Ablation of palladin in adult heart causes dilated cardiomyopathy associated with intercalated disc abnormalities
- IRCCS Humanitas Research Hospital, Italy
- Institute of Genetic and Biomedical Research, Italy
- University of California, San Diego, United States
- University of Florence, Italy
- University of North Carolina at Chapel Hill, United States
- Goethe University Hospital, Germany
- University of Münster, Germany
- University G d' Annunzio of Chieti, Italy
Abstract
Palladin (PALLD) belongs to the PALLD/myopalladin (MYPN)/myotilin family of actin-associated immunoglobulin-containing proteins in the sarcomeric Z-line. PALLD is ubiquitously expressed in several isoforms and its longest 200 kDa isoform, predominantly expressed in striated muscle, shows high structural homology to MYPN. MYPN gene mutations are associated with human cardiomyopathies, whereas the role of PALLD in the heart has remained unknown, partly due to embryonic lethality of PALLD knockout mice. In a yeast two-hybrid screening, CARP/Ankrd1 and FHOD1 were identified as novel interaction partners of PALLD's N-terminal region. To study the role of PALLD in the heart, we generated conditional (cPKO) and inducible (cPKOi) cardiomyocyte-specific PALLD knockout mice. While cPKO mice exhibited no pathological phenotype, ablation of PALLD in adult cPKOi mice caused progressive cardiac dilation and systolic dysfunction, associated with reduced cardiomyocyte contractility, intercalated disc abnormalities, and fibrosis, demonstrating that PALLD is essential for normal cardiac function. Double cPKO and MYPN knockout (MKO) mice exhibited a similar phenotype as MKO mice, suggesting that MYPN does not compensate for the loss of PALLD in cPKO mice. Altered transcript levels of MYPN and PALLD isoforms were found in myocardial tissue from human dilated and ischemic cardiomyopathy patients, whereas their protein expression levels were unaltered.
Data availability
All data generated and analysed during this study are included in the manuscript and figure supplements. Source Data files have been provided for all figures.
Article and author information
Author details
Simona Boncompagni
Funding
Fondazione Telethon (GGP12282)
- Marie-Louise Bang
Ministero dell'Università e della Ricerca (2010R8JK2X_006)
- Marie-Louise Bang
Horizon 2020 Framework Programme (777204)
- Corrado Poggesi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Nuno Guimarães-Camboa, Goethe University Frankfurt, Germany
Ethics
Animal experimentation: All animal studies were approved by the Italian Ministry of Health and performed in full compliance with the rules and regulations of the European Union (Directive 2010/63/EU of the European Parlia- ment) and Italy (Council of 22 September 2010; directive from the Italian Ministry of Health) on the protection of animals used for scientific purposes.
Human subjects: Human myocardial biopsies from cardiomyopathy patients were obtained from Leipzig Heart Center, Germany following approval by the institutional review board (protocol #240/16-ek) and signed informed consent from the patients according to the principles of the Declaration of Helsinki. Myocardial biopsies from healthy donors rejected for transplantation were obtained from Careggi University Hospital, Florence, Italy (protocol #2006/0024713; renewed May 2009).
Version history
- Received: March 14, 2022
- Preprint posted: April 30, 2022 (view preprint)
- Accepted: March 15, 2023
- Accepted Manuscript published: March 16, 2023 (version 1)
- Version of Record published: April 3, 2023 (version 2)
Copyright
© 2023, Mastrototaro et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Ablation of palladin in adult heart causes dilated cardiomyopathy associated with intercalated disc abnormalities
eLife 12:e78629.
https://doi.org/10.7554/eLife.78629
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