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.
-
Muscle Stem Cell Response to Perturbations of the Neuromuscular Junction Are Attenuated With AgingNCBI Gene Expression Omnibus, GSE165978.
-
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.
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
- Shahragim Tajbakhsh, Institut Pasteur, France
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.
Metrics
-
- 3,096
- Page views
-
- 453
- Downloads
-
- 8
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Developmental Biology
- Stem Cells and Regenerative Medicine
Co-regulated genes of the Imprinted Gene Network are involved in the control of growth and body size, and imprinted gene dysfunction underlies human paediatric disorders involving the endocrine system. Imprinted genes are highly expressed in the pituitary gland, among them, Dlk1, a paternally expressed gene whose membrane-bound and secreted protein products can regulate proliferation and differentiation of multiple stem cell populations. Dosage of circulating DLK1 has been previously implicated in the control of growth through unknown molecular mechanisms. Here we generate a series of mouse genetic models to modify levels of Dlk1 expression in the pituitary gland and demonstrate that the dosage of DLK1 modulates the process of stem cell commitment with lifelong impact on pituitary gland size. We establish that stem cells are a critical source of DLK1, where embryonic disruption alters proliferation in the anterior pituitary, leading to long-lasting consequences on growth hormone secretion later in life.
-
- Developmental Biology
- Stem Cells and Regenerative Medicine
Using embryonic stem cells (ESCs) in regenerative medicine or in disease modeling requires a complete understanding of these cells. Two main distinct developmental states of ESCs have been stabilized in vitro, a naïve pre-implantation stage and a primed post-implantation stage. Based on two recently published CRISPR-Cas9 knockout functional screens, we show here that the exit of the naïve state is impaired upon heme biosynthesis pathway blockade, linked in mESCs to the incapacity to activate MAPK- and TGFβ-dependent signaling pathways after succinate accumulation. In addition, heme synthesis inhibition promotes the acquisition of 2 cell-like cells in a heme-independent manner caused by a mitochondrial succinate accumulation and leakage out of the cell. We further demonstrate that extracellular succinate acts as a paracrine/autocrine signal, able to trigger the 2C-like reprogramming through the activation of its plasma membrane receptor, SUCNR1. Overall, this study unveils a new mechanism underlying the maintenance of pluripotency under the control of heme synthesis.
