Genomic instability in the naturally and prematurely aged myocardium

F. De Majo, L. Martens, J.C. Hegenbarth, F. Ruhle, M.R. Hamczyk, R.M. Nevado, V. Andres, E. Hilbold, C. Bar, T. Thum, M. de Boer, D.J. Duncker, B. Schroen, A.S. Armand, M. Stoll, L.J. De Windt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Genomic instability, the unresolved accumulation of DNA variants, is hypothesized as one of the contributors to the natural aging process. We assessed the frequency of unresolved DNA damage reaching the transcriptome of the murine myocardium during the course of natural aging and in hearts from four distinct mouse models of premature aging with established aging-related cardiac dysfunctions. RNA sequencing and variant calling based on total RNA sequencing was compared between hearts from naturally aging mice, mice with cardiomyocyte-specific deficiency of Ercc1, a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity, Tert-deficient mice with reduced telomere length, and a mouse model of human Hutchinson- Gilford progeria syndrome (HGPS). Our results demonstrate that no enrichment in variants is evident in the naturally aging murine hearts until 2 y of age from the HGPS mouse model or mice with reduced telomere lengths. In contrast, a dramatic accumulation of variants was evident in Ercc1 cardiomyocyte-specific knockout mice with deficient DNA repair machinery, in mice with reduced mitochondrial antioxidant capacity, and in the intestine, liver, and lung of naturally aging mice. Our data demonstrate that genomic instability does not evidently contribute to naturally aging of the mouse heart in contrast to other organs and support the contention that the endogenous DNA repair machinery is remarkably active to maintain genomic integrity in cardiac cells throughout life.
Original languageEnglish
Article numbere2022974118
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number36
DOIs
Publication statusPublished - 7 Sept 2021

Keywords

  • CANCER
  • DEATH
  • DNA repair&nbsp
  • DNA-DAMAGE
  • EXPRESSION
  • FRAMEWORK
  • LONGEVITY
  • MICE
  • MUTATION
  • NUCLEAR ABNORMALITIES
  • RNA-seq
  • TELOMERE LENGTH
  • aging&nbsp
  • genomic instability&nbsp
  • oxidative stress&nbsp

Fingerprint

Dive into the research topics of 'Genomic instability in the naturally and prematurely aged myocardium'. Together they form a unique fingerprint.

Cite this