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.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)