Rapamycin ameliorates age-related hearing loss in C57BL/6J mice by enhancing autophagy in the SGNs
Rapamycin ameliorates age-related hearing loss in C57BL/6J mice by enhancing autophagy in the SGNs
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雷帕霉素通过增强 SGN 的自噬来改善 C57BL/6J 小鼠与年龄相关的听力损失
DOI：
10.1016/j.neulet.2022.136493
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发表时间：
2022-01
影响因子：
2.5
通讯作者：
Chunfu Dai
中科院分区：
文献类型：
--
作者：
Hongyan Liu;Feitian Li;Xuanyi Li;Qianru Wu;Chunfu Dai
自噬在神经退行性疾病中起致病作用。然而，自噬在年龄相关性听力损失（ARHL）发病机制中的作用仍然不清楚。使用自然衰老的C57 BL/6 J小鼠来鉴定自噬在ARHL中的作用，并且给予雷帕霉素（mTOR的哺乳动物靶标抑制剂）34周以探索雷帕霉素在ARHL中的潜在治疗作用。我们发现自噬体的数量和微管相关蛋白1轻链3B（LC 3B）的表达随着小鼠年龄的增长而减少。自噬相关蛋白（Atg）Beclin 1和Atg 5的表达以及LC 3-II/I的比例在老年小鼠中减少，而mTOR活性在老年小鼠中逐渐增加。雷帕霉素改善听觉脑干反应（ABR）阈值（在8，12和24 kHz）。进一步的探索表明，螺旋神经节神经元（SGN）密度增加，响应于雷帕霉素的管理。实验组基底回SGNs的凋亡率降低，而自噬活性增加。同时，实验组mTOR活性降低。我们的研究结果表明，与年龄相关的自噬缺陷可能会导致老年SGN的凋亡增加。雷帕霉素通过抑制mTOR激活增强SGN的自噬，从而改善ARHL。靶向自噬的治疗策略可能为ARHL的治疗提供一种潜在的方法。
Autophagy plays a pathogenic role in neurodegenerative disease. However, the involvement of autophagy in the pathogenesis of age-related hearing loss (ARHL) remains obscure. Naturally aged C57BL/6J mice were used to identify the role of autophagy in ARHL, and rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, was administered for 34 weeks to explore the potential therapeutic effect of rapamycin in ARHL. We found that the number of autophagosomes and the expression of microtubule-associated protein 1 light chain 3B (LC3B) decreased as the mice aged. The expression of autophagy-related (Atg) proteins, including Beclin1 and Atg5, and the ratio of LC3-II/I was reduced in aged mice, while mTOR activity in aged mice gradually increased. Rapamycin improved the auditory brainstem response (ABR) threshold (at 8, 12, and 24 kHz). Further exploration demonstrated that spiral ganglion neuron (SGN) density was enhanced in response to administration of rapamycin. The rate of apoptosis in the basal turn SGNs was decreased, whereas autophagy activity was increased in the experimental group. Meanwhile, mTOR activity in the experimental group was decreased. Our findings indicate that age-related deficiency in autophagy may lead to increased apoptosis of aged SGNs. Rapamycin enhances autophagy of SGNs by inhibiting mTOR activation, resulting in amelioration of ARHL. Therapeutic strategy targeting autophagy may provide a potential approach for treating ARHL.
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影响因子：
2.8
作者：
Schettino, Amy E.;Lauer, Amanda M.
通讯作者：
Lauer, Amanda M.
影响因子：
--
作者：
Kamogashira T;Fujimoto C;Yamasoba T
通讯作者：
Yamasoba T
DOI：
10.1042/bj20111451
发表时间：
2012-01-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Lee J;Giordano S;Zhang J
通讯作者：
Zhang J
DOI：
10.18632/aging.101045
发表时间：
2016-09-23
期刊：
Aging
影响因子：
--
作者：
Frisina RD;Ding B;Zhu X;Walton JP
通讯作者：
Walton JP
影响因子：
6.6
作者：
Menardo, Julien;Tang, Yong;Wang, Jing
通讯作者：
Wang, Jing