@article{0c169942b8d24f9b817ce5ada2ddf150,
title = "Disrupted mechanobiology links the molecular and cellular phenotypes in familial dilated cardiomyopathy",
abstract = "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, δK210. We determined the molecular mechanism of δK210 and used computational modeling to predict that the mutation should reduce the force per sarcomere. In mutant cardiomyocytes, we found that δK210 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.",
keywords = "Cardiomyopathy, Contractility, Mechanobiology, Muscle, Troponin",
author = "Clippinger, {Sarah R.} and Cloonan, {Paige E.} and Lina Greenberg and Melanie Ernst and Stump, {W. Tom} and Greenberg, {Michael J.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Stuart Campbell and Francesco Pasqualini for sharing their code for the simulations and sarcomeric structure analysis, respectively. We acknowledge Mike Ostap and Ken Margulies for extremely helpful discussions during the early planning phases of this project. We also acknowledge Drew Braet for technical assistance and Samantha Barrick for assistance with biochemical experiments. We acknowledge the Washington University Institute of Materials Science and Engineering for the use of microfabrication instruments and staff assistance, and we thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital (St. Louis, MO) for the Genome Engineering and Induced Pluripotent Stem Cell Center, which provided the genome editing service (National Cancer Institute Cancer Center Support Grant P30 CA091842). Confocal microscopy was performed through the Washington University Center for Cellular Imaging supported by Washington University School of Medicine, The Children{\textquoteright}s Discovery Institute of Washington University and St. Louis Children{\textquoteright}s Hospital (CDI-CORE-2015-505), and the Foundation for Barnes- Funding Information: Jewish Hospital (3770). Exome sequencing was performed by the McDonnell Genome Institute. Funding for this project was provided by a pilot grant from the Children{\textquoteright}s Discovery Institute of Washington University and St. Louis Children{\textquoteright}s Hospital, the Washington University Center for Cellular Imaging (CDI-CORE-2015-505), the National Institutes of Health (R00HL123623 and R01HL141086 [to M.J.G.]; T32EB018266 [to S.R.C.]), and the March of Dimes Foundation (FY18-BOC-430198 [to M.J.G.]). Publisher Copyright: {\textcopyright} 2019 National Academy of Sciences. All rights reserved.",
year = "2019",
month = sep,
day = "3",
doi = "10.1073/pnas.1910962116",
language = "English",
volume = "116",
pages = "17831--17840",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "36",
}