Rapamycin-mediated mTOR inhibition impairs silencing of sex chromosomes and the pachytene piRNA pathway in the mouse testis.

Zhiping Zhu,Mengneng Xiong,Ke Zheng,Qiuling Yue,Suwen Tian,Shuya Zhang,Wenxiu He,Yingwen Zhang,Zheng Sun,Chaoyang Huang,Yuebei Li,Jie Xie,Shun Bai,Lan Ye

doi:10.18632/aging.101740

Abstract

Mechanistic target of rapamycin (mTOR) controls cell growth and metabolism in response to environmental and metabolic signals. Rapamycin robustly extends the lifespan in mammals and has clinical relevance in organ transplantation and cancer therapy but side effects include male infertility. Here, we report that chronic rapamycin treatment causes spermatogenic arrest in adult male mice due to defects in sex body formation and meiotic sex chromosome inactivation (MSCI). Many sex chromosome-linked genes were up-regulated in isolated pachytene spermatocytes from rapamycin-treated mice. RNA-Seq analysis also identified mRNAs encoding the core piRNA pathway components were decreased. Furthermore, rapamycin treatment was associated with a drastic reduction in pachytene piRNA populations. The inhibitory effects of rapamycin on spermatogenesis were partially reversible, with restoration of testis mass and sperm motility within 2 months of treatment cessation. Collectively, we have defined an essential role of mTOR in MSCI and identified a novel function as a regulator of small RNA homeostasis in male germ cells.

Highlights

Mechanistic target of rapamycin is a conserved serine/threonine protein kinase that regulates cell survival and metabolism in response to extra- and intracellular signals that include nutrients, growth factors, cellular energy, and stress. mTOR resides in two structurally and functionally distinct multiprotein complexes, mTORC1 and mTORC2 [1,2,3,4]
To study the potential function of mTOR signaling in male germ cell development, we used chronic rapamycin treatment at approximately the same dose that was used to extend lifespan, and found that rapamycin-mediated prolonged inhibition of mTOR signaling causes male infertility, meiotic defects resulting from disruption in the meiotic silencing of sex chromosomes
ATR is a key mediator of meiotic silencing, and it is a member of the phosphatidylinositol-3 kinase-like kinase (PIKK) family which includes mTOR [49]

Summary

Introduction

Mechanistic target of rapamycin (mTOR) is a conserved serine/threonine protein kinase that regulates cell survival and metabolism in response to extra- and intracellular signals that include nutrients, growth factors, cellular energy, and stress. mTOR resides in two structurally and functionally distinct multiprotein complexes, mTORC1 and mTORC2 [1,2,3,4]. Mechanistic target of rapamycin (mTOR) is a conserved serine/threonine protein kinase that regulates cell survival and metabolism in response to extra- and intracellular signals that include nutrients, growth factors, cellular energy, and stress. The mTORC1 complex requires the mTOR-associated adaptor protein Raptor and activates ribosomal biogenesis and protein translation by phosphorylation of the ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1) [5, 6]. Activation of mTOR signaling has been associated with cancer pathogenesis, prompting investigation of rapamycin and rapalogs for the treatment of cancers [11, 12]. Rapamycin is FDA approved as immunosuppressant, and its analogs Temsirolimus and Everolimus have been approved for the treatment of advanced-stage renal cell carcinoma and Tuberous Sclerosis complex genetic disease, respectively [1]. Whether rapamycin affects meiosis and gem cell development in mammals still remains to be defined

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