Abstract
BackgroundAge-related hearing loss (ARHL), also known as presbycusis, is the most common sensory impairment seen in elderly people. However, the cochlear aging process does not affect people uniformly, suggesting that both genetic and environmental (e.g., noise, ototoxic drugs) factors and their interaction may influence the onset and severity of ARHL. Considering the potential links between thyroid hormone, mitochondrial activity, and hearing, here, we probed the role of p43, a N-terminally truncated and ligand-binding form of the nuclear receptor TRα1, in hearing function and in the maintenance of hearing during aging in p43−/− mice through complementary approaches, including in vivo electrophysiological recording, ultrastructural assessments, biochemistry, and molecular biology.ResultsWe found that the p43−/− mice exhibit no obvious hearing loss in juvenile stages, but that these mice developed a premature, and more severe, ARHL resulting from the loss of cochlear sensory outer and inner hair cells and degeneration of spiral ganglion neurons. Exacerbated ARHL in p43−/− mice was associated with the early occurrence of a drastic fall of SIRT1 expression, together with an imbalance between pro-apoptotic Bax, p53 expression, and anti-apoptotic Bcl2 expression, as well as an increase in mitochondrial dysfunction, oxidative stress, and inflammatory process. Finally, p43−/− mice were also more vulnerable to noise-induced hearing loss.ConclusionsThese results demonstrate for the first time a requirement for p43 in the maintenance of hearing during aging and highlight the need to probe the potential link between human THRA gene polymorphisms and/or mutations and accelerated age-related deafness or some adult-onset syndromic deafness.
Highlights
Age-related hearing loss (ARHL), known as presbycusis, is the most common sensory impairment seen in elderly people
We found that Thyroid hormone receptor alpha (TRα) 1,2 immunoreactivity was present in both the cytoplasm and nuclei of Inner hair cell (IHC), Outer hair cell (OHC), and spiral ganglion neurons (SGNs), but only in the nuclei of their supporting cells in wild-type controls (WT) mice (Additional file 1: Fig. S1AF)
P43−/− mice displayed a reduction in TRα immunoreactivity in the cytoplasm of OHCs and IHCs and, to a lesser extent, in those of SGNs, but not in the nuclei of the sensory neural cells and supporting cells (Additional file 1: Fig. S1G-L), suggesting that p43 deletion did not affect nuclear TRα expression
Summary
Age-related hearing loss (ARHL), known as presbycusis, is the most common sensory impairment seen in elderly people. The cochlear aging process does not affect people uniformly, suggesting that both genetic and environmental (e.g., noise, ototoxic drugs) factors and their interaction may influence the onset and severity of ARHL. Age-related hearing loss (ARHL), or presbycusis, is the hearing loss that occurs gradually in most people, as they age. This type of hearing loss is generally associated with difficulty in speech discrimination, as well as in sound detection and localization, in noise. The age of onset and severity of ARHL is highly variable This is probably due to the complexity of intrinsic (genetic predisposition) and external (e.g., noise, ototoxic drugs) factors and their interaction. The exact mechanisms driving the age-related degeneration of the cochlear structures remain poorly understood
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