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 11

Autophagy in the auditory hair cells is disrupted in Tsc1-cKO mice.

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Autophagy in the auditory hair cells is disrupted in Tsc1-cKO mice. (A) ...
(A) Rapamycin enhanced autophagic flux in the cochleae of Tsc1-cKO mice. Western blotting analysis of LC3 and P62 expression in cochleae of untreated Tsc1-cKO mice and rapamycin-treated Tsc1-cKO mice. Densitometric analysis of the blots showing the ratios of LC3II and P62 to β-actin (n = 3). Values represent means ± SEM. (B) Representative images of GFP-LC3 transgenic mice and Tsc1-cKO/GFP-LC3 transgenic mice with neomycin treatment. Cytosolic GFP was diffuse and uniformly distributed throughout the cytoplasm in hair cells of Tsc1-cKO/GFP-LC3 transgenic mice. In GFP-LC3 transgenic mice, however, punctate GFP was observed. Enlarged images of OHCs outlined by white lines illustrate punctate fluorescence. Images were taken from the middle turn. n = 3. Scale bar: 2 μm. (C) Representative TEM images of autophagic vacuoles in outer hair cells of GFP-LC3 transgenic mice and Tsc1-cKO/GFP-LC3 transgenic mice with neomycin treatment. Enlarged images of OHCs outlined by the red lines indicate autophagic vacuoles in the outer hair cells. n = 3. Scale bar: 2 μm. Data represent the mean ± SEM. **P < 0.01, ***P < 0.001, by 2-tailed Student’s t test.