Open AccessActivation of Rictor/mTORC2 signaling acts as a pivotal strategy to protect against sensorineural hearing loss
Author(s) -
Xiaolong Fu,
Peipei Li,
Linqing Zhang,
Yuning Song,
Yachun An,
Aizhen Zhang,
Wenwen Liu,
Chao Ye,
Yuan Zhang,
Rongyu Yue,
Xiaoyang Sun,
Renjie Chai,
Haibo Wang,
Jiangang Gao
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2107357119
Subject(s) - mtorc2 , ototoxicity , pi3k/akt/mtor pathway , hearing loss , sirolimus , medicine , sensorineural hearing loss , protein kinase b , pharmacology , cancer research , signal transduction , mtorc1 , biology , cisplatin , microbiology and biotechnology , audiology , chemotherapy
Significance The mechanistic target of rapamycin (mTOR) plays a central role in growth, metabolism, and aging. It is assembled into two multiprotein complexes, namely, mTORC1 and mTORC2. We previously demonstrated the efficacy of sirolimus in ARHL in mice by decreasing mTORC1. However, the aspect of mTORC2 regulation in the cochlea is poorly characterized. Herein, based on pharmacological and genetic interventions, we found that a high dose of sirolimus resulted in severe hearing loss by reducing the mTORC2/AKT signaling pathway in the cochlea. Furthermore, selective activation of mTORC2 could protect against hearing loss induced by acoustic trauma and cisplatin-induced ototoxicity. Hence, the therapeutic activation of mTORC2 in conjunction with decreasing mTORC1 might represent a promising and effective strategy in preventing hearing loss.