1. Genetics and Genomics

Quantitative proteomic analysis of skeletal muscles from wild-type and transgenic mice carrying recessive Ryr1 mutations linked to congenital myopathies

  1. Jan Eckhardt
  2. Alexis Ruiz
  3. Stéphane Koenig
  4. Maud Frieden
  5. Hervé Meier
  6. Alexander Schmidt
  7. Susan Treves  Is a corresponding author
  8. Francesco Zorzato  Is a corresponding author
  1. Basel University Hospital, Switzerland
  2. University of Geneva, Switzerland
  3. University of Basel, Switzerland
https://doi.org/10.7554/eLife.83618
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Cite this article
  1. Jan Eckhardt
  2. Alexis Ruiz
  3. Stéphane Koenig
  4. Maud Frieden
  5. Hervé Meier
  6. Alexander Schmidt
  7. Susan Treves
  8. Francesco Zorzato
(2023)
Quantitative proteomic analysis of skeletal muscles from wild-type and transgenic mice carrying recessive Ryr1 mutations linked to congenital myopathies
eLife 12:e83618.
https://doi.org/10.7554/eLife.83618
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Abstract

Skeletal muscles are a highly structured tissue responsible for movement and metabolic regulation, which can be broadly subdivided into fast and slow twitch muscles with each type expressing common as well as specific sets of proteins. Congenital myopathies are a group of muscle diseases leading to a weak muscle phenotype caused by mutations in a number of genes including RYR1. Patients carrying recessive RYR1 mutations usually present from birth and are generally more severely affected, showing preferential involvement of fast twitch muscles as well as extraocular and facial muscles. In order to gain more insight into the pathophysiology of recessive RYR1-congential myopathies, we performed relative and absolute quantitative proteomic analysis of skeletal muscles from wild-type and transgenic mice carrying p.Q1970fsX16 and p.A4329D RyR1 mutations which were identified in a child with a severe congenital myopathy. Our in-depth proteomic analysis shows that recessive RYR1 mutations not only decrease the content of RyR1 protein in muscle, but change the expression of 1130, 753 and 967 proteins EDL, soleus and extraocular muscles, respectively. Specifically, recessive RYR1 mutations affect the expression level of proteins involved in calcium signaling, extracellular matrix, metabolism and ER protein quality control. This study also reveals the stoichiometry of major proteins involved in excitation contraction coupling and identifies novel potential pharmacological targets to treat RyR1-related congenital myopathies.

Data availability

All data, code, and materials used in the analysis are available in some form to any researcher for purposes of reproducing or extending the analysis. Mass spectrometry data has been deposited to the ProteomeXchange Consortium via the Pride partner repository (http://ebi.ac.uk/pride) with the following access number PXD036789.Project website: http://www.ebi.ac.uk/pride/archive/projects/PXD036789Original western blot figures have been uploaded as a zipped file as source data 1 and 2.

The following data sets were generated

Article and author information

Author details

  1. Jan Eckhardt

    Departments of Biomedicine, Basel University Hospital, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  2. Alexis Ruiz

    Department of Biomedicine, Basel University Hospital, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  3. Stéphane Koenig

    Department of cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  4. Maud Frieden

    Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7135-0874

  5. Hervé Meier

    Departments of Biomedicine, Basel University Hospital, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  6. Alexander Schmidt

    Proteomics Core Facility, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  7. Susan Treves

    Department of Biomedicine, Basel University Hospital, Basel, Switzerland
    For correspondence
    susan.treves@unibas.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0007-9631

  8. Francesco Zorzato

    Department of Biomedicine, Basel University Hospital, Basel, Switzerland
    For correspondence
    fzorzato@usb.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8469-7065

Funding

Swiss National Science Foundation (31003A-184765)

  • Susan Treves

NeRab

  • Susan Treves

RYR1 Foundation

  • Francesco Zorzato

Swiss Muscle Foundation FSRMM

  • Susan Treves

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 experiments involving animals were carried out on 12 weeks old male wild type and dHT mice littermates. Experimental procedures were approved by the Cantonal Veterinary Authority of Basel Stadt (BS Kantonales Veterinäramt Permit numbers 1728). All experiments were performed in accordance with relevant guidelines and regulations.

Copyright

© 2023, Eckhardt 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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  1. Jan Eckhardt
  2. Alexis Ruiz
  3. Stéphane Koenig
  4. Maud Frieden
  5. Hervé Meier
  6. Alexander Schmidt
  7. Susan Treves
  8. Francesco Zorzato
(2023)
Quantitative proteomic analysis of skeletal muscles from wild-type and transgenic mice carrying recessive Ryr1 mutations linked to congenital myopathies
eLife 12:e83618.
https://doi.org/10.7554/eLife.83618

Share this article

https://doi.org/10.7554/eLife.83618

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