Cmah deficiency may lead to age-related hearing loss by influencing miRNA-PPAR mediated signaling pathway.

Juhong Zhang,Anting Xu,Na Wang

doi:10.7717/peerj.6856

Abstract

BackgroundPrevious evidence has indicated CMP-Neu5Ac hydroxylase (Cmah) disruption inducesaging-related hearing loss (AHL). However, its function mechanisms remain unclear. This study was to explore the mechanisms of AHL by using microarray analysis in the Cmah deficiency animal model.MethodsMicroarray dataset GSE70659 was available from the Gene Expression Omnibus database, including cochlear tissues from wild-type and Cmah-null C57BL/6J mice with old age (12 months, n = 3). Differentially expressed genes (DEGs) were identified using the Linear Models for Microarray data method and a protein–protein interaction (PPI) network was constructed using data from the Search Tool for the Retrieval of Interacting Genes database followed by module analysis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery. The upstream miRNAs and potential small-molecule drugs were predicted by miRwalk2.0 and Connectivity Map, respectively.ResultsA total of 799 DEGs (449 upregulated and 350 downregulated) were identified. Upregulated DEGs were involved in Cell adhesion molecules (ICAM1, intercellular adhesion molecule 1) and tumor necrosis factor (TNF) signaling pathway (FOS, FBJ osteosarcoma oncogene; ICAM1), while downregulated DEGs participated in PPAR signaling pathway (PPARG, peroxisome proliferator-activated receptor gamma). A PPI network was constructed, in which FOS, ICAM1 and PPARG were ranked as hub genes and PPARG was a transcription factor to regulate other target genes (ICAM1, FOS). Function analysis of two significant modules further demonstrated PPAR signaling pathway was especially important. Furthermore, mmu-miR-130b-3p, mmu-miR-27a-3p, mmu-miR-27b-3p and mmu-miR-721 were predicted to regulate PPARG. Topiramate were speculated to be a potential small-molecule drug to reverse DEGs in AHL.ConclusionsPPAR mediated signaling pathway may be an important mechanism for AHL. Downregulation of the above miRNAs and use of topiramate may be potential treatment strategies for ALH by upregulating PPARG.

Highlights

Hearing loss is the most common sensorineural deficit in the elderly, and it is estimated that 700 million persons have moderate to profound hearing loss worldwide in 2015, with approximately 30% of them occurred in their seventies and 50% in their eighties (Niklaus, Dirk & Rudolf, 2011; Hjalte, Brännström & Gerdtham, 2012; Quaranta et al, 2015)
799 genes were identified as Differentially expressed genes (DEGs) between WT and CMP-Neu5Ac hydroxylase (Cmah)-null mice based on the threshold of p < 0.05 and |logFC| >0.5, including 449 upregulated and 350 downregulated genes (such as Ucp1, uncoupling protein 1; Acadm, acyl-Coenzyme A dehydrogenase, medium chain)
16 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched for upregulated DEGs, including extracellular matrix (ECM)-receptor interaction (LAMA1, laminin, alpha 1; ITGA5, integrin subunit alpha 5), Cell adhesion molecules (ICAM1, intercellular adhesion molecule 1; ITGA5), Focal adhesion (LAMA1; ITGA5), Cytokine-cytokine receptor interaction (TNFSF13B, tumor necrosis factor (TNF) superfamily member 13b) and TNF signaling pathway (FOS; ICAM1); while 20 KEGG pathways were for downregulated DEGs, including Oxidative phosphorylation (UQCRC2, ubiquinol cytochrome c reductase core protein 2), metabolism related and PPAR signaling pathway (ACADM; PPAR signaling pathways (PPARG), Peroxisome proliferator-activated receptor gamma; UCP1; SCD1, stearoyl-Coenzyme A desaturase 1) (Table 1)

Summary

Introduction

Hearing loss is the most common sensorineural deficit in the elderly, and it is estimated that 700 million persons have moderate to profound hearing loss worldwide in 2015, with approximately 30% of them occurred in their seventies and 50% in their eighties (Niklaus, Dirk & Rudolf, 2011; Hjalte, Brännström & Gerdtham, 2012; Quaranta et al, 2015). AHL animal model experiments confirmed ROS excessively accumulated (Riva et al, 2007), but antioxidant enzymes [such as superoxide dismutase (SOD), reduced glutathione (GSH)/oxidized glutathione (GSSG)] strongly decreased in the cochlear spiral ganglion neurons and hair cells (Coling et al, 2009; Menardo et al, 2012). Oxidative stress may result in mitochondrial DNA mutations (Markaryan, Nelson & Raul Hinojosa, 2009; Yamasoba et al, 2007) and subsequently initiate BCl-2/Bax and caspase-3 mediated apoptotic pathways in the sensory cells and neurons of the cochlea (Du et al, 2015; Huang et al, 2016), which contribute to the development of hearing loss. Expressed genes (DEGs) were identified using the Linear Models for Microarray data method and a protein– protein interaction (PPI) network was constructed using data from the Search Tool for the Retrieval of Interacting Genes database followed by module analysis.

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Conclusion