Activation of AKT/mammalian target of rapamycin signaling in the peripheral blood of women with premature ovarian insufficiency and its correlation with FMR1 expression

Abstract

Background The protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates early follicular activation and follicular pool maintenance in female germline cells. Fragile X mental retardation 1 (FMR1) regulates folliculogenesis and it is variably expressed in patients with Premature Ovary Insufficiency. FMR1 expression is supposed to be linked to AKT/mTOR signaling in an ovarian response dependent manner as demonstrated in recent invitro and invivo studies in the female germline invitro and invivo. Methods We evaluated changes in the expression of AKT/mTOR signaling pathway genes by real time PCR in the peripheral blood of 74 patients with Premature Ovarian Insufficiency and 56 fertile controls and correlated their expression with FMR1 expression. Results Expression of the genes AKT1, TSC2, mTOR, and S6K was significantly more abundant in patients with POI than in the controls. For AKT1, TSC2 and mTOR, gene expression was not affected by FMR1-CGG repeat number in the 5´-untranslated region. FMR1 and S6K expression levels, however, were significantly upregulated in patients with POI and an FMR1 premutation. Independent of a premutation, expression of mTOR, S6K, and TSC2 was significantly correlated with that of FMR1 in all patients. Furthermore, when grouped according to ovarian reserve, this effect remained significant only for mTOR and S6K, with higher significance note in patients with Premature Ovarian Insufficiency than in the controls. Conclusions In Premature ovarian insufficiency patients, activation of AKT/mTOR signaling pathway is remarkable and putatively pathognomonic. Additionally, it seems to be triggered by an FMR1/mTOR/S6K linkage mechanism, most relevant in premutation carriers.

BCAA insufficiency leads to premature ovarian insufficiency via ceramide‐induced elevation of ROS

“…In the past decades, many studies have revealed the nutrient composition of the diet is important for homeostasis. Specifically, it has been reported the amino acid sensing protein mTOR is an important factor in the development of POI (Rehnitz et al , 2022 ; Xu et al , 2022 ). These results suggested that amino acid metabolism might have significant impacts on POI.…”

Aggression Results in the Phosphorylation of ERK1/2 in the Nucleus Accumbens and the Dephosphorylation of mTOR in the Medial Prefrontal Cortex in Female Syrian Hamsters

“…Although it did not reach significance, a trend for an increase in the phosphorylation of ERK1/2 in the medial prefrontal cortex was noted. The phosphorylation of mTOR positively regulates the phosphorylation of the FMRP, the FMRP kinase S6K, and negatively regulates the activity of the FMRP phosphatase PP2Ac [ 33 , 34 , 35 ]. Thus, a transient decrease in the phosphorylation of mTOR may be a novel, non-canonical mechanism by which to induce translational events that induce long-lasting synaptic changes.…”

Aging conundrum: A perspective for ovarian aging

“…The AKT/mTOR signaling pathway controls ovarian folliculogenesis by maintaining the PMF pool, including PMF activation, GC proliferation, and oocyte-GC intercellular communication (175). Studies have shown significant activation of the AKT/ mTOR/S6K signaling pathway in humans with POI (176). Therefore, regulating the AKT/mTOR/S6K signaling pathways, such as AKT activators and mTOR activators, can induce further follicular maturation and development in women with POI (176).…”

“…Studies have shown significant activation of the AKT/ mTOR/S6K signaling pathway in humans with POI (176). Therefore, regulating the AKT/mTOR/S6K signaling pathways, such as AKT activators and mTOR activators, can induce further follicular maturation and development in women with POI (176).…”