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
- 1 Department of Otolaryngology, Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 2 Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 3 Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
- 4 Navy Clinical Medical School, Anhui Medical University, Hefei, China
- 5 Department of Otorhinolaryngology, Head and Neck Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- 6 Institute of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany
- 7 Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai, China
- 8 In Vitro Fertility (IVF) Center Department of Obstetrics and Gynecology, the Sixth Medical Center of PLA General Hospital, Beijing, China
received: December 1, 2019 ; accepted: March 3, 2020 ; published: April 2, 2020 ;https://doi.org/10.18632/aging.102977
How to Cite
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.
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.
AMPK: Adenosine 5’-Monophosphate activated Protein Kinase; ROS: Reactive Oxygen Species; ABR: Auditory Brainstem Response; EP: Endocochlear Potential; CtBP2: Carboxyl-terminal Binding Protein 2; GluR: Glutamate Receptor; IHC: Inner Hair Cell; OHC: Outer Hair Cell; SGN: Spiral Ganglion Neuron; SV: Stria Vascularis; OC: Organ of Corti; 4-HNE: 4-Hydroxynonenal; mTOR: Mammalian Target of Rapamycin; mTORC1: Mammalian Target of Rapamycin Complex 1; JNK: C-Jun N-terminal kinase; Bcl-2: B-Cell Lymphoma 2; Bax: Bcl2-Associated X protein; Bim: Bcl-2 Interacting Mediator of cell death; PTS: Permanent Threshold Shift; NIHL: Noise-Induced Hearing Loss.