Leptin mitigates heat stress-induced senescence in porcine Sertoli cells through modulation of ATM-p53, ERK1/2, and AMPK-mTORC1 signaling.

Abstract

Mammalian spermatogenesis is highly sensitive to temperature fluctuations. Sertoli cells provide essential support for germ cell development and are vulnerable to heat stress-induced cellular damage. Heat stress, known to impair spermatogenesis and induce cellular senescence in various cells, poses a significant threat to male fertility. Given that leptin possesses anti-senescence potential, this study investigates its ability to alleviate heat stress-induced senescence in Sertoli cells and explores the underlying molecular mechanisms. Our results demonstrate that heat stress triggers accumulation of reactive oxygen species (ROS) (P < 0.05), resulting in DNA damage that ultimately drives Sertoli cell senescence. Leptin effectively mitigates senescence through multiple pathways. Specifically, leptin enhances antioxidant enzyme activity (P < 0.05) and inhibits the ATM-p53 pathway, thereby reducing DNA damage. Furthermore, leptin activates the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, reversing G1 phase arrest. Additionally, leptin promotes autophagy via the AMPK-mTORC1 pathway. Concurrently, leptin reduces the activity of senescence-associated β-galactosidase (SA-β-gal) and lessens the release of senescence-associated secretory phenotype (SASP) factors (P < 0.05), thus slowing senescence progression. In conclusion, leptin exerts a protective effect against heat stress-induced senescence in Sertoli cells, offering novel insights into potential strategies for the prevention of heat stress-related male infertility.