Muscular dystrophy mouse models and congenital sensorineural hearing deficits: Implication of muscle proteins in function of inner ear

Purpose: Sensorineural hearing loss is found in many inherited forms of muscular dystrophy. Hearing loss has also been reported in the X-linked muscular dystrophy mouse model mdx that lacks dystrophin (the protein defective in Duchenne muscular dystrophy (DMD)). We have been investigating non-muscle manifestations of DMD in a panel of mdx mice with allelic mutations of dystrophin and have shown that some non-muscle manifestations are linked to abnormal expression of carboxy terminus isoforms of dystrophin. To determine whether a specific isoform was implicated in the hearing abnormalities, we studied mdx^Cr3 mice with a 3′ mutation of dystrophin and in whom all known dystrophin isoforms are absent. For comparison, we studied the mdx strain with a 5′ mutation of dystrophin and in whom only full-length dystrophin is disrupted. In addition, to investigate other proteins associated with dystrophin we investigated the dy/dy mouse that is defective in laminin expression and has a severe muscular dystrophy phenotype. Laminin interfaces between the extracellular matrix and dystrophin via the transmembrane dystrophin-associated-glycoprotein complex. Methods: Auditory brainstem response (ABR) audiometry to pure tones was used to evaluate cochlear function. 10 mdx, 4 mdxCv3, 6 dy/dy, and 16 age-matched C57BL/6J control mice were studied. Animals were anesthetized and both ears of each mouse were stimulated separately with a closed tube sound delivery system at frequencies of 4,8,16, and 32 kHz. The average threshold for each group was determined for each frequency and statistically compared with a two-way ANOVA to determine differences in auditory function. Results: mdx and mdxCv3 showed no statistical difference in ABR thresholds as compared 13 controls. The dy/dy mice demonstrated elevated auditory thresholds at all frequencies tested. The increasec thresholds ranged from 17 to 25 dB across the four frequencies with p<0.001. Conclusions. Finding normal hearing in the mdx mouse was unexpected and conflicts with work of other investigators (Raynor et al., The Laryngoscope, 107:1053-1056, 1997). It suggests that dystrophin and its carboxy terminus isoforms do not play a critical role in hearing in the mouse. In contrast, our data suggest that laminin is necessary for normal hearing and identifies the dy/dy mouse as a novel model for studying sensorineural hearing loss associated with muscular dystrophy.