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.
View: Text | PDF
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

×

Figure 3

Deletion of mTORC1 in the NSE protects mice against ARHL.

Options: View larger image (or click on image) Download as PowerPoint
Deletion of mTORC1 in the NSE protects mice against ARHL. (A) Mice conta...
(A) Mice containing a floxed Raptor allele were crossed with transgenic mice expressing Cre under the control of the Atoh1 promoter. The resultant Cre-mediated deletion of Raptor exon 6 leads to a frameshift mutation that produces a nonfunctional protein. (B) The tdTomato-positive cells were isolated using FACS. tdTomato-positive hair cells (2.63%) were encircled by the solid line. (C) tdTomato-positive cells were sorted out for Western blot. Western blot analysis of the tdTomato-positive cells revealed a dramatic decrease in Raptor expression and inactivation of mTORC1 (decreased expression of p-S6 and p-P70S6K) in Raptor-cKO/tdTomato mice. The 2 columns with the same label indicate the same sample loaded onto a second well; n ≥ 3 for each group. (D–K) Reduced age-related threshold shifts in Raptor-cKO mice, as measured by either ABR (D and F–H) or DPOAE assessments (E and I–K). Threshold shifts were compared between Raptor-cKO (n ≥ 6) and WT (n ≥ 4) mice at the same time point (9, 12, and 17 months, respectively). The group sizes were as follows: 3 months: n = 4 for control, n = 8 for Raptor-cKO; 9 months: n = 5 for control, n = 8 for Raptor-cKO; 12 months: n = 6 for each group; 17 months: n = 6 for control, n = 8 for Raptor-cKO. Data represent the mean ± SEM. *P < 0.5, **P < 0.01, ***P < 0.001, by 2-tailed Student’s t test.