Age-related endoplasmic reticulum stress represses testosterone synthesis via attenuation of the circadian clock in Leydig cells

内分泌学 未折叠蛋白反应 内科学 昼夜节律 塔普斯加尔金 内质网 每2 生物钟 睾酮(贴片) 衣霉素 生物 间质细胞 细胞生物学 化学 时钟 医学 促黄体激素 激素
作者
Lei Gao,Dengke Gao,Jing Zhang,Cuimei Li,Meina Wu,Yaoyao Xiao,Luda Yang,Tiantian Ma,Xiaoyu Wang,Manhui Zhang,Dan Yang,Tao Pan,Haisen Zhang,Aihua Wang,Yaping Jin,Huatao Chen
出处
期刊:Theriogenology [Elsevier BV]
卷期号:189: 137-149 被引量:16
标识
DOI:10.1016/j.theriogenology.2022.06.010
摘要

Senile animals exhibit a high risk of elevated endoplasmic reticulum (ER) stress, attenuated circadian clock, and impaired steroidogenesis in testes. However, how these three processes are intertwined in mouse Leydig cells remains unclear. In this study, a mouse model of aging and hydrogen peroxide (H2O2)-induced senescent TM3 Leydig cells were used to dissect the connections among ER stress, circadian oscillators, and steroidogenesis in Leydig cells. Additionally, thapsigargin (Tg, 60 nM)/tunicamycin (Tm, 60 ng/mL)-induced ER stress were established to investigate the underlying mechanisms by which ER stress regulated testosterone synthesis via circadian clock-related signaling pathways in TM3 cells and primary Leydig cells. Elevated ER stress, attenuated circadian clock, and diminished steroidogenesis were detected in the testes of aged mice (24-month-old) and H2O2-induced (200 μM) senescent TM3 cells in comparison with their control groups. Tg/Tm-induced ER stress reduced the transcription of the circadian clock and steroidogenic genes in TM3 cells and LH-treated (100 ng/mL) primary Leydig cells. Furthermore, 4-phenylbutyric acid (4-PBA, 1 μM), an inhibitor of ER stress, alleviated the inhibitory effect of Tg-mediated ER stress on Per2:Luc oscillations in primary Leydig cells isolated from mPer2Luc knock-in mice, and attenuated the repressive effect of H2O2-induced or Tg-mediated ER stress on the transcription of circadian clock and steroidogenic genes expression and testosterone synthesis in TM3 cells. Collectively, these data indicate that age-related ER stress represses testosterone synthesis via attenuation of the circadian clock in Leydig cells.
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