title: The Rapamycin-Sensitive Complex of Mammalian Target of Rapamycin Is Essential to Maintain Male Fertility.
abstract: The mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin and its analogs are being increasingly used in solid-organ transplantation. A commonly reported side effect is male subfertility to infertility, yet the precise mechanisms of mTOR interference with male fertility remain obscure. With the use of a conditional mouse genetic approach we demonstrate that deficiency of mTORC1 in the epithelial derivatives of the Wolffian duct is sufficient to cause male infertility. Analysis of spermatozoa from Raptor fl/fl*KspCre mice revealed an overall decreased motility pattern. Both epididymis and seminal vesicles displayed extensive organ regression with increasing age. Histologic and ultrastructural analyses demonstrated increased amounts of destroyed and absorbed spermatozoa in different segments of the epididymis. Mechanistically, genetic and pharmacologic mTORC1 inhibition was associated with an impaired cellular metabolism and a disturbed protein secretion of epididymal epithelial cells. Collectively, our data highlight the role of mTORC1 to preserve the function of the epididymis, ductus deferens, and the seminal vesicles. We thus reveal unexpected new insights into the frequently observed mTORC1 inhibitor side effect of male infertility in transplant recipients.
authors.affiliation: Renal Division, University Medical Center Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs University Freiburg, Freiburg, Germany; Faculty of Biology, Albert-Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schell
authors.affiliation: Renal Division, University Medical Center Freiburg, Freiburg, Germany; Faculty of Neuroanatomy, Albert-Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kretz
authors.affiliation: Renal Division, University Medical Center Freiburg, Freiburg, Germany; Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
authors.affiliation: Renal Division, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Betina
authors.initials: B
authors.lastname: Kiefer
authors.affiliation: Renal Division, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Renal Division, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Sellung
authors.affiliation: Renal Division, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Tillmann
authors.initials: T
authors.lastname: Bork
authors.affiliation: Division of Urology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Leiber
authors.affiliation: Biozentrum Basel, University of Basel, Basel, Switzerland.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.affiliation: Center for Reproductive Medicine and Andrology, University Hospital Münster, Münster, Germany.
authors.forename: Con
authors.initials: C
authors.lastname: Mallidis
authors.affiliation: Center for Reproductive Medicine and Andrology, University Hospital Münster, Münster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schlatt
authors.affiliation: Anatomy III, Cell Biology, Ludwig-Maximillians University Munich, Munich, Germany.
authors.forename: Artur
authors.initials: A
authors.lastname: Mayerhofer
authors.affiliation: Renal Division, University Medical Center Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs University Freiburg, Freiburg, Germany; BIOSS Center for Biological Signalling Studies, Albert-Ludwigs University Freiburg, Freiburg, Germany; Center for Systems Biology (ZBSA), Albert-Ludwigs University Freiburg, Freiburg, Germany. Electronic address: tobias.huber@uniklinik-freiburg.de.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.affiliation: Renal Division, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Grahammer
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D005298:Fertility / Q000187:drug effects*; D008297:Male; D008322:Mammals; D000076222:Mechanistic Target of Rapamycin Complex 1; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000187:drug effects*; D010766:Phosphorylation; D012669:Seminal Vesicles / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus