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Research Paper|Volume 11, Issue 1|pp 185—208

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

Zhiping Zhu1,2, Qiuling Yue1, Jie Xie1, Shuya Zhang1, Wenxiu He1, Shun Bai1, Suwen Tian1, Yingwen Zhang1, Mengneng Xiong1, Zheng Sun3, Chaoyang Huang4, Yuebei Li5, Ke Zheng1, Lan Ye1
  • 1State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
  • 2The People's Hospital of Gaochun, Nanjing, China
  • 3Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
  • 4Heart and Vascular Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzho, Zhejiang 310003, China
  • 5The First Medical School of Nanjing Medical University, Nanjing, China

* * Equal contribution

Received: September 26, 2018Accepted: December 19, 2018Published: January 13, 2019
https://doi.org/10.18632/aging.101740

Copyright: © 2019 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.