Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload
- Institute of Genetic and Biomedical Research (IRGB) - National Research Council (CNR), Milan unit, Italy
- IRCCS Humanitas Research Hospital, United States
- King's College London BHF Centre of Research Excellence, United Kingdom
- University of Florence, Italy
- Telethon Institute of Genetics and Medicine (TIGEM), Italy
- IRCCS Humanitas Research Hospital, Italy
- University of California San Diego, United States
- National Research Council, Italy
- University of Muenster, Germany
- King's College London, United Kingdom
Abstract
Myopalladin (MYPN) is a striated muscle-specific immunoglobulin domain-containing protein located in the sarcomeric Z-line and I-band. MYPN gene mutations are causative for dilated (DCM), hypertrophic and restrictive cardiomyopathy. In a yeast two-hybrid screening, MYPN was found to bind to titin in the Z-line, which was confirmed by microscale thermophoresis. Cardiac analyses of MYPN knockout (MKO) mice showed the development of mild cardiac dilation and systolic dysfunction, associated with decreased myofibrillar isometric tension generation and increased resting tension at longer sarcomere lengths. MKO mice exhibited a normal hypertrophic response to transaortic constriction (TAC), but rapidly developed severe cardiac dilation and systolic dysfunction, associated with fibrosis, increased fetal gene expression, higher intercalated disc fold amplitude, decreased calsequestrin-2 protein levels, and increased desmoplakin and SORBS2 protein levels. Cardiomyocyte analyses showed delayed Ca2+ release and reuptake in unstressed MKO mice as well as reduced Ca2+ spark amplitude post-TAC, suggesting that altered Ca2+ handling may contribute to the development of DCM in MKO mice.
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All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.
Article and author information
Author details
Funding
Fondazione Telethon (GGP12282)
- Marie-Louise Bang
Ministero dell'Istruzione, dell'Università e della Ricerca (2010R8JK2X_006)
- Marie-Louise Bang
Ministero della Salute (RF-MUL-2007-666195)
- Marie-Louise Bang
Fondazione Cariplo (2007.5812)
- Marie-Louise Bang
Agenzia Spaziale Italiana (2015-009-R.0)
- Marie-Louise Bang
European Commission (777204)
- Corrado Poggesi
Wellcome Trust (201543/Z/16)
- Mathias Gautel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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 Parliament) and Italy (Council of 22 September 2010; directive from the Italian Ministry of Health) on the protection of animals use for scientific purposes.
Copyright
© 2021, Filomena 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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Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload
eLife 10:e58313.
https://doi.org/10.7554/eLife.58313
