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Rs1894720 polymorphism in MIAT increased susceptibility to age‐related hearing loss by modulating the activation of miR‐29b/SIRT1/PGC‐1α signaling
Author(s) -
Hao Shaojuan,
Wang Le,
Zhao Kun,
Zhu Xiaodan,
Ye Fanglei
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.27773
Subject(s) - pathogenesis , biology , apoptosis , signal transduction , terminal deoxynucleotidyl transferase , flow cytometry , western blot , endocrinology , microbiology and biotechnology , medicine , tunel assay , immunology , biochemistry , gene
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 + H 2 O 2, a negative control + H 2 O 2, MIAT + H 2 O 2 , or H 2 O 2 + 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.