Corentin Affortit1,2, François Casas3, Jean-Luc Puel1,2, Marc Lenoir1,2, Sabine Ladrech1,2, Jean-Charles Ceccato1,2, Jérôme Bourien1,2, Carolanne Coyat1,2, Jing Wang4,5,6. 1. INSERM - UMR 1051, Institut des Neurosciences de Montpellier, 80 rue Augustin Fliche, 34295, Montpellier, France. 2. Université de Montpellier, 34000, Montpellier, France. 3. INRA, UMR 866 Dynamique Musculaire et Métabolisme,, 34060, Montpellier, France. 4. INSERM - UMR 1051, Institut des Neurosciences de Montpellier, 80 rue Augustin Fliche, 34295, Montpellier, France. jing.wang@inserm.fr. 5. Université de Montpellier, 34000, Montpellier, France. jing.wang@inserm.fr. 6. ENT Department, CHU Montpellier, 34295, Montpellier, France. jing.wang@inserm.fr.
Abstract
BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: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. RESULTS: 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. CONCLUSIONS: 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 humanTHRA gene polymorphisms and/or mutations and accelerated age-related deafness or some adult-onset syndromic deafness.
Authors: Lily Ng; Emily Cordas; Xuefeng Wu; Kristen R Vella; Anthony N Hollenberg; Douglas Forrest Journal: Endocrinology Date: 2015-08-04 Impact factor: 4.736
Authors: M Knipper; C Bandtlow; L Gestwa; I Köpschall; K Rohbock; B Wiechers; H P Zenner; U Zimmermann Journal: Development Date: 1998-09 Impact factor: 6.868