1. Stem Cells and Regenerative Medicine

Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration

  1. Wenxuan Liu
  2. Alanna Klose
  3. Sophie Forman
  4. Nicole D Paris
  5. Lan Wei-LaPierre
  6. Mariela Cortés-Lopéz
  7. Aidi Tan
  8. Morgan Flaherty
  9. Pedro Miura
  10. Robert T Dirksen
  11. Joe V Chakkalakal  Is a corresponding author
  1. University of Rochester Medical Center, United States
  2. University of Rochester, United States
  3. University of Nevada, United States
  4. Tsinghua University, China
https://doi.org/10.7554/eLife.26464
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  1. Wenxuan Liu
  2. Alanna Klose
  3. Sophie Forman
  4. Nicole D Paris
  5. Lan Wei-LaPierre
  6. Mariela Cortés-Lopéz
  7. Aidi Tan
  8. Morgan Flaherty
  9. Pedro Miura
  10. Robert T Dirksen
  11. Joe V Chakkalakal
(2017)
Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration
eLife 6:e26464.
https://doi.org/10.7554/eLife.26464
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  3. Download .RIS

Abstract

Neuromuscular junction degeneration is a prominent aspect of sarcopenia, the age-associated loss of skeletal muscle integrity. Previously, we showed that muscle stem cells activate and contribute to mouse neuromuscular junction regeneration in response to denervation (1). Here, we examined gene expression profiles and neuromuscular junction integrity in aged mouse muscles, and unexpectedly found limited denervation despite a high level of degenerated neuromuscular junctions. Instead, degenerated neuromuscular junctions were associated with reduced contribution from muscle stem cells. Indeed, muscle stem cell depletion was sufficient to induce neuromuscular junction degeneration at a younger age. Conversely, prevention of muscle stem cell and derived myonuclei loss was associated with attenuation of age-related neuromuscular junction degeneration, muscle atrophy, and the promotion of aged muscle force generation. Our observations demonstrate that deficiencies in muscle stem cell fate and post-synaptic myogenesis provide a cellular basis for age-related neuromuscular junction degeneration and associated skeletal muscle decline.

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Author details

  1. Wenxuan Liu

    Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Alanna Klose

    Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Sophie Forman

    Department of Biology, University of Rochester, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Nicole D Paris

    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:" 0000-0003-0654-0983

  5. Lan Wei-LaPierre

    Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Mariela Cortés-Lopéz

    Department of Biology, University of Nevada, Reno, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Aidi Tan

    Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.

  8. Morgan Flaherty

    Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Pedro Miura

    Department of Biology, University of Nevada, Reno, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Robert T Dirksen

    Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Joe V Chakkalakal

    Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
    For correspondence
    joe_chakkalakal@urmc.rochester.edu
    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

Funding

National Institute on Aging (RO1AG051456)

  • Joe V Chakkalakal

Congressionally Directed Medical Research Programs (W81XWH-14-1-0454)

  • Joe V Chakkalakal

NYSTEM (C026877)

  • Wenxuan Liu

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

Ethics

Animal experimentation: 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. Work with mice was conducted in accordance with protocols approved by the University Committee on Animal Resources, University of Rochester Medical Center protocol(#101565/2013-002)

Copyright

© 2017, Liu 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. Wenxuan Liu
  2. Alanna Klose
  3. Sophie Forman
  4. Nicole D Paris
  5. Lan Wei-LaPierre
  6. Mariela Cortés-Lopéz
  7. Aidi Tan
  8. Morgan Flaherty
  9. Pedro Miura
  10. Robert T Dirksen
  11. Joe V Chakkalakal
(2017)
Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration
eLife 6:e26464.
https://doi.org/10.7554/eLife.26464

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https://doi.org/10.7554/eLife.26464

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Further reading

    1. Cell Biology
    2. Stem Cells and Regenerative Medicine

    Inducible depletion of adult skeletal muscle stem cells impairs the regeneration of neuromuscular junctions

    Wenxuan Liu, Lan Wei-LaPierre ... Joe V Chakkalakal
    Research Article Updated

    Skeletal muscle maintenance depends on motor innervation at neuromuscular junctions (NMJs). Multiple mechanisms contribute to NMJ repair and maintenance; however muscle stem cells (satellite cells, SCs), are deemed to have little impact on these processes. Therefore, the applicability of SC studies to attenuate muscle loss due to NMJ deterioration as observed in neuromuscular diseases and aging is ambiguous. We employed mice with an inducible Cre, and conditionally expressed DTA to deplete or GFP to track SCs. We found SC depletion exacerbated muscle atrophy and type transitions connected to neuromuscular disruption. Also, elevated fibrosis and further declines in force generation were specific to SC depletion and neuromuscular disruption. Fate analysis revealed SC activity near regenerating NMJs. Moreover, SC depletion aggravated deficits in reinnervation and post-synaptic morphology at regenerating NMJs. Therefore, our results propose a mechanism whereby further NMJ and skeletal muscle decline ensues upon SC depletion and neuromuscular disruption.