Tuberous sclerosis complex-mediated mTORC1 overactivation promotes age-related hearing loss
Tuberous sclerosis complex-mediated mTORC1 overactivation promotes age-related hearing loss
复制标题
结节性硬化症复合物介导的 mTORC1 过度激活促进年龄相关性听力损失
DOI：
10.1172/jci98058
复制
发表时间：
2018-11-01
影响因子：
15.9
通讯作者：
Gao, Jiangang
中科院分区：
文献类型：
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作者：
Fu, Xiaolong;Sun, Xiaoyang;Gao, Jiangang
在人类和许多品系的小鼠中，年龄相关性听力损失(ARHL)的潜在分子机制尚未完全确定。这种常见的与年龄相关的疾病被认为与氧化应激密切相关。在这里，我们证明了mTORC1信号在衰老小鼠的耳蜗神经感觉上皮(NSE)中被高度和特异地激活，雷帕霉素注射可以预防ARHL。为了进一步研究mTORC1信号在ARHL中的具体作用，我们建立了NSE特异性缺失mTORC1信号调节因子Raptor或TSC1的小鼠模型。猛禽-CKO小鼠发生听力损失的速度比WT仔鼠慢得多。相反，TSC1的缺失会导致耳蜗毛细胞的早期死亡，从而加速听力损失。TSC1-CKO耳蜗表现出氧化应激和抗氧化防御功能受损的特点。雷帕霉素和抗氧化剂N-乙酰半胱氨酸在体内挽救了TSC1-CKO毛细胞的损伤。此外，我们还发现，在耳蜗毛细胞中，过氧化物体是参与mTORC1信号调节的初始信号细胞器。综上所述，我们的发现认为mTORC1信号过度活跃是ARHL的关键原因之一，并提示降低耳蜗毛细胞中mTORC1的活性可能是预防ARHL的潜在策略。
The underlying molecular mechanisms of age-related hearing loss (ARHL) in humans and many strains of mice have not been fully characterized. This common age-related disorder is assumed to be closely associated with oxidative stress. Here, we demonstrate that mTORC1 signaling is highly and specifically activated in the cochlear neurosensory epithelium (NSE) in aging mice, and rapamycin injection prevents ARHL. To further examine the specific role of mTORC1 signaling in ARHL, we generated murine models with NSE-specific deletions of Raptor or Tsc1, regulators of mTORC1 signaling. Raptor-cKO mice developed hearing loss considerably more slowly than WT littermates. Conversely, Tsc1 loss led to the early-onset death of cochlear hair cells and consequently accelerated hearing loss. Tsc1-cKO cochleae showed features of oxidative stress and impaired antioxidant defenses. Treatment with rapamycin and the antioxidant N-acetylcysteine rescued Tsc1-cKO hair cells from injury in vivo. In addition, we identified the peroxisome as the initial signaling organelle involved in the regulation of mTORC1 signaling in cochlear hair cells. In summary, our findings identify overactive mTORC1 signaling as one of the critical causes of ARHL and suggest that reduction of mTORC1 activity in cochlear hair cells may be a potential strategy to prevent ARHL.