Age-related elevation of O-GlcNAc causes meiotic arrest in male mice.
Age-related elevation of O-GlcNAc causes meiotic arrest in male mice.
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DOI：
10.1038/s41420-023-01433-x
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发表时间：
2023-05-15
影响因子：
7
通讯作者：
Yao, Bing
中科院分区：
文献类型：
--
作者：
Qian, Zhang;Li, Chuwei;Zhao, Shanmeizi;Zhang, Hong;Ma, Rujun;Ge, Xie;Jing, Jun;Chen, Li;Ma, Jinzhao;Yang, Yang;Zheng, Lu;Zhang, Kemei;He, Zhaowanyue;Xue, Mengqi;Lin, Ying;Jueraitetibaike, Kadiliya;Feng, Yuming;Cao, Chun;Tang, Ting;Sun, Shanshan;Teng, Hui;Zhao, Wei;Yao, Bing
近年来，推迟生育已成为一个严重的社会问题。由于睾丸老化，男性生育能力与年龄呈负相关。精子发生随着年龄的增长而受损，但其分子机制尚不清楚。动态翻译后修饰O-linked N-acetylglucosamine （O-GlcNAc）是一种单糖修饰，已被证明可在多种系统中驱动衰老过程，但尚未对其在睾丸和男性生殖衰老中的作用进行研究。因此，本研究旨在研究O-GlcNAc随年龄的变化，探讨O-GlcNAc在精子发生中的作用。在这里，我们证明了老年小鼠精子发生的下降与O-GlcNAc的升高有关。O-GlcNAc特异性定位于精原细胞和精母细胞的分化，表明其在减数分裂的起始和进展中起着至关重要的作用。通过使用化学抑制剂Thiamet-G禁用O-GlcNAcase (OGA)，模拟年轻小鼠中O-GlcNAc的年龄相关性升高，可以重现老年小鼠精子发生的损害。从机制上讲，睾丸中O-GlcNAc的升高导致突触和重组缺陷导致减数分裂粗线阻滞。此外，使用O-GlcNAc转移酶（OGT）抑制剂降低老年睾丸中的O-GlcNAc可以部分挽救与年龄相关的精子发生障碍。我们的研究结果强调，O-GlcNAc作为一种新的翻译后修饰，参与减数分裂进程，并在衰老过程中驱动精子发生的损害。
In recent years, the postponement of childbearing has become a critical social issue. Male fertility is negatively associated with age because of testis aging. Spermatogenesis is impaired with age, but the molecular mechanism remains unknown. The dynamic posttranslational modification O-linked N-acetylglucosamine (O-GlcNAc), which is a type of monosaccharide modification, has been shown to drive the process of aging in various systems, but it has not yet been investigated in the testis and male reproductive aging. Thus, this study aims to investigate the alteration of O-GlcNAc with aging and explore the role of O-GlcNAc in spermatogenesis. Here, we demonstrate that the decline in spermatogenesis in aged mice is associated with elevation of O-GlcNAc. O-GlcNAc is specifically localized in differentiating spermatogonia and spermatocytes, indicating its crucial role in meiotic initiation and progression. Mimicking the age-related elevation of O-GlcNAc in young mice by disabling O-GlcNAcase (OGA) using the chemical inhibitor Thiamet-G can recapitulate the impairment of spermatogenesis in aged mice. Mechanistically, the elevation of O-GlcNAc in the testis leads to meiotic pachytene arrest due to defects in synapsis and recombination. Furthermore, decreasing O-GlcNAc in aged testes using an O-GlcNAc transferase (OGT) inhibitor can partially rescue the age-related impairment of spermatogenesis. Our results highlight that O-GlcNAc, as a novel posttranslational modification, participates in meiotic progression and drives the impairment of spermatogenesis during aging.
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