Telomere shortening is a hallmark of genetic cardiomyopathies.

Abstract

This study demonstrates that significantly shortened telomeres are a hallmark of cardiomyocytes (CMs) from individuals with end-stage hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) as a result of heritable defects in cardiac proteins critical to contractile function. Positioned at the ends of chromosomes, telomeres are DNA repeats that serve as protective caps that shorten with each cell division, a marker of aging. CMs are a known exception in which telomeres remain relatively stable throughout life in healthy individuals. We found that, relative to healthy controls, telomeres are significantly shorter in CMs of genetic HCM and DCM patient tissues harboring pathogenic mutations: TNNI3, MYBPC3, MYH7, DMD, TNNT2, and TTN Quantitative FISH (Q-FISH) of single cells revealed that telomeres were significantly reduced by 26% in HCM and 40% in DCM patient CMs in fixed tissue sections compared with CMs from age- and sex-matched healthy controls. In the cardiac tissues of the same patients, telomere shortening was not evident in vascular smooth muscle cells that do not express or require the contractile proteins, an important control. Telomere shortening was recapitulated in DCM and HCM CMs differentiated from patient-derived human-induced pluripotent stem cells (hiPSCs) measured by two independent assays. This study reveals telomere shortening as a hallmark of genetic HCM and DCM and demonstrates that this shortening can be modeled in vitro by using the hiPSC platform, enabling drug discovery.

• Authors: Alex C Y Chang, Andrew C H Chang, Anna Kirillova, Koki Sasagawa, Willis Su, Gerhard Weber, Jue Lin, Vittavat Termglinchan, Ioannis Karakikes, Timon Seeger, Alexandra M Dainis, John T Hinson, Jonathan Seidman, Christine E Seidman, John W Day, Euan Ashley, Joseph C Wu, Helen M Blau
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 37 Pg. 9276-9281 (09 11 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 30150400 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2018 the Author(s). Published by PNAS.

Chemical References

• Muscle Proteins

Topics

• Cardiomyopathy, Dilated (genetics, metabolism, pathology)
• Cardiomyopathy, Hypertrophic, Familial (genetics, metabolism, pathology)
• Cell Division
• Female
• Humans
• Induced Pluripotent Stem Cells (metabolism, pathology)
• Male
• Muscle Proteins (genetics, metabolism)
• Mutation
• Telomere Shortening