Endogenous SIRT3 activity is dispensable for normal hearing recovery after noise exposure in young adult mice

Abstract

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