mouse model was established using dehydroepiandrosterone (DHEA) administration.
- Mice were treated with an mTOR inhibitor (KU-0063794) or vehicle.
- Hormone levels (estrogen, progesterone), ovarian morphology, and protein/microRNA expression (mTOR, p-mTOR, PCNA, miR-21) were analyzed.
Main Results:
- PCOS mice exhibited increased body weight, elevated estrogen and progesterone, cystic follicles, reduced corpora lutea, and enhanced mTOR/p-mTOR and PCNA expression.
- mTOR inhibition partially attenuated DHEA-induced weight gain and reduced mTOR/p-mTOR signaling but did not restore corpora lutea or normalize estrogen levels.
- miR-21 expression was significantly upregulated in PCOS mice, and this upregulation persisted even after mTOR inhibition.
Conclusions:
- mTOR signaling is activated in PCOS and can be pharmacologically inhibited.
- mTOR inhibition alone is insufficient to normalize steroidogenesis, ovulation, or miR-21 expression in this PCOS model.
- These findings suggest that miR-21 regulation in PCOS may involve pathways independent of mTOR signaling.
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