Interplay between miR-21 and mTOR signaling in an experimental mouse model of polycystic ovary syndrome

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 (E-2) and progesterone (P-4) 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 E-2 (p < 0.001), P-4 (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, E-2 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.