Noise-induced hearing loss (NIHL) affects millions of people worldwide and presents a large social and personal burden. Pharmacological activation of SIRT3, a regulator of the mitochondrial oxidative stress response, has a protective effect on hearing thresholds after traumatic noise damage in mice. In contrast, the role of endogenously activated SIRT3 in hearing recovery has not been established. Here we tested the hypothesis that SIRT3 is required in mice for recovery of auditory thresholds after a noise exposure that confers a temporary threshold shift (TTS). SIRT3-specific immunoreactivity is present in outer hair cells, around the post-synaptic regions of inner hair cells, and faintly within inner hair cells. Prior to noise exposure, homozygous Sirt3-KO mice have slightly but significantly higher thresholds than their wild-type littermates measured by the auditory brainstem response (ABR), but not by distortion product otoacoustic emissions (DPOAE). Moreover, homozygous Sirt3-KO mice display a significant reduction in the progression of their peak 1 amplitude at higher frequencies prior to noise exposure. After exposure to a single sub-traumatic noise dose that does not permanently reduce cochlear function, compromise cell survival, or damage synaptic structures in wild-type mice, there was no difference in hearing function between the two genotypes, measured by ABR and DPOAE. The numbers of hair cells and auditory synapses were similar in both genotypes before and after noise exposure. These loss-of-function studies complement previously published gain-of-function studies and help refine our understanding of SIRT3's role in cochlear homeostasis under different damage paradigms. They suggest that SIRT3 may promote spiral ganglion neuron function. They imply that cellular mechanisms of homeostasis, in addition to the mitochondrial oxidative stress response, act to restore hearing after TTS. Finally, we present a novel application of a biomedical statistical analysis for identifying changes between peak 1 amplitude progressions in ABR waveforms after damage.
18Occupational noise-induced hearing loss (NIHL) affects millions of people worldwide and presents a large 19 social and personal burden. Some genetic variants in the mitochondrial oxidative stress response correlate 20 strongly with susceptibility to NIHL in both humans and mice. Here we test the hypothesis that SIRT3, a 21 regulator of the mitochondrial oxidative stress response, is required in mice for endogenous recovery of 22 auditory thresholds after a sub-traumatic noise exposure. We expose homozygous Sirt3-KO mice and their 23 wild-type littermates to a noise dose that confers a temporary threshold shift, but is not sufficient to 24 permanently reduce cochlear function, compromise cell survival, or damage synaptic structures. We find no 25 difference in hearing function after recovery from noise exposure between the two genotypes, when measured 26 by either auditory brainstem response (ABR) or distortion product otoacoustic emissions (DPOAE). We show 27 that SIRT3-specific immunoreactivity is present in outer hair cells, around the post-synaptic regions of inner 28 hair cells, and faintly within inner hair cells. Nonetheless, outer hair cells and auditory synapses show no 29 increase in loss after noise exposure in the homozygous Sirt3-KO mouse. These data show that SIRT3-30 dependent processes are not necessary for endogenous hearing recovery after a single, sub-traumatic noise 31 exposure. They demonstrate the existence of cellular mechanisms of cochlear homeostasis in addition to the 32 mitochondrial oxidative stress response. We also present a novel statistical analysis for identifying differences 33 between peak 1 amplitude progressions in ABR waveforms. 34
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.