INSERM - UMR 1051, Institut des Neurosciences de Montpellier, 80 rue Augustin Fliche, 34295, Montpellier, France.
Université de Montpellier, 34000, Montpellier, France.
BMC Biol. 2021 Feb 1;19(1):18. doi: 10.1186/s12915-021-00953-1.
Age-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.
We 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.
These 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.
年龄相关性听力损失（ARHL），也称为老年性聋，是老年人最常见的感觉障碍。然而，耳蜗老化过程并不会均匀地影响所有人，这表明遗传和环境（例如噪声、耳毒性药物）因素及其相互作用可能会影响 ARHL 的发病和严重程度。考虑到甲状腺激素、线粒体活性和听力之间的潜在联系，在这里，我们通过互补的方法，包括体内电生理记录、超微结构评估、生物化学和分子生物学，研究了 p43（核受体 TRα1 的 N 端截断和配体结合形式）在听力功能中的作用，以及 p43 小鼠在衰老过程中维持听力的作用。
我们发现 p43 小鼠在幼年阶段没有明显的听力损失，但这些小鼠出现了过早且更严重的 ARHL，这是由于耳蜗感觉内外毛细胞的丧失和螺旋神经节神经元的退化所致。p43 小鼠的 ARHL 加重与 SIRT1 表达的急剧下降有关，同时还伴有促凋亡 Bax、p53 表达和抗凋亡 Bcl2 表达之间的失衡，以及线粒体功能障碍、氧化应激和炎症过程的增加。最后，p43 小鼠也更容易受到噪声性听力损失的影响。
这些结果首次证明了 p43 在衰老过程中维持听力的必要性，并强调需要探究人类 THRA 基因多态性和/或突变与加速性年龄相关性耳聋或某些成年发病的综合征性耳聋之间的潜在联系。
