PMID- 31693862 OWN - NLM STAT- MEDLINE DCOM- 20200615 LR - 20220623 IS - 1530-6860 (Electronic) IS - 0892-6638 (Linking) VI - 33 IP - 12 DP - 2019 Dec TI - SIRT1 facilitates primordial follicle recruitment independent of deacetylase activity through directly modulating Akt1 and mTOR transcription. PG - 14703-14716 LID - 10.1096/fj.201900782R [doi] AB - 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.-Zhang, T., Du, X., Zhao, L., He, M., Lin, L., Guo, C., Zhang, X., Han, J., Yan, H., Huang, K., Sun, G., Yan, L., Zhou, B., Xia, G., Qin, Y., Wang, C. SIRT1 facilitates primordial follicle recruitment independent of deacetylase activity through directly modulating Akt1 and mTOR transcription. FAU - Zhang, Tuo AU - Zhang T AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. FAU - Du, Xinhua AU - Du X AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. FAU - Zhao, Lihua AU - Zhao L AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. AD - Department of Pathology and Hepatology, The 5th Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China. FAU - He, Meina AU - He M AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. FAU - Lin, Lin AU - Lin L AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. FAU - Guo, Chuanhui AU - Guo C AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. FAU - Zhang, Xinran AU - Zhang X AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. FAU - Han, Jun AU - Han J AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. FAU - Yan, Hao AU - Yan H AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. FAU - Huang, Kun AU - Huang K AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. FAU - Sun, Guanghong AU - Sun G AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. FAU - Yan, Lei AU - Yan L AD - Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China. AD - National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan, China. AD - The Key Laboratory of Reproductive Endocrinology, Shandong University, Ministry of Education, Jinan, China. AD - Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, China. FAU - Zhou, Bo AU - Zhou B AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. FAU - Xia, Guoliang AU - Xia G AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. AD - Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China College of Life Science, Ningxia University, Yinchuan, China. FAU - Qin, YingYing AU - Qin Y AD - Department of Pathology and Hepatology, The 5th Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China. AD - National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan, China. AD - The Key Laboratory of Reproductive Endocrinology, Shandong University, Ministry of Education, Jinan, China. AD - Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, China. AD - Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China. FAU - Wang, Chao AU - Wang C AD - State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191106 PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - EC 2.7.11.1 (Akt1 protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.5.1.- (Sirt1 protein, mouse) RN - EC 3.5.1.- (Sirtuin 1) SB - IM MH - Animals MH - Cells, Cultured MH - Female MH - Mice MH - Mice, Inbred C57BL MH - Mice, Inbred ICR MH - Mice, Inbred NOD MH - Mice, SCID MH - Ovarian Follicle/cytology/*metabolism MH - Promoter Regions, Genetic MH - Protein Binding MH - Proto-Oncogene Proteins c-akt/*genetics/metabolism MH - Sirtuin 1/genetics/*metabolism MH - TOR Serine-Threonine Kinases/*genetics/metabolism MH - *Transcriptional Activation OTO - NOTNLM OT - in vitro activation OT - ovary OT - primordial follicle activation OT - resveratrol EDAT- 2019/11/07 06:00 MHDA- 2020/06/17 06:00 CRDT- 2019/11/07 06:00 PHST- 2019/11/07 06:00 [pubmed] PHST- 2020/06/17 06:00 [medline] PHST- 2019/11/07 06:00 [entrez] AID - 10.1096/fj.201900782R [doi] PST - ppublish SO - FASEB J. 2019 Dec;33(12):14703-14716. doi: 10.1096/fj.201900782R. Epub 2019 Nov 6.