Tuberous sclerosis complex–mediated mTORC1 overactivation promotes age-related hearing loss
Xiaolong Fu, … , Haibo Wang, Jiangang Gao
Xiaolong Fu, … , Haibo Wang, Jiangang Gao
Published November 1, 2018; First 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 8

Rapamycin treatment prevents the hearing loss phenotype in Tsc1-cKO mice.

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Rapamycin treatment prevents the hearing loss phenotype in Tsc1-cKO mice...
(A) Schematic of rapamycin treatment (1 mg/kg i.p. every other day) to examine its effects on hearing in Tsc1-cKO mice. (B) Immunohistochemistry to detect p-S6 and hematoxylin staining of cochlear sections from Tsc1-cKO mice treated with or without rapamycin. n = 3. Scale bar: 20 μm. (C) SEM images showed that many hair cells disappeared in the middle turn of the cochlea in Tsc1-cKO mice; however, there were no obvious differences between Tsc1-cKO mice injected with rapamycin and WT control mice. n = 3. Scale bars: 10 μm. (D) Cochleograms of Tsc1-cKO mice (n = 8), Tsc1-cKO mice treated with rapamycin starting at P14 (n = 10), and Tsc1-cKO mice treated with rapamycin starting at P30 (n = 10). The cochleograms were recorded in the mice at 5 months of age. Graph shows the percentage loss of OHCs as a function of percentage distance from the apex. (E) Age-related click ABR hearing threshold results for Tsc1-cKO mice (n = 8), Tsc1-cKO mice treated with rapamycin starting at P14 (n = 10), and Tsc1-cKO mice treated with rapamycin starting at P30 (n = 10) at the same time points. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, by 2-tailed Student’s t test or 1-way ANOVA with Holm-Šidák multiple-comparisons test.