Aging
Navigate
Submit an Article
Priority Research Paper|Volume 12, Issue 7|pp 5590—5611

Down-regulation of AMPK signaling pathway rescues hearing loss in TFB1 transgenic mice and delays age-related hearing loss

Jingjing Zhao1,2,3, Gen Li1,2,3, Xuan Zhao4, Xin Lin5, Yunge Gao1,2,3, Nuno Raimundo6, Geng-Lin Li7, Wei Shang4,8, Hao Wu1,2,3, Lei Song1,2,3
  • 1Department of Otolaryngology, Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • 2Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • 3Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
  • 4Navy Clinical Medical School, Anhui Medical University, Hefei, China
  • 5Department of Otorhinolaryngology, Head and Neck Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
  • 6Institute of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany
  • 7Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai, China
  • 8In Vitro Fertility (IVF) Center Department of Obstetrics and Gynecology, the Sixth Medical Center of PLA General Hospital, Beijing, China
* Equal contribution
Received: December 1, 2019Accepted: March 3, 2020Published: April 2, 2020
https://doi.org/10.18632/aging.102977

Copyright © 2020 Zhao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

AMP-activated protein kinase (AMPK) integrates the regulation of cell growth and metabolism. AMPK activation occurs in response to cellular energy decline and mitochondrial dysfunction triggered by reactive oxygen species (ROS). In aged Tg-mtTFB1 mice, a mitochondrial deafness mouse model, hearing loss is accompanied with cochlear pathology including reduced endocochlear potential (EP) and loss of spiral ganglion neurons (SGN), inner hair cell (IHC) synapses and outer hair cells (OHC). Accumulated ROS and increased apoptosis signaling were also detected in cochlear tissues, accompanied by activation of AMPK. To further explore the role of AMPK signaling in the auditory phenotype, we used genetically knocked out AMPKα1 as a rescue to Tg-mtTFB1 mice and observed: improved ABR wave I, EP and IHC function, normal SGNs, IHC synapses morphology and OHC survivals, with decreased ROS, reduced pro-apoptotic signaling (Bax) and increased anti-apoptotic signaling (Bcl-2) in the cochlear tissues, indicating that reduced AMPK attenuated apoptosis via ROS-AMPK-Bcl2 pathway in the cochlea. To conclude, AMPK hyperactivation causes accelerated presbycusis in Tg-mtTFB1 mice by redox imbalance and dysregulation of the apoptosis pathway. The effects of AMPK downregulation on pro-survival function and reduction of oxidative stress indicate AMPK serves as a target to rescue or relieve mitochondrial hearing loss.