1. Biochemistry and Chemical Biology
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Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload

  1. Maria Carmela Filomena
  2. Daniel L Yamamoto
  3. Pierluigi Carullo
  4. Roman Medvedev
  5. Andrea Ghisleni
  6. Nicoletta Piroddi
  7. Beatrice Scellini
  8. Roberta Crispino
  9. Francesca D'Autilia
  10. Jianlin Zhang
  11. Arianna Felicetta
  12. Simona Nemska
  13. Simone Serio
  14. Chiara Tesi
  15. Daniele Catalucci
  16. Wolfgang A Linke
  17. Roman Polishchuk
  18. Corrado Poggesi
  19. Mathias Gautel
  20. Marie-Louise Bang  Is a corresponding author
  1. Institute of Genetic and Biomedical Research (IRGB) - National Research Council (CNR), Milan unit, Italy
  2. IRCCS Humanitas Research Hospital, United States
  3. King's College London BHF Centre of Research Excellence, United Kingdom
  4. University of Florence, Italy
  5. Telethon Institute of Genetics and Medicine (TIGEM), Italy
  6. IRCCS Humanitas Research Hospital, Italy
  7. University of California San Diego, United States
  8. National Research Council, Italy
  9. University of Muenster, Germany
  10. King's College London, United Kingdom
Research Article
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Cite this article as: eLife 2021;10:e58313 doi: 10.7554/eLife.58313

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.

Data availability

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

  1. Maria Carmela Filomena

    Department of Biomedicine, Institute of Genetic and Biomedical Research (IRGB) - National Research Council (CNR), Milan unit, Rozzano (Milan), Italy
    Competing interests
    The authors declare that no competing interests exist.
  2. Daniel L Yamamoto

    Department of Biomedicine, Institute of Genetic and Biomedical Research (IRGB) - National Research Council (CNR), Milan unit, Rozzano (Milan), Italy
    Competing interests
    The authors declare that no competing interests exist.
  3. Pierluigi Carullo

    Department of Biomedicine, Institute of Genetic and Biomedical Research (IRGB) - National Research Council (CNR), Milan unit, Rozzano, Italy
    Competing interests
    The authors declare that no competing interests exist.
  4. Roman Medvedev

    Department of Cardiac Surgery, IRCCS Humanitas Research Hospital, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1174-2993
  5. Andrea Ghisleni

    Randall Division of Cell and Molecular Biophysics,, King's College London BHF Centre of Research Excellence, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8456-5903
  6. Nicoletta Piroddi

    Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
    Competing interests
    The authors declare that no competing interests exist.
  7. Beatrice Scellini

    Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
    Competing interests
    The authors declare that no competing interests exist.
  8. Roberta Crispino

    Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (Naples), Italy
    Competing interests
    The authors declare that no competing interests exist.
  9. Francesca D'Autilia

    N/A, IRCCS Humanitas Research Hospital, Rozzano, Italy
    Competing interests
    The authors declare that no competing interests exist.
  10. Jianlin Zhang

    Department of Medicine, University of California San Diego, La Jolla (CA), United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Arianna Felicetta

    IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy
    Competing interests
    The authors declare that no competing interests exist.
  12. Simona Nemska

    N/A, IRCCS Humanitas Research Hospital, Rozzano, Italy
    Competing interests
    The authors declare that no competing interests exist.
  13. Simone Serio

    IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy
    Competing interests
    The authors declare that no competing interests exist.
  14. Chiara Tesi

    Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
    Competing interests
    The authors declare that no competing interests exist.
  15. Daniele Catalucci

    Biomedicine, National Research Council, Pieve Emanuele, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7041-6114
  16. Wolfgang A Linke

    Institute of Physiology II, University of Muenster, Muenster, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0801-3773
  17. Roman Polishchuk

    Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (Naples), Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7698-1955
  18. Corrado Poggesi

    Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
    Competing interests
    The authors declare that no competing interests exist.
  19. Mathias Gautel

    King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  20. Marie-Louise Bang

    Department of Biomedicine, Institute of Genetic and Biomedical Research (IRGB) - National Research Council (CNR), Milan unit, Rozzano (Milan), Italy
    For correspondence
    marie-louise.bang@cnr.it
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8859-5034

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.

Reviewing Editor

  1. W. Glen Pyle, University of Guelph, Canada

Publication history

  1. Received: April 27, 2020
  2. Accepted: September 23, 2021
  3. Accepted Manuscript published: September 24, 2021 (version 1)

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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