SIRT1 facilitates primordial follicle recruitment independent of deacetylase activity through directly modulating Akt1 and mTOR transcription

Abstract

In female mammals, the majority of primordial follicles (PFs) are physiologically quiescent, and only a few of them are activated and enter the growing follicle pool. Specific molecules, such as mammalian target of rapamycin (mTOR) and the serine/threonine kinase Akt (AKT), have been proven to be important for PF activation. However, how the transcription of these genes is regulated is not clear. Although activators of mTOR or AKT have been successfully used to rescue the fertility of patients with premature ovarian insufficiency, the low efficacy and unclear safety profile of these drugs hinder their clinical use in the in vitro activation (IVA) of PFs. Here, sirtuin 1 (SIRT1), an NAD-dependent deacetylase, was demonstrated to activate mouse PFs independent of its deacetylase activity. SIRT1 was prominently expressed in pregranulosa cells (pGCs) and oocytes, and its expression was increased during PF activation. PF activation was achieved by either up-regulating SIRT1 with a specific activator or overexpressing SIRT1. Moreover, SIRT1 knockdown in oocytes or pGCs could significantly suppress PF activation. Further studies demonstrated that SIRT1 enhanced both Akt1 and mTOR expression by acting more as a transcription cofactor, directly binding to the respective gene promoters, than as a deacetylase. Importantly, we explored the potential clinical applications of targeting SIRT1 in IVA via short-term treatment of cultured ovaries from mice and human ovarian tissues to activate PFs by applying the SIRT1 activator resveratrol. RSV-induced IVA could be a candidate strategy to develop more efficient procedures for future clinical treatment of infertility.

Nicotinamide Supplementation during the In Vitro Maturation of Oocytes Improves the Developmental Competence of Preimplantation Embryos: Potential Link to SIRT1/AKT Signaling

“…On the other hand, Riley et al reported that inhibition of AKT significantly affected the normal physiology and hatching of blastocysts [22], while silencing the function of fatty acid synthase, an essential enzyme catalyze biogenesis of fatty acids, negatively influenced the hatching of embryos mainly through the downregulation of AKT [30]. Importantly, the activation of AKT/mTOR signaling in mouse oocytes and primordial follicles following the administration of resveratrol, an SIRT1 activator, was reported [19]. However, endoplasmic reticulum stress-induced SIRT1 upregulation was mediated by PI3K/AKT/GSK3β signaling in non-embryonic cells [45].…”

Expression Regulation and Physiological Role of Transcription Factor FOXO3a During Ovarian Follicular Development

“… Long et al (2019) reported that oocyte-specific SIRT1-overexpressing mice demonstrated an improved follicle reserve and a prolonged ovarian lifespan by continuously activating FOXO3a and suppressing mTOR. Furthermore, SIRT1 can facilitate primordial follicle recruitment through directly modulating PKB and mTOR transcription, independent of deacetylase activity ( Zhang T. et al, 2019 ). High-fat diet-induced obesity may accelerate ovarian follicle development and the rate of follicle loss by activating mTOR and suppressing SIRT1 signaling.…”

lncRNA GAS5 inhibits malignant progression by regulating macroautophagy and forms a negative feedback regulatory loop with the miR‑34a/mTOR/SIRT1 pathway in colorectal cancer

“…Recently, there has been a focus on positive or negative feedback regulations between lncRNAs and their target miRNAs (43). SIRT1 has been reported to activate the mTOR pathway directly in different conditions (23), and notably, GAS5 is one of the downstream targets that is negatively regulated by the mTOR pathway (24). Thus, we examined the effect of mTOR activation or silencing on the GAS5/miR-34a axis and SIRT1 expression in CRC cells.…”

“…Regarding mammalian targets of rapamycin(mTOR), it was found to be involved in regulating macroautophagy activity independent of its enzymatic function based on cumulative evidence. Additionally, it has been reported that SIRT1 can activate the mTOR signaling pathway under different conditions (23). However, some studies have indicated that SIRT1 acts as a negative regulator of mTOR (33).…”

“…The above results indicated that miR-34a participates in regulating GAS5-mediated macroautophagy and maintained CRC cells in an equilibrium state through the mTOR/SIRT1 pathway. More importantly, it has been reported that SIRT1 enhances mTOR expression in different conditions (23), and under conditions in which mTOR activity is high, GAS5 translation is promoted due to the presence of the 5'-TOR sequence. Conversely, when mTOR activity is low, this in turn results in accumulation of GAS5 transcripts (24).…”