Tuberous sclerosis complex–mediated mTORC1 overactivation promotes age-related hearing loss
Xiaolong Fu, … , Haibo Wang, Jiangang Gao
Xiaolong Fu, … , Haibo Wang, Jiangang Gao
Published September 24, 2018
Citation Information: J Clin Invest. 2018;128(11):4938-4955. https://doi.org/10.1172/JCI98058.
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Research Article Aging Neuroscience

Tuberous sclerosis complex–mediated mTORC1 overactivation promotes age-related hearing loss

Abstract

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.

Authors

Xiaolong Fu, Xiaoyang Sun, Linqing Zhang, Yecheng Jin, Renjie Chai, Lili Yang, Aizhen Zhang, Xiangguo Liu, Xiaochun Bai, Jianfeng Li, Haibo Wang, Jiangang Gao

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Figure 9

Tsc1-cKO mice exhibit oxidative stress in the organ of Corti.

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Tsc1-cKO mice exhibit oxidative stress in the organ of Corti. (A) Immun...
(A) Immunolabeled 4-HNE (green) and 3-NT (red) staining in the organ of Corti with DAPI staining (blue) in Tsc1-cKO mice was stronger than that in WT controls at P30. n = 3. Scale bars: 20 μm. (B) Quantitative real-time PCR analysis of collected inner hair cells showed that the expression levels of the antioxidant factors Gsr, Glrx, Nqo1, and Gpx2 were significantly decreased, while the levels of the pro-oxidant factors Lpo and Alox15 were significantly increased, in Tsc1-cKO mice compared with WT controls; however, the expression levels of the antioxidant factors Gsr and Glrx were significantly increased, and the levels of the pro-oxidant factors Lpo and Alox15 were significantly increased, in Tsc1-cKO mice (n = 5) injected with rapamycin compared with WT controls (n = 5). (C) Effects of NAC on hair cell survival in Tsc1-cKO mice (n = 5). Scale bar: 20 μm. (D) Effects of NAC on mTORC1 signaling activity. Western blot analysis results are presented as the relative expression in Tsc1-cKO mice with or without NAC treatment (n = 4). (E) Representative senescence-associated β-galactosidase (SA β-gal) staining of the basilar membrane of the cochlea in Tsc1-cKO (n = 3) and WT mice (n = 3) at P40. Scale bar: 20 μm. (F) TEM images of normally appearing OHCs in WT mice and abnormal morphology of OHCs (n = 5) in Tsc1-cKO mice. The cytoplasm of OHCs shows numerous abnormal vacuoles. The cell bodies also show several aberrant structures (red arrow) in Tsc1-cKO mice. Scale bar: 10 μm. Data represent the mean ± SEM. *P < 0.5, **P < 0.01, ***P < 0.001, by 2-tailed Student’s t test.