Glycolysis as key regulatory step in FSH-induced rat Sertoli cell proliferation: Role of the mTORC1 pathway

• Published in: Biochimie 2023-11, Vol.214, p.145-156
• Main Authors: Centola, Cecilia Lucia, Dasso, Marina Ercilia, Soria, Julio Daniel, Riera, Maria Fernanda, Meroni, Silvina Beatriz, Galardo, Maria Noel
• Format: Article
• Language: English
• Subjects: Glycolysis; mTORC1; Proliferation; Sertoli cell
• ISSN: 0300-9084; 1638-6183
• DOI: 10.1016/j.biochi.2023.07.007

The definitive number of Sertoli cells (SCs), achieved during the proliferative periods, defines the spermatogenic capacity in adulthood. It is recognized that FSH is the main mitogen targeting SC and that it exerts its action, at least partly, through the activation of the PI3K/Akt/mTORC1 pathway. mTORC1 controls a large number of cellular functions, including glycolysis and cell proliferation. Interestingly, recent evidence revealed that the glycolytic flux might modulate mTORC1 activity and, consequently, cell cycle progression. Although mature SC metabolism has been thoroughly studied, several aspects of metabolism regulation in proliferating SC are still to be elucidated. The objective of this study was to explore whether aerobic glycolysis is regulated by FSH through mTORC1 pathway in proliferating SC, and to assess the involvement of glycolysis in the regulation of SC proliferation. The present study was carried out utilizing 8-day-old rat SC cultures. The results obtained show that FSH enhances glycolytic flux through the induction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and lactate dehydrogenase A (LDHA) in an mTORC1 dependent manner. In addition, PFKFB3 and LDH inhibitors prevent FSH from activating mTORC1 and stimulating SC proliferation and glycolysis, presumably through mTORC1 pathway inhibition. In summary, FSH simultaneously regulates SC proliferation and glycolysis in an mTORC1 dependent manner, and glycolysis seems to cooperate with FSH in the stimulation of both cellular functions through the modulation of the same signalling pathway. Therefore, a positive feedback between the mTORC1 pathway and glycolysis triggered by FSH is hypothesized. A schematic model of the cooperative role of glycolysis in the regulation of Sertoli cell proliferation by FSH through the mTORC1 signalling pathway. FSH upregulates glycolysis and proliferation in an mTORC1-dependent manner by inducing PFKFB3, LDHA, CCND1 and CCND2 expression due to enhanced c-Myc transcriptional activity (red pathway). Simultaneously, the higher glycolytic flux promoted by FSH might lead to the activation of the mTORC1 signalling pathway, which is involved in the upregulation of PFKFB3, LDHA, CCND1 and CCND2 expression trough c-Myc (blue pathway). [Display omitted] •FSH regulates Sertoli cell proliferation and aerobic glycolysis trough mTORC1.•Glycolysis cooperates with FSH in stimulating proliferation and glycolytic flux.•mTORC1 and glycolysis under FSH sti