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Integrated liver and serum proteomics reveal sexual dimorphism and alteration of several immune response proteins in an aging Werner syndrome mouse model

ABSTRACT: Werner syndrome is a progeroid disorder caused by mutations in a protein (Wrn) containing both a DNA exonuclease and DNA helicase domain. In this study, we identified proteins that exhibit abundance differences in the serum and liver tissue of wild type and Wrn mutant mice at four and ten months of age using a label-free Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) approach. Although Wrn mutant mice exhibited fatty liver by the age of ten months, gene ontology analysis on differentially expressed proteins revealed sexual dimorphism. Alterations only in specific immunoglobulin molecules were common biomarkers in the fatty liver and serum of both Wrn mutant females and males with age.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Michel Lebel

PROVIDER: MSV000091632 | MassIVE | Tue Apr 04 09:00:00 BST 2023

REPOSITORIES: MassIVE

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Project description:Werner syndrome (WS) is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for WS is believed to be involved in different aspects of transcription, replication, and/or DNA repair. We generated a mouse model with a deletion in the helicase domain of the murine WRN homologue that recapitulates most of the WS phenotypes including an abnormal hyaluronic acid excretion, higher reactive oxygen species (ROS) levels, increased genomic instability and cancer incidence resulting in a 10-15% decreased life span expectancy. In addition, WS patients and Wrn mutant mice show hallmarks of a metabolic syndrome including premature visceral obesity, hypertriglyceridemia, insulin-resistant diabetes type 2 and associated cardiovascular diseases. In this study, we compared the expression profile of liver tissues from 9 months old Wrn mutant treated with a standard diet supplemented with 0.04% resveratrol and wild type animals fed with standard diet only. Resveratrol is a calorie restriction mimetic. Gene set enrichment analysis of the microarray data indicated that reseveratrol-treated Wrn mutant mice exhibited down-regulation of genes normally decreased in several transgenic mouse models of hepatoma. In addition, resvratrol-treated Wrn mutant mice also exhibited a decrease in the expression of genes involved fatty acid metabolism and PPAR signaling pathways. Resvratrol-treated Wrn mutant mice also increased the expression of genes involved in steroid and cholesterol biosynthesis, xenobiotic metabolisms as well as inflammation. Finally, resveratrol improved insulin-resistance and the hyperglycemia but had no impact on dyslipidemia and mean life span of Wrn mutant mice. Microarray analyses were performed on the liver tissues of 9 months old mice. Four independent biological replicates of this experiment (wild type vs resveratrol treated Wrn helicase mutant mice) were carried out with a dye swap on two replicates of each genotype.

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Integrated liver and serum proteomics reveal sexual dimorphism and alteration of several immune response proteins in an aging Werner syndrome mouse model

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