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Igf1 haploinsufficiency accelerates age-related hearing loss and increases noise-induced cochlear injury

AutorCelaya, Adelaida M. ; Rodriguez-de la Rosa, Lourdes ; Pulido,Sara; Zubeldia, José M. ; Pallardó, Federico V.; Varela-Nieto, Isabel
Fecha de publicación2016
CitaciónHeAl Conference (2016)
ResumenInsulin growth factor type 1 (IGF-1) is a neurotrophic factor fundamental for the regulation of cochlear development, growth and differentiation. Human IGF-1 deficiency is associated with poor growth rates, mental retardation and syndromic hearing loss (OMIM608747). Equally, Igf1-/- mice are barren dwarfs with poor survival rates and congenital profound deafness. Low levels of IGF-1 are also associated with hearing loss and presbyacusis in related human genetic syndromes. In this work we present the heterozygous Igf1+/- mouse as genetic model of these hearing disorders. The auditory phenotype of young Igf1+/- mice is similar to that of their wild type littermates. However, during ageing genetic haploinsufficiency adds to the physiological age-related decrease in the levels of circulating IGF-1 that fall below a pathological threshold earlier than the wild type mice. IGF-1 levels show an inverse correlation with auditory thresholds. IGF-1 haploinsufficiency accelerates progressive hearing loss and causes increased susceptibility to environmental stressors like noise. Noise exposure causes an irrecoverable increase of auditory thresholds in heterozygous mice, matched by an exacerbated cellular damage in the cochlea, infiltration of Iba1+ cells and apoptosis. At the molecular level, the chronic IGF-1 haploinsufficiency causes a pro-inflammatory state in the cochlea with higher expression of Tgfb1 and Il1b. After noise exposure, the cochlear inflammatory response increases, accompanied by the hyperactivation of stress-related kinases (JNK) in heterozygous mice, which is maintained even a month after damage. Along these alterations, IGF-1 haploinsufficient mice show a defective activation of pro-survival (AKT), antioxidant and anti-inflammatory routes. These data point to IGF1 as a genetic factor contributing to age-related hearing loss.
DescripciónResumen del trabajo presentado a la Hearing Across the Lifespan Conference (HeAl), celebrada en Cernobbio (Italia) del 2 al 4 de junio de 2016.
URIhttp://hdl.handle.net/10261/154163
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