Murine muscle stem cell response to perturbations of the neuromuscular junction are attenuated with aging

  1. Jacqueline Larouche
  2. Mahir Mohiuddin
  3. Jeongmoon J Choi
  4. Peter J Ulintz
  5. Paula M Fraczek
  6. Kaitlyn Sabin
  7. Sethuramasundaram Pitchiaya
  8. Sarah J Kurpiers
  9. Jesus Castor-Macias
  10. Wenxuan Liu
  11. Robert Louis Hastings
  12. Lemuel A Brown
  13. James F Markworth
  14. Kanishka De Silva
  15. Benjamin D Levi
  16. Sofia D Merajver
  17. Gregorio Valdez
  18. Joe V Chakkalakal
  19. Young Jang  Is a corresponding author
  20. Susan Brooks  Is a corresponding author
  21. Carlos A Aguilar  Is a corresponding author
  1. University of Michigan, United States
  2. Georgia Institute of Technology, United States
  3. University of Rochester, United States
  4. Brown University, United States
  5. University of Texas Southwestern, United States
  6. University of Rochester Medical Center, United States

Abstract

During aging and neuromuscular diseases, there is a progressive loss of skeletal muscle volume and function impacting mobility and quality of life. Muscle loss is often associated with denervation and a loss of resident muscle stem cells (satellite cells or MuSCs), however, the relationship between MuSCs and innervation has not been established. Herein, we administered severe neuromuscular trauma to a transgenic murine model that permits MuSC lineage tracing. We show that a subset of MuSCs specifically engraft in a position proximal to the neuromuscular junction (NMJ), the synapse between myofibers and motor neurons, in healthy young adult muscles. In aging and in a mouse model of neuromuscular degeneration (Cu/Zn superoxide dismutase knockout – Sod1-/-), this localized engraftment behavior was reduced. Genetic rescue of motor neurons in Sod1-/- mice reestablished integrity of the NMJ in a manner akin to young muscle and partially restored MuSC ability to engraft into positions proximal to the NMJ. Using single cell RNA-sequencing of MuSCs isolated from aged muscle, we demonstrate that a subset of MuSCs are molecularly distinguishable from MuSCs responding to myofiber injury and share similarity to synaptic myonuclei. Collectively, these data reveal unique features of MuSCs that respond to synaptic perturbations caused by aging and other stressors.

Data availability

Data have been deposited to GEO under accession code GSE165978.

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

Article and author information

Author details

  1. Jacqueline Larouche

    Biomedical Engineering, University of Michigan, 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
  2. Mahir Mohiuddin

    BIomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jeongmoon J Choi

    BIomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Peter J Ulintz

    Biomedical Engineering, University of Michigan, 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:" 0000-0002-2037-8655
  5. Paula M Fraczek

    Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kaitlyn Sabin

    Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sethuramasundaram Pitchiaya

    Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Sarah J Kurpiers

    Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jesus Castor-Macias

    Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Wenxuan Liu

    Pharmacology & Physiology, University of Rochester, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Robert Louis Hastings

    10Dept. of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Lemuel A Brown

    Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. James F Markworth

    Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Kanishka De Silva

    Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Benjamin D Levi

    Dept. of Surgery, University of Texas Southwestern, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Sofia D Merajver

    Internal Medicine-Hematology/Oncology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Gregorio Valdez

    Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0375-4532
  18. Joe V Chakkalakal

    Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8440-7312
  19. Young Jang

    BIomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
    For correspondence
    young.jang@gatech.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9489-2104
  20. Susan Brooks

    Internal Medicine-Hematology/Oncology, University of Michigan, Ann Arbor, United States
    For correspondence
    svbrooks@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
  21. Carlos A Aguilar

    Biomedical Engineering, University of Michigan, 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 on Aging (P01 AG051442)

  • Susan Brooks

Congressionally Directed Medical Research Programs (W81XWH1810653)

  • Benjamin D Levi

Congressionally Directed Medical Research Programs (W81XWH2010795)

  • Benjamin D Levi

Breast Cancer Research Foundation

  • Peter J Ulintz
  • Sofia D Merajver

National Science Foundation (DGE 1256260)

  • Jacqueline Larouche

National Institute on Aging (R01 AG051456)

  • Joe V Chakkalakal

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

  • Susan Brooks
  • Carlos A Aguilar

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR071379)

  • Benjamin D Levi

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R61 AR078072)

  • Benjamin D Levi

3M Foundation

  • Carlos A Aguilar

American Federation for Aging Research

  • Carlos A Aguilar

National Institute on Aging (P30 AG024824)

  • Susan Brooks
  • Carlos A Aguilar

Congressionally Directed Medical Research Programs (W81XWH2010336)

  • Young Jang
  • Carlos A Aguilar

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (IACUC protocol #: PRO00008428, PRO00006689) of the University of Michigan.

Reviewing Editor

  1. Shahragim Tajbakhsh, Institut Pasteur, France

Publication history

  1. Preprint posted: May 29, 2020 (view preprint)
  2. Received: January 21, 2021
  3. Accepted: July 28, 2021
  4. Accepted Manuscript published: July 29, 2021 (version 1)
  5. Version of Record published: August 12, 2021 (version 2)

Copyright

© 2021, Larouche 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. Jacqueline Larouche
  2. Mahir Mohiuddin
  3. Jeongmoon J Choi
  4. Peter J Ulintz
  5. Paula M Fraczek
  6. Kaitlyn Sabin
  7. Sethuramasundaram Pitchiaya
  8. Sarah J Kurpiers
  9. Jesus Castor-Macias
  10. Wenxuan Liu
  11. Robert Louis Hastings
  12. Lemuel A Brown
  13. James F Markworth
  14. Kanishka De Silva
  15. Benjamin D Levi
  16. Sofia D Merajver
  17. Gregorio Valdez
  18. Joe V Chakkalakal
  19. Young Jang
  20. Susan Brooks
  21. Carlos A Aguilar
(2021)
Murine muscle stem cell response to perturbations of the neuromuscular junction are attenuated with aging
eLife 10:e66749.
https://doi.org/10.7554/eLife.66749

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