Rs1894720 polymorphism in MIAT increased susceptibility to age-related hearing loss by modulating the activation of miR-29b/SIRT1/PGC-1α signaling.

BACKGROUND: MIAT may be implicated in the pathogenesis of age-related hearing loss (AHL). This study aimed to clarify the effect of a MIAT signaling pathway on the risk of AHL.

METHODS: Terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, auditory brainstem response (ABR) and quantitative hair cell counts were used to compare the hearing functions in different groups of mice. 5,5,6,6-Tetrachloro-1,1,3,3-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) dye method was used to establish the potential association between mitochondrial dysfunction and aging. Real-time polymerase chain reaction, Western blot analysis, computational analysis, and luciferase assay were conducted to establish a myocardial infarction associated transcript (MIAT) signaling pathway, whose role in the pathogenesis of AHL was further validated by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and flow cytometry.

RESULTS: Aged C57BL/6 mice were associated with a more severe level of hair cell loss, while exhibiting a higher ABR threshold at various frequencies as well as a lower percentage of inner/outer hair cells. A reduced mitochondrial membrane potential in the cochleae of aged C57BL/6 mice indicated the presence of mitochondrial dysfunction in these mice. Relative expression of MIAT, Sirtuin1 (SIRT1), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) was downregulated in aged mice, with microRNA-29b (miR-29b) being highly expressed. Also, MIAT binds to miR-29b, an inhibitor of SIRT1 expression. The regulatory relationship among MIAT, miR-29b, and SIRT1 was further validated by comparing the differentiated expression of these factors in cells treated with phosphate-buffered saline + H2 O2, a negative control + H2 O2, MIAT + H2 O2 , or H2 O2  + anti-miR-29b.

CONCLUSION: MIAT could elevate the expression of SIRT1/PGC-1α via downregulating miR-29b. And the downregulated SIRT/PGC-1α increased the incidence of AHL via promoting the apoptosis of cochlear hair cells.