1. Computational and Systems Biology

Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function

  1. Jeffrey Molendijk
  2. Ronnie Blazev
  3. Richard J Mills
  4. Yaan-Kit Ng
  5. Kevin I Watt
  6. Daryn Chau
  7. Paul Gregorevic
  8. Peter J Crouch
  9. James BW Hilton
  10. Leszek Lisowski
  11. Peixiang Zhang
  12. Karen Reue
  13. Aldons J Lusis
  14. James Hudson
  15. David E James
  16. Marcus M Seldin
  17. Benjamin L Parker  Is a corresponding author
  1. University of Melbourne, Australia
  2. QIMR Berghofer Medical Research Institute, Australia
  3. University of California, Irvine, United States
  4. University of Sydney, Australia
  5. University of California, Los Angeles, United States
https://doi.org/10.7554/eLife.82951
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  1. Jeffrey Molendijk
  2. Ronnie Blazev
  3. Richard J Mills
  4. Yaan-Kit Ng
  5. Kevin I Watt
  6. Daryn Chau
  7. Paul Gregorevic
  8. Peter J Crouch
  9. James BW Hilton
  10. Leszek Lisowski
  11. Peixiang Zhang
  12. Karen Reue
  13. Aldons J Lusis
  14. James Hudson
  15. David E James
  16. Marcus M Seldin
  17. Benjamin L Parker
(2022)
Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function
eLife 11:e82951.
https://doi.org/10.7554/eLife.82951
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Abstract

Improving muscle function has great potential to improve the quality of life. To identify novel regulators of skeletal muscle metabolism and function, we performed a proteomic analysis of gastrocnemius muscle from 73 genetically distinct inbred mouse strains, and integrated the data with previously acquired genomics and >300 molecular/phenotypic traits via quantitative trait loci mapping and correlation network analysis. These data identified thousands of associations between protein abundance and phenotypes and can be accessed online (https://muscle.coffeeprot.com/) to identify regulators of muscle function. We used this resource to prioritize targets for a functional genomic screen in human bioengineered skeletal muscle. This identified several negative regulators of muscle function including UFC1, an E2 ligase for protein UFMylation. We show UFMylation is up-regulated in a mouse model of amyotrophic lateral sclerosis, a disease that involves muscle atrophy. Furthermore, in vivo knockdown of UFMylation increased contraction force, implicating its role as a negative regulator of skeletal muscle function.

Data availability

The proteomics data generated in this study are deposited to the ProteomeXchange Consortium via the PRIDE (Perez-Riverol et al., 2019) under the identifiers PXD032729, PXD034913 and PXD035170. The code used for downstream analysis of proteomic data can be found at: https://github.com/JeffreyMolendijk/skeletal_muscle.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Jeffrey Molendijk

    Department of Anatomy and Physiology, University of Melbourne, Melbourne, Australia
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6575-504X

  2. Ronnie Blazev

    Department of Anatomy and Physiology, University of Melbourne, Melbourne, Australia
    Competing interests
    No competing interests declared.

  3. Richard J Mills

    QIMR Berghofer Medical Research Institute, Brisbane, Australia
    Competing interests
    No competing interests declared.

  4. Yaan-Kit Ng

    Department of Anatomy and Physiology, University of Melbourne, Melbourne, Australia
    Competing interests
    No competing interests declared.

  5. Kevin I Watt

    Department of Anatomy and Physiology, University of Melbourne, Melbourne, Australia
    Competing interests
    No competing interests declared.

  6. Daryn Chau

    Department of Biological Chemistry, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.

  7. Paul Gregorevic

    Department of Anatomy and Physiology, University of Melbourne, Melbourne, Australia
    Competing interests
    No competing interests declared.

  8. Peter J Crouch

    Department of Anatomy and Physiology, University of Melbourne, Melbourne, Australia
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7777-4747

  9. James BW Hilton

    Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, Australia
    Competing interests
    No competing interests declared.

  10. Leszek Lisowski

    Children's Medical Research Institute, University of Sydney, Sydney, Australia
    Competing interests
    No competing interests declared.

  11. Peixiang Zhang

    Department of Human Genetics/Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  12. Karen Reue

    Department of Human Genetics/Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  13. Aldons J Lusis

    Department of Human Genetics/Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  14. James Hudson

    QIMR Berghofer Medical Research Institute, Brisbane, Australia
    Competing interests
    No competing interests declared.

  15. David E James

    School of Life and Environmental Science, University of Sydney, Sydney, Australia
    Competing interests
    David E James, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5946-5257

  16. Marcus M Seldin

    Department of Biological Chemistry, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8026-4759

  17. Benjamin L Parker

    Department of Anatomy and Physiology, University of Melbourne, Melbourne, Australia
    For correspondence
    ben.parker@unimelb.edu.au
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1818-2183

Funding

National Health and Medical Research Council (APP1184363)

  • Karen Reue
  • Marcus M Seldin
  • Benjamin L Parker

National Institute of Health (HL147883)

  • Aldons J Lusis

National Institute of Health (DK117850)

  • Aldons J Lusis

Weary Dunlop Foundation (NA)

  • Benjamin L Parker

The ALS Association (21-DDC-574)

  • Paul Gregorevic
  • Peter J Crouch

National Health and Medical Research Council (APP2009642)

  • Benjamin L Parker

National Health and Medical Research Council (APP2013189)

  • Richard J Mills

National Health and Medical Research Council (APP1156562)

  • Paul Gregorevic
  • Benjamin L Parker

National Institute of Health (HL138193)

  • Marcus M Seldin

National Institute of Health (DK130640)

  • Marcus M Seldin

National Institute of Health (DK097771)

  • Marcus M Seldin

National Institute of Health (GM115318)

  • Karen Reue

National Institute of Health (AG070959)

  • Aldons J Lusis

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 rAAV6 intramuscular injection mouse experiments were approved by The University of Melbourne Animal Ethics Committee (AEC ID1914940) and conformed to the National Health and Medical Research Council of Australia guidelines regarding the care and use of experimental animals. All studies involving the use of SOD1G37R mice and non-transgenic littermates were approved by a University of Melbourne Animal Experimentation Ethics Committee (approval #2015124) and conformed with guidelines of the Australian National Health and Medical Research Council.

Copyright

© 2022, Molendijk 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. Jeffrey Molendijk
  2. Ronnie Blazev
  3. Richard J Mills
  4. Yaan-Kit Ng
  5. Kevin I Watt
  6. Daryn Chau
  7. Paul Gregorevic
  8. Peter J Crouch
  9. James BW Hilton
  10. Leszek Lisowski
  11. Peixiang Zhang
  12. Karen Reue
  13. Aldons J Lusis
  14. James Hudson
  15. David E James
  16. Marcus M Seldin
  17. Benjamin L Parker
(2022)
Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function
eLife 11:e82951.
https://doi.org/10.7554/eLife.82951

Share this article

https://doi.org/10.7554/eLife.82951

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