The Mechanisms Of Rapamycin And MTOR Signaling Parthway On Spermatogenesis

Mammalian target of rapamycin(mTOR)is a serine/threonine protein kinase,which is a central regulator of cellular metabolic and is involved in all aspects of cellular fuction.It intergrates with a variety of develpmental and metabolic inputs to regualate growth and metabolism.The mTOR inhibitor rapamycin and its analogs have been widely used in cancer therapy and transplanation.But it also have many side effects,such as insulin resistance and increased onset of diabets.Additionally,the renal-transplant recipients treated with rapamycin lead to gonadal dysfuction and infertility,which prestnted low sperm count and a decrease in motility.Hence,we investigated the role of mTOR in spermatogenesis.Here we show that chronic rapamycin treated mice are sterile and exhibited disrupted spermatogenesis.The sex chromosomes assembles incorrectly,accompanied by disruption of meiotic sex chromosomes inactivation(MSCI)and increased numerous of X-and Y-linked genes,as well as attenuated recruitment of ATR on the XY body.Additionally,chronic rapamycin dramatically reduced piRNAs bulk,which is dependent on decreased mTORC2 signaling,as MILI associated piRNAs are drastically reduced in mTORC2 subunit Rictor knockout testes while remained expressed in mTORCl subunit Raptor knockout testes.After cessation of rapamycin treatment for 2 months,the testes mass and morphology were restored despite having a mild effect on mTORC1 signaling.Collectively these results define an essential role of mTOR in silencing of sex chromosomes and expands the role of mTOR action in maintaining small RNA homeostasis in mouse testes.