Mammalian target of rapamycin (mTOR): a central regulator of male fertility?

Abstract

Mammalian target of rapamycin (mTOR) is a central regulator of cellular metabolic phenotype and is involved in virtually all aspects of cellular function. It integrates not only nutrient and energy-sensing pathways but also actin cytoskeleton organization, in response to environmental cues including growth factors and cellular energy levels. These events are pivotal for spermatogenesis and determine the reproductive potential of males. Yet, the molecular mechanisms by which mTOR signaling acts in male reproductive system remain a matter of debate. Here, we review the current knowledge on physiological and molecular events mediated by mTOR in testis and testicular cells. In recent years, mTOR inhibition has been explored as a prime strategy to develop novel therapeutic approaches to treat cancer, cardiovascular disease, autoimmunity, and metabolic disorders. However, the physiological consequences of mTOR dysregulation and inhibition to male reproductive potential are still not fully understood. Compelling evidence suggests that mTOR is an arising regulator of male fertility and better understanding of this atypical protein kinase coordinated action in testis will provide insightful information concerning its biological significance in other tissues/organs. We also discuss why a new generation of mTOR inhibitors aiming to be used in clinical practice may also need to include an integrative view on the effects in male reproductive system.

Keywords:

• mTOR
• Sertoli cells
• spermatogenesis
• male reproduction
• fertility

Disclosure statement

This work was supported by the Portuguese “Fundação para a Ciência e a Tecnologia”—FCT: T.T. Jesus (SFRH/BD/103518/2014); M.G. Alves (IFCT2015 and PTDC/BIM-MET/4712/2014); P.F. Oliveira (IFCT2015 and PTDC/BBB-BQB/1368/2014); CICS-UBI (Pest-C/SAU/UI0709/2014); UMIB (Pest-OE/SAU/UI0215/2014) and co-funded by FEDER funds through the POCI – COMPETE 2020 – Operational Program Competitiveness and Internationalization in Axis I – Strengthening research, technological development, and innovation (Project POCI-01–0145-FEDER-007491) and National Funds by FCT (Project UID/Multi/00709/2013)via Programa Operacional Fatores de Competitividade-COMPETE/QREN & FSE and POPH funds. The funding agencies had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

The authors report no conflicts of interest.

Additional information

Funding

Fundação para a Ciência e a Tecnologia [PTDC/BBB-BQB/1368/2014,PTDC/BIM-MET/4712/2014,Pest-C/SAU/UI0709/2014,Pest-OE/SAU/UI0215/2014,SFRH/BD/103518/2014,SFRH/BPD/108837/2014,SFRH/BPD/80451/2011].