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

J Cell Biochem. 2019 Apr;120(4):4975-4986. doi: 10.1002/jcb.27773. Epub 2018 Dec 16.

Abstract

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.

Keywords: MIAT; age-related hearing loss; rs1894720; single-nucleotide polymorphism; sirtuin.

MeSH terms

  • Aged
  • Animals
  • Apoptosis / genetics
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
  • Polymorphism, Single Nucleotide*
  • Presbycusis / blood
  • Presbycusis / genetics*
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • Sirtuin 1 / metabolism*
  • Transfection

Substances

  • MIRN29 microRNA, mouse
  • MIRN29a microRNA, human
  • Miat long non-coding RNA
  • MicroRNAs
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • RNA, Long Noncoding
  • SIRT1 protein, human
  • Sirt1 protein, mouse
  • Sirtuin 1

Supplementary concepts

  • Age-Related Hearing Impairment 1