A comparative study of age-related hearing loss in wild type and insulin-like growth factor I deficient mice

Abstract

Insulin-like growth factor-I (IGF-I) belongs to the family of insulin-related peptides that fulfils a key role during the late development of the nervous system. Human IGF1 mutations cause profound deafness, poor growth and mental retardation. Accordingly, Igf1−/− null mice are dwarfs that have low survival rates, cochlear alterations and severe sensorineural deafness. Presbycusis (age-related hearing loss) is a common disorder associated with aging that causes social and cognitive problems. Aging is also associated with a decrease in circulating IGF-I levels and this reduction has been related to cognitive and brain alterations, although there is no information as yet regarding the relationship between presbycusis and IGF-I biodisponibility. Here we present a longitudinal study of wild type Igf1+/+ and null Igf1−/− mice from 2 to 12 months of age comparing the temporal progression of several parameters: hearing, brain morphology, cochlear cytoarchitecture, insulin-related factors and IGF gene expression and IGF-I serum levels. Complementary invasive and non-invasive techniques were used, including auditory brainstem-evoked response (ABR) recordings and in vivo MRI brain imaging. Igf1−/− null mice presented profound deafness at all the ages studied, without any obvious worsening of hearing parameters with aging. Igf1+/+ wild type mice suffered significant age-related hearing loss, their auditory thresholds and peak I latencies augmenting as they aged, in parallel with a decrease in the circulating levels of IGF-I. Accordingly, there was an age-related spiral ganglion degeneration in wild type mice that was not evident in the Igf1 null mice. However, the Igf1−/− null mice in turn developed a prematurely aged stria vascularis reminiscent of the diabetic strial phenotype. Our data indicate that IGF-I is required for the correct development and maintenance of hearing, supporting the idea that IGF-I-based therapies could contribute to prevent or ameliorate age-related hearing loss.

Insulin Receptor Substrate 2 (IRS2)-Deficient Mice Show Sensorineural Hearing Loss That Is Delayed by Concomitant Protein Tyrosine Phosphatase 1B (PTP1B) Loss of Function

“…These features are similar to those observed in the Igf1 -/-mice (19,20) and also in patients carrying homozygous IGF1 mutations (15,16). Therefore, understanding the role of IRS2 in hearing function is crucial to identify new sites for therapeutic intervention on hearing loss.…”

“…IGF-1 is required for the late differentiation of the cochlear ganglion neurons and thus for the correct innervation of the cochlea (24). Accordingly, the cochlear ganglion of Igf1-null mice presents a significant decrease in the number and size of neurons and hypomyelination (20,22). These data suggest that IGF-1 actions on the innervation of the cochlear ganglia could be mediated by signaling through IRS2.…”

“…Hearing was evaluated by studying the auditory brainstem response (ABR) following standard methods (19,20). Click and 8-to 40-kHz tone burst stimuli were generated with SigGenRP™ software (Tucker-Davis Technologies, Alachua, FL, USA) and presented from 90 to 20 decibel sound pressure level (dB SPL) in 5-10 dB SPL steps.…”

“…Mouse cochleae were processed as reported (20,22 (38,39) was used to estimate the total volume of main cochlear structures, by point counting on target regions identified in systematically sampled sections throughout the cochlea. The interactive test grids and control of the motorized stage were provided by the CAST stereological software package (v.2,3,2,0; Visiopharm).…”

“…Similarly, Igf1 -/-mice exhibit delayed myelination (17,18), severe sensorineural deafness (19,20) and progressive blindness (21). The cochlea of IGF-1-deficient mice presents an abnormal tectorial membrane, increased neuronal apoptosis, poor myelination of nerve fibers (22,23) and impaired activation of protein kinase B (PKB; AKT) and rapid accelerated fibrosarcoma (RAF) kinases (24).…”