title: Impact of vitamin C on the cardiometabolic and inflammatory profiles of mice lacking a functional Werner syndrome protein helicase.
abstract: Werner syndrome (WS) is a premature aging disorder caused by mutations in a DNA helicase/exonuclease. Mice lacking the helicase domain of this protein exhibit metabolic abnormalities that are reversed by vitamin C. In this study, we used a targeted metabolomic approach to identify serum metabolites significantly altered in young mutant mice treated with or without vitamin C. We also measured several serum inflammatory and cardiometabolic factors. We show that young mutant mice exhibit an increase in serum hydroxyproline and plasminogen activator inhibitor-1 (PAI-1), markers of cardiovascular diseases and inflammation, before they exhibit morphological anomalies in different tissues. We also observed an increase in three very long chain lysophosphatidylcholines underlying peroxisome perturbation. Vitamin C reversed the concentrations of these metabolites and PAI-1 to wild type values. Transcriptomic analyses on the liver of mutant mice revealed a decrease in the expression of genes involved in fatty acid degradation compared to wild type animals. Vitamin C treatment increased the expression of genes involved in glutathione metabolism and the synthesis of unsaturated fatty acids in these mice. These results show that changes at the transcriptomic level concord with the alterations of several serum metabolites in these mice. Finally, we found that a mislocalization of the Wrn mutant protein in the liver endoplasmic reticulum fraction increased oxidative stress in that cellular compartment. Vitamin C reversed this oxidative stress. To conclude, this study provides novel potential predictive cardiometabolic biomarkers in WS that will allow the assessment of the impact of vitamin C on patients with WS.
authors.affiliation: Centre de recherche du CHU de Québec, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada.
authors.forename: Lucie
authors.initials: L
authors.lastname: Aumailley
authors.affiliation: Quebec Heart and Lung Institute, Faculty of Medicine, Laval University, Quebec, Quebec, Canada.
authors.forename: Marie Julie
authors.initials: MJ
authors.lastname: Dubois
authors.affiliation: Centre de recherche du CHU de Québec, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada.
authors.forename: Chantal
authors.initials: C
authors.lastname: Garand
authors.affiliation: Quebec Heart and Lung Institute, Faculty of Medicine, Laval University, Quebec, Quebec, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Marette
authors.affiliation: Centre de recherche du CHU de Québec, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada. Electronic address: michel.lebel@crchudequebec.ulaval.ca.
authors.forename: Michel
authors.initials: M
authors.lastname: Lebel
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D018925:Chemokines / Q000097:blood*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis; D005978:Glutathione / Q000378:metabolism; D006909:Hydroxyproline / Q000097:blood; D008099:Liver / Q000473:pathology; D008244:Lysophosphatidylcholines / Q000097:blood; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D018384:Oxidative Stress; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D017382:Reactive Oxygen Species / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics*; D013154:Spleen / Q000473:pathology; D059467:Transcriptome / Q000187:drug effects; D014898:Werner Syndrome / Q000188:drug therapy* / Q000235:genetics; D000071657:Werner Syndrome Helicase
chemical_list: D018925:Chemokines; D005231:Fatty Acids, Unsaturated; D008244:Lysophosphatidylcholines; D017395:Plasminogen Activator Inhibitor 1; D017382:Reactive Oxygen Species; D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase; C499253:Wrn protein, mouse; D005978:Glutathione; D001205:Ascorbic Acid; D006909:Hydroxyproline
keywords: Endoplasmic reticulum; Metabolomic; Mouse aging; Transcriptome; Vitamin C; Werner syndrome