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 7

Degeneration of cochlear stereocilia in Tsc1-cKO mice.

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Degeneration of cochlear stereocilia in Tsc1-cKO mice. SEM images of the...
SEM images of the organ of Corti at the middle turn obtained fromTsc1-cKO (B, C, and E–J) and WT (A and D) mice. (A) Both OHCs and IHCs were regular and aligned normally in WT mice at 4 months. (B) OHCs were partially lost in Tsc1-cKO mice at P40. (C) In Tsc1-cKO mice at 4 months, OHCs mostly disappeared, whereas IHCs appeared to be normally regulated along the basilar membrane of the cochlea. (D) The normal morphology of IHCs in the middle turns of the cochlea in WT mice at 4 months. (E) Fused stereocilia (arrowheads) were first observed at 3 months in the middle turn of the cochlea in Tsc1-cKO mice. (F–J) Fused stereocilia (arrowheads) increased in number from 4 months (F) to 8 months (H). Lost IHCs (asterisks) began to appear at 5 months (G) in the middle turn of the cochlea in Tsc1-cKO mice. The middle turn of the cochlea in Tsc1-cKO mice at 8 months retained several IHCs (H–J), which frequently demonstrate long stereocilia (arrows) and fused stereocilia (arrowheads). n = 5 for each group. Scale bars: 10 μm.