1. Cell Biology
  2. Stem Cells and Regenerative Medicine

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

  1. Wenxuan Liu
  2. Lan Wei-LaPierre
  3. Alanna Klose
  4. Robert T Dirksen
  5. Joe V Chakkalakal  Is a corresponding author
  1. University of Rochester Medical Center, United States
https://doi.org/10.7554/eLife.09221
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  1. Wenxuan Liu
  2. Lan Wei-LaPierre
  3. Alanna Klose
  4. Robert T Dirksen
  5. Joe V Chakkalakal
(2015)
Inducible depletion of adult skeletal muscle stem cells impairs the regeneration of neuromuscular junctions
eLife 4:e09221.
https://doi.org/10.7554/eLife.09221
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Abstract

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.

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Author details

  1. Wenxuan Liu

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

  2. 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.

  3. Alanna Klose

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

  4. 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.

  5. Joe V Chakkalakal

    Department of Orthopaedics and Rehabilitation, Center for Musculoskeletal Research, 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.

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. 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

© 2015, 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. Lan Wei-LaPierre
  3. Alanna Klose
  4. Robert T Dirksen
  5. Joe V Chakkalakal
(2015)
Inducible depletion of adult skeletal muscle stem cells impairs the regeneration of neuromuscular junctions
eLife 4:e09221.
https://doi.org/10.7554/eLife.09221

Share this article

https://doi.org/10.7554/eLife.09221

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Further reading

    1. Stem Cells and Regenerative Medicine

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

    Wenxuan Liu, Alanna Klose ... Joe V Chakkalakal
    Research Advance Updated

    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 (Liu et al., 2015). 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.