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

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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 (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.

DOI: http://dx.doi.org/10.7554/eLife.26464.001

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Most cited references 41

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Satellite cells are essential for skeletal muscle regeneration: the cell on the edge returns centre stage.

Frédéric Relaix, Peter S. Zammit (2012)

Following their discovery in 1961, it was speculated that satellite cells were dormant myoblasts, held in reserve until required for skeletal muscle repair. Evidence for this accumulated over the years, until the link between satellite cells and the myoblasts that appear during muscle regeneration was finally established. Subsequently, it was demonstrated that, when grafted, satellite cells could also self-renew, conferring on them the coveted status of 'stem cell'. The emergence of other cell types with myogenic potential, however, questioned the precise role of satellite cells. Here, we review recent recombination-based studies that have furthered our understanding of satellite cell biology. The clear consensus is that skeletal muscle does not regenerate without satellite cells, confirming their pivotal and non-redundant role.

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Development of the vertebrate neuromuscular junction.

J Sanes, J Lichtman (1999)

We describe the formation, maturation, elimination, maintenance, and regeneration of vertebrate neuromuscular junctions (NMJs), the best studied of all synapses. The NMJ forms in a series of steps that involve the exchange of signals among its three cellular components--nerve terminal, muscle fiber, and Schwann cell. Although essentially any motor axon can form NMJs with any muscle fiber, an additional set of cues biases synapse formation in favor of appropriate partners. The NMJ is functional at birth but undergoes numerous alterations postnatally. One step in maturation is the elimination of excess inputs, a competitive process in which the muscle is an intermediary. Once elimination is complete, the NMJ is maintained stably in a dynamic equilibrium that can be perturbed to initiate remodeling. NMJs regenerate following damage to nerve or muscle, but this process differs in fundamental ways from embryonic synaptogenesis. Finally, we consider the extent to which the NMJ is a suitable model for development of neuron-neuron synapses.

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Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise.

Gregorio Valdez, Juan Tapia, Hyuno Kang … (2010)

The cellular basis of age-related behavioral decline remains obscure but alterations in synapses are likely candidates. Accordingly, the beneficial effects on neural function of caloric restriction and exercise, which are among the most effective anti-aging treatments known, might also be mediated by synapses. As a starting point in testing these ideas, we studied the skeletal neuromuscular junction (NMJ), a large, accessible peripheral synapse. Comparison of NMJs in young adult and aged mice revealed a variety of age-related structural alterations, including axonal swellings, sprouting, synaptic detachment, partial or complete withdrawal of axons from some postsynaptic sites, and fragmentation of the postsynaptic specialization. Alterations were significant by 18 mo of age and severe by 24 mo. A life-long calorie-restricted diet significantly decreased the incidence of pre- and postsynaptic abnormalities in 24-mo-old mice and attenuated age-related loss of motor neurons and turnover of muscle fibers. One month of exercise (wheel running) in 22-mo-old mice also reduced age-related synaptic changes but had no effect on motor neuron number or muscle fiber turnover. Time-lapse imaging in vivo revealed that exercise partially reversed synaptic alterations that had already occurred. These results demonstrate a critical effect of aging on synaptic structure and provide evidence that interventions capable of extending health span and lifespan can partially reverse these age-related synaptic changes.

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Author and article information

Contributors

Amy J Wagers: Role: Reviewing editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (hwp): eLife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 06 June 2017

Publication date Collection: 2017

Volume: 6

Electronic Location Identifier: e26464

Affiliations

[1 ]deptDepartment of Orthopaedics and Rehabilitation , Center for Musculoskeletal Research, University of Rochester Medical Center , Rochester, United States

[2 ]deptDepartment of Biomedical Genetics , University of Rochester Medical Center , Rochester, United States

[3 ]deptDepartment of Biology , University of Rochester , Rochester, United States

[4 ]deptDepartment of Pharmacology and Physiology , University of Rochester Medical Center , Rochester, United States

[5 ]deptDepartment of Biology , University of Nevada , Reno, United States

[6 ]deptBioinformatics Division and Center for Synthetic and Systems Biology , Tsinghua University , Beijing, China

[7 ]deptTNLIST/Department of Automation , Tsinghua University , Beijing, China

[8 ]deptStem Cell and Regenerative Medicine Institute , University of Rochester Medical Center , Rochester, United States

[9 ]deptThe Rochester Aging Research Center , University of Rochester Medical Center , Rochester, United States

Harvard University , United States

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joe_chakkalakal@ 123456urmc.rochester.edu

Author information

Nicole D Paris http://orcid.org/0000-0003-0654-0983

Joe V Chakkalakal http://orcid.org/0000-0002-8440-7312

Article

Publisher ID: 26464

DOI: 10.7554/eLife.26464

PMC ID: 5462534

PubMed ID: 28583253

SO-VID: 0f0a6b30-a1c6-4fe6-bcc5-c96691b1cbb6

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This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 03 March 2017

Date accepted : 20 May 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000049, National Institute on Aging;

Award ID: RO1AG051456

Award Recipient : Joe V Chakkalakal

Funded by: FundRef http://dx.doi.org/10.13039/100000090, Congressionally Directed Medical Research Programs;

Award ID: W81XWH-14-1-0454

Award Recipient : Joe V Chakkalakal

Funded by: FundRef http://dx.doi.org/10.13039/100003194, New York Stem Cell Foundation;

Award ID: C026877

Award Recipient : Wenxuan Liu

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

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Author impact statement Building on previous work (Liu et al., 2015), it is shown that depletion or rescue of adult skeletal muscle stem cells is sufficient to induce or attenuate age-associated neuromuscular junction deterioration respectively.

ScienceOpen disciplines: Life sciences

Keywords: satellite cell,sarcopenia,aging,sprouty,denervation,synapse,mouse

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ScienceOpen disciplines: Life sciences

Keywords: satellite cell, sarcopenia, aging, sprouty, denervation, synapse, mouse

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

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Abstract

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Universal stem cells

Most cited references 41

Satellite cells are essential for skeletal muscle regeneration: the cell on the edge returns centre stage.

Development of the vertebrate neuromuscular junction.

Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise.

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