Murine muscle stem cell response to perturbations of the neuromuscular junction are attenuated with aging
- University of Michigan, United States
- Georgia Institute of Technology, United States
- University of Rochester, United States
- Brown University, United States
- University of Texas Southwestern, United States
- 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.
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Muscle Stem Cell Response to Perturbations of the Neuromuscular Junction Are Attenuated With AgingNCBI Gene Expression Omnibus, GSE165978.
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Single-nucleus RNA-seq identifies transcriptional heterogeneity in multinucleated skeletal myofibersNCBI Gene Expression Omnibus, GSE147127.
Article and author information
Author details
Jacqueline Larouche
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.
Reviewing Editor
- Shahragim Tajbakhsh, Institut Pasteur, France
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.
Version history
- Preprint posted: May 29, 2020 (view preprint)
- Received: January 21, 2021
- Accepted: July 28, 2021
- Accepted Manuscript published: July 29, 2021 (version 1)
- 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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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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