Melatonin regulates the activities of ovary and delays the fertility decline in female animals via MT1/AMPK pathway

Abstract

Female fertility irreversibly declines with aging, and this is primarily associated with the decreased quality and quantity of oocytes. To evaluate whether a long‐term of melatonin treatment would improve the fertility of aged mice, different concentrations of melatonin (10−3, 10−5, 10−7 mol/L) were supplemented into drinking water. Melatonin treatments improved the litter sizes of mice at the age of 24 weeks. Mice treated with 10−5 mol/L melatonin had the largest litter size among other concentrations. At this optimal concentration, melatonin not only significantly increased the total number of oocytes but also their quality, having more oocytes with normal morphology that could generate more blastocyst after in vitro fertilization in melatonin (10−5 mol/L)‐treated group than that in the controls. When these blastocysts were transferred to recipients, the litter size was also significantly larger in melatonin treated mice than that in controls. The increases in TAOC and SOD level and decreases in MDA were detected in ovaries and uterus from melatonin‐treated mice compared to the controls. Melatonin reduced ROS level and maintained mitochondrial membrane potential in the oocytes cultured in vitro. Mechanistically studies revealed that the beneficial effects of melatonin on oocytes were mediated by MT1 receptor and AMPK pathway. Thereafter, MT1 knocking out (MT1‐KO) were generated and shown significantly reduced number of oocytes and litter size. The expression of SIRT1, C‐myc, and CHOP were downregulated in the ovary of MT1‐KO mice, but SIRT1 and p‐NF‐kB protein level were elevated in response to disturbed redox balance. The results have convincingly proven that melatonin administration delays ovary aging and improves fertility in mice via MT1/AMPK pathway.

Identification of Loci and Pathways Associated with Heifer Conception Rate in U.S. Holsteins

“…Some of the differentially expressed genes have functions relating to fertility through cellular signaling and regulation of the immune system ( PLCB1, PIK3R1, EPHA3 and CD109 ) or embryonic development ( TIAM1 and SYNE1 ). Others had functions relating to cellular adhesion ( ABLIM3, CADPS, MEG3, SDK2, STC1 and STX16 ), DNA binding and repair ( AHDC1 and POLD3 ) , cellular signaling events ( DCP1A, FNIP2, PIK3R1, PKHD1, PLCB1 and NTRK2 ) and metabolism ( FHIT ) [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. Unfortunately, some of the differentially expressed candidate gene functions are still uncharacterized (CHD9, KIAA0825, MAP6, PRKG1, RAB3C, ROBO1, UPK1B and ZCCHC14) .…”

Continuous treatment with cisplatin induces the oocyte death of primordial follicles without activation

“…Multiple studies have indicated that melatonin grants protective effects on ovarian follicles against the toxicity induced by gonadotoxic agents such as palmitic acid (PA), Di (2-Ethylhexyl) phthalate, and nicotine. [39][40][41][42] Melatonin's proposed protective benefits are based on documentation of inhibition of ER stress, reduction of reactive oxygen species (ROS) levels, and inhibition of apoptosis. Previous literature 26,27 indicated that melatonin significantly decreased the cisplatin-mediated phosphorylation of PTEN, AKT, and translocation of FOXO3a from the nucleus to cytoplasm in primordial oocytes, blocking the activation of primordial follicles in the mouse ovary.…”

SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

“…In our work, we first confirmed the expression of melatonin receptor MT1 in both primary and immortalized microglia. MT1 is coupled to Gi and Gq proteins, and its activation inhibits the formation of cyclic AMP, activates AMP-activated protein kinase (AMPK) signaling, and inhibits phospho-CREB and protein-kinase A signaling [55][56][57]. This isoform, in particular, was here chosen because of its known involvement in the neuroprotective actions of melatonin, as from experimental models of newborn hypoxic-ischemic brain injury [17].…”