title: Noise-Induced Loss of Hair Cells and Cochlear Synaptopathy Are Mediated by the Activation of AMPK.
abstract: Noise-induced hearing loss (NIHL) is a major unresolved public health problem. Here, we investigate pathomechanisms of sensory hair cell death and suggest a novel target for protective intervention. Cellular survival depends upon maintenance of energy homeostasis, largely by AMP-activated protein kinase (AMPK). In response to a noise exposure in CBA/J mice, the levels of phosphorylated AMPKα increased in hair cells in a noise intensity-dependent manner. Inhibition of AMPK via siRNA or the pharmacological inhibitor compound C attenuated noise-induced loss of outer hair cells (OHCs) and synaptic ribbons, and preserved auditory function. Additionally, noise exposure increased the activity of the upstream AMPK kinase liver kinase B1 (LKB1) in cochlear tissues. The inhibition of LKB1 by siRNA attenuated the noise-increased phosphorylation of AMPKα in OHCs, reduced the loss of inner hair cell synaptic ribbons and OHCs, and protected against NIHL. These results indicate that noise exposure induces hair cell death and synaptopathy by activating AMPK via LKB1-mediated pathways. Targeting these pathways may provide a novel route to prevent NIHL.
  
  
  
  Our results demonstrate for the first time that the activation of AMP-activated protein kinase (AMPK) α in sensory hair cells is noise intensity dependent and contributes to noise-induced hearing loss by mediating the loss of inner hair cell synaptic ribbons and outer hair cells. Noise induces the phosphorylation of AMPKα1 by liver kinase B1 (LKB1), triggered by changes in intracellular ATP levels. The inhibition of AMPK activation by silencing AMPK or LKB1, or with the pharmacological inhibitor compound C, reduced outer hair cell and synaptic ribbon loss as well as noise-induced hearing loss. This study provides new insights into mechanisms of noise-induced hearing loss and suggests novel interventions for the prevention of the loss of sensory hair cells and cochlear synaptopathy.
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Kayla
authors.initials: K
authors.lastname: Hill
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Hu
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Xianren
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425 shasu@musc.edu.
authors.forename: Su-Hua
authors.identifier: 0000-0002-4425-8586
authors.initials: SH
authors.lastname: Sha
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000161:Acoustic Stimulation; D000429:Alcohol Oxidoreductases; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D056970:Co-Repressor Proteins; D003051:Cochlea / Q000187:drug effects / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006198:Hair Cells, Auditory / Q000378:metabolism / Q000473:pathology*; D006317:Hearing Loss, Noise-Induced / Q000209:etiology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009622:Noise / Q000009:adverse effects*; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000627:therapeutic use; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000502:physiology
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D010750:Phosphoproteins; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; D018091:Receptors, AMPA; C516138:dorsomorphin; D000429:Alcohol Oxidoreductases; C111341:Ctbp2 protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C104722:glutamate receptor ionotropic, AMPA 2
keywords: activation of AMPK; cochlear synaptopathy; noise-induced hearing loss; protection of noise-induced hearing loss; sensory hair cells