Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 36, Pages 17831-17840Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1910962116
Keywords
cardiomyopathy; mechanobiology; troponin; contractility; muscle
Categories
Funding
- National Cancer Institute Cancer Center Support Grant [P30 CA091842]
- Washington University School of Medicine
- St. Louis Children's Hospital [CDI-CORE-2015-505]
- Foundation for Barnes-Jewish Hospital [3770]
- Children's Discovery Institute of Washington University
- Washington University Center for Cellular Imaging [CDI-CORE-2015-505]
- National Institutes of Health [R00HL123623, R01HL141086, T32EB018266]
- March of Dimes Foundation [FY18-BOC-430198]
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Familial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and a major indicator for heart transplant. The disease is frequently caused by mutations of sarcomeric proteins; however, it is not well understood how these molecular mutations lead to alterations in cellular organization and contractility. To address this critical gap in our knowledge, we studied the molecular and cellular consequences of a DCM mutation in troponin-T, Delta K210. We determined the molecular mechanism of Delta K210 and used computational modeling to predict that the mutation should reduce the force per sarcomere. In mutant cardiomyocytes, we found that Delta K210 not only reduces contractility but also causes cellular hypertrophy and impairs cardiomyocytes' ability to adapt to changes in substrate stiffness (e.g., heart tissue fibrosis that occurs with aging and disease). These results help link the molecular and cellular phenotypes and implicate alterations in mechanosensing as an important factor in the development of DCM.
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