Abstract

The acute traumatic or surgical loss of skeletal muscle, known as volumetric muscle loss (VML), is a devastating type of injury that results in exacerbated and persistent inflammation followed by fibrosis. The mechanisms that mediate the magnitude and duration of the inflammatory response and ensuing fibrosis after VML remain understudied and as such, the development of regenerative therapies has been limited. To address this need, we profiled how lipid mediators, which are potent regulators of the immune response after injury, varied with VML injuries that heal or result in fibrosis. We observed that non-healing VML injuries displayed increased pro-inflammatory eicosanoids and a lack of pro-resolving lipid mediators. Treatment of VML with a pro-resolving lipid mediator synthesized from docosahexaenoic acid, called Maresin 1, ameliorated fibrosis through reduction of neutrophils and macrophages and enhanced recovery of muscle strength. These results expand our knowledge of the dysregulated immune response that develops after VML and identify a novel immuno-regenerative therapeutic modality in Maresin 1.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE215808

The following data sets were generated

Article and author information

Author details

  1. Jesus A Castor-Macias

    Department of Biomedical Engineering, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jacqueline A Larouche

    Department of Biomedical Engineering, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9380-3547
  3. Emily C Wallace

    Department of Biomedical Engineering, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Bonnie D Spence

    Department of Biomedical Engineering, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Alec Eames

    Department of Biomedical Engineering, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Pamela Duran

    Department of Biomedical Engineering, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Benjamin A Yang

    Department of Biomedical Engineering, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Paula M Fraczek

    Department of Biomedical Engineering, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Carol A Davis

    Department of Molecular and Integrative Physiology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Susan V Brooks

    Department of Biomedical Engineering, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Krishna Rao Maddipati

    Department of Pathology, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. James F Markworth

    Department of Animal Sciences, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5348-1464
  13. Carlos A Aguilar

    Department of Biomedical Engineering, University of Michigan-Ann Arbor, Ann Arbor, United States
    For correspondence
    caguilar@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3830-0634

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30 AR069620)

  • Carlos A Aguilar

Congressionally Directed Medical Research Programs (W81XWH2010336)

  • Carlos A Aguilar

Congressionally Directed Medical Research Programs (W81XWH2110491)

  • Carlos A Aguilar

3M Foundation

  • Carlos A Aguilar

American Federation for Aging Research

  • Carlos A Aguilar

National Science Foundation (2045977)

  • Carlos A Aguilar

Defense Advanced Research Projects Agency (D20AC0002)

  • Carlos A Aguilar

Hevolution Foundation

  • Carlos A Aguilar

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Christopher L-H Huang, University of Cambridge, United Kingdom

Ethics

Animal experimentation: All mice were fed normal chow ad libitum and housed on a 12:12 hour light-dark cycle under UM veterinary staff supervision. Allprocedures were approved by the Institutional Animal Care and Use Committee (IACUC) andwere in accordance with the U.S. National Institute of Health (NIH).

Version history

  1. Preprint posted: November 20, 2022 (view preprint)
  2. Received: January 26, 2023
  3. Accepted: December 21, 2023
  4. Accepted Manuscript published: December 22, 2023 (version 1)
  5. Version of Record published: January 24, 2024 (version 2)

Copyright

© 2023, Castor-Macias 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. Jesus A Castor-Macias
  2. Jacqueline A Larouche
  3. Emily C Wallace
  4. Bonnie D Spence
  5. Alec Eames
  6. Pamela Duran
  7. Benjamin A Yang
  8. Paula M Fraczek
  9. Carol A Davis
  10. Susan V Brooks
  11. Krishna Rao Maddipati
  12. James F Markworth
  13. Carlos A Aguilar
(2023)
Maresin 1 repletion improves muscle regeneration after volumetric muscle loss
eLife 12:e86437.
https://doi.org/10.7554/eLife.86437

Share this article

https://doi.org/10.7554/eLife.86437

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