IGF-1 Haploinsufficiency Causes Age-Related Chronic Cochlear Inflammation and Increases Noise-Induced Hearing Loss

Adelaida M Celaya,Isabel Varela-Nieto,José M Zubeldia,Carlos Romá-Mateo,Carlos Avendaño,Lourdes Rodríguez-De La Rosa,Jose M Bermúdez-Muñoz,Federico V Pallardó

doi:10.3390/cells10071686

Abstract

Insulin-like growth factor 1 (IGF-1) deficiency is an ultrarare syndromic human sensorineural deafness. Accordingly, IGF-1 is essential for the postnatal maturation of the cochlea and the correct wiring of hearing in mice. Less severe decreases in human IGF-1 levels have been associated with other hearing loss rare genetic syndromes, as well as with age-related hearing loss (ARHL). However, the underlying mechanisms linking IGF-1 haploinsufficiency with auditory pathology and ARHL have not been studied. Igf1-heterozygous mice express less Igf1 transcription and have 40% lower IGF-1 serum levels than wild-type mice. Along with ageing, IGF-1 levels decreased concomitantly with the increased expression of inflammatory cytokines, Tgfb1 and Il1b, but there was no associated hearing loss. However, noise exposure of these mice caused increased injury to sensory hair cells and irreversible hearing loss. Concomitantly, there was a significant alteration in the expression ratio of pro- and anti-inflammatory cytokines in Igf1+/− mice. Unbalanced inflammation led to the activation of the stress kinase JNK and the failure to activate AKT. Our data show that IGF-1 haploinsufficiency causes a chronic subclinical proinflammatory age-associated state and, consequently, greater susceptibility to stressors. This work provides the molecular bases to further understand hearing disorders linked to IGF-1 deficiency.

Highlights

Age-related hearing loss (ARHL) is a disabling pathology that affects one third of the population over 65 years
Human insulin-like growth factor 1 (IGF-1) homozygous deficiency is an ultrarare disease associated with dwarfism, mental retardation, and syndromic sensorineural hearing loss (SNHL) [4]
There is a gradual decrease in IGF-1 and an increase in the generation of pro-oxidative and proinflammatory products that have an impact on tissue homeostasis and longevity [39,45,46]

Summary

Introduction

Age-related hearing loss (ARHL) is a disabling pathology that affects one third of the population over 65 years. Human insulin-like growth factor 1 (IGF-1) homozygous deficiency is an ultrarare disease associated with dwarfism, mental retardation, and syndromic sensorineural hearing loss (SNHL) [4]. IGF-1 heterozygous mutations have not been associated with congenital SNHL yet [5,6,7]. Rare human illnesses such as Laron and Turner syndromes show a close association between low IGF-1 serum levels and progressive SNHL [8,9,10,11]. Circulating IGF-1 levels in mammals undergo a physiological age-related decrease [12,13] that has been associated with cognitive decline and neurodegeneration [14,15], as well as with SNHL [11]

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Conclusion