Abstract
Age-related hearing loss is a major unresolved public health problem. We have previously elucidated that the activation of cochlear miR-34a is correlated with age-related hearing loss in C57BL/6 mice. A growing body of evidence points that aberrant autophagy promotes cell death during the development of multiple age-related diseases. The aim of this study was to investigate the role of miR-34a-involved disorder of autophagy in the pathogenesis of age-related hearing loss. Our results showed that miR-34a expression was markedly upregulated in the aging cochlea accompanied with impairment of autophagic flux. In the inner ear HEI-OC1 cell line, miR-34a overexpression resulted in an accumulation of phagophores and impaired autophagosome–lysosome fusion, and led to cell death subsequently. Notably, autophagy-related protein 9A (ATG9A), an autophagy protein, was significantly decreased after miR-34a overexpression. Knockdown of ATG9A inhibited autophagy flux, which is similar to the effects of miR-34a overexpression. Moreover, ursodeoxycholic acid significantly rescued miR-34a-induced HEI-OC1 cell death by restoring autophagy activity. Collectively, these findings increase our understanding of the biological effects of miR-34a in the development of age-related hearing loss and highlight miR-34a as a promising therapeutic target for its treatment.
Highlights
Age-related hearing loss (AHL), known as presbycusis, is a complex degenerative disease, afflicting ~ 50% of people by age 65 years and older.[1,2] Hearing loss can impair everyday communication in the elderly, causing loneliness and isolation[3] that make AHL a risk factor for Alzheimer's disease, dementia, depression and other neuropsychiatric diseases.[3,4,5] The detailed mechanisms underlying AHL remain largely unknown
Auditory brainstem response (ABR) measurement was used to monitor the progression of AHL
To determine whether the functional deficits corresponded to the extent and the localization of hair cell loss, hair cell counts were proceeded by cochleae surface preparations and calculation after the ABR measurements
Summary
Age-related hearing loss (AHL), known as presbycusis, is a complex degenerative disease, afflicting ~ 50% of people by age 65 years and older.[1,2] Hearing loss can impair everyday communication in the elderly, causing loneliness and isolation[3] that make AHL a risk factor for Alzheimer's disease, dementia, depression and other neuropsychiatric diseases.[3,4,5] The detailed mechanisms underlying AHL remain largely unknown. Growing studies proved that miRNAs regulate aging in worms (Caenorhabditis elegans), mice and humans.[28,29] Recently, miRNAs were observed in the cochlea and suggested to play an important role in the cochlear pathology.[11,30] Of interest is miR-34a, which has been implicated as a prime candidate inducing senescence, cell cycle arrest, autophagy and cell death.[31,32] Our previous study has confirmed that miR-34a is Received 26.2.17; revised 27.7.17; accepted 02.8.17; Edited by B Zhivotovsky miR-34a impairs autophagy causing hair cell death J Pang et al linked to AHL,[11] but the detailed mechanism is not fully understood. MiR-34a was reported to be pathologically altered and observed as one of the modulators that regulate autophagy in many neurodegenerative diseases.[23,33]
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