Manfrevola Francesco, Mosca Nicola, Mele Vincenza Grazia, Chioccarelli Teresa, Martinez Guillaume, Coutton Charles, Mattia Monica, Pezzullo Mariaceleste, Fasano Silvia, Cobellis Gilda, Potenza Nicoletta, Chianese Rosanna
Department of Experimental Medicine, University of Campania L. Vanvitelli, Naples, Italy.
Department of Environmental, Biological, Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy.
Aging Cell. 2025 Jun;24(6):e70023. doi: 10.1111/acel.70023. Epub 2025 Apr 18.
Male fertility declines during aging. This process mainly affects spermatogonia and Sertoli cells, leading to impaired spermatogenesis and poor-quality sperm production. Circular RNAs (circRNAs) are covalently closed RNA molecules produced by backsplicing. In the field of male reproduction, circRNAs boast great potential in the regulation of spermatogenesis and sperm morpho-functional skills. However, their potential role in age-related male reproductive anomalies remains largely elusive. Here, we analyzed the reproductive phenotype of the aged male mouse experimental model, pointing our attention to a putative functional link between circRNAs and Sertoli cell survival. Our results confirm several testicular age-related defects including: (i) altered morphology of the seminiferous epithelium; (ii) affected spermatogenesis; and (iii) decreased sperm production. In particular, aged spermatozoa (SPZ) were decreased in number in association with low motility and abnormal morphology (sperm head anomalies and tail bents). The expression analysis of selective spermatic circRNAs demonstrated a de-regulated expression profile in Aged versus Young SPZ. Among them, we turned the lens on circAbcb9 as a spermatic circRNA potentially involved in the Sertoli cell senescence pathway via the circRNA/miRNA/mRNA network (ceRNET). Indeed, a significant shutdown of circAbcb9-dependent network associated with a prominent increase in Sertoli cell senescence occurred in Aged testis. Interestingly, circAbcb9 was also expressed in human SPZ at decreased levels in Aged men, suggesting a conserved role. Collectively, our study stimulates greater interest in circRNAs as involved in the molecular mechanisms behind the age-related effect on Sertoli cell survival, also providing new implications for fused protein in sarcoma (FUS) protein in sertolian circRNA biogenesis.
男性生育能力在衰老过程中会下降。这一过程主要影响精原细胞和支持细胞，导致精子发生受损和精子质量下降。环状RNA（circRNAs）是通过反向剪接产生的共价闭合RNA分子。在男性生殖领域，circRNAs在精子发生和精子形态功能调节方面具有巨大潜力。然而，它们在与年龄相关的男性生殖异常中的潜在作用在很大程度上仍不清楚。在此，我们分析了老年雄性小鼠实验模型的生殖表型，将注意力指向circRNAs与支持细胞存活之间的假定功能联系。我们的结果证实了几个与睾丸衰老相关的缺陷，包括：（i）生精上皮形态改变；（ii）精子发生受影响；（iii）精子产量下降。特别是，老年精子数量减少，同时活力低且形态异常（精子头部异常和尾部弯曲）。对选择性精子circRNAs的表达分析表明，老年精子与年轻精子相比表达谱失调。其中，我们聚焦于circAbcb9，它作为一种精子circRNA，可能通过circRNA/miRNA/mRNA网络（ceRNET）参与支持细胞衰老途径。事实上，在老年睾丸中，与支持细胞衰老显著增加相关的circAbcb9依赖性网络显著关闭。有趣的是，circAbcb9在老年男性的人类精子中也有表达，但其水平降低，这表明其作用具有保守性。总的来说，我们的研究激发了人们对circRNAs的更大兴趣，因为它们参与了与年龄相关的支持细胞存活影响背后的分子机制，也为支持细胞circRNA生物发生中的融合蛋白（FUS）蛋白提供了新的启示。
