Skeletal muscle as an experimental model of choice to study tissue aging and rejuvenation

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Abstract

Skeletal muscle is among the most age-sensitive tissues in mammal organisms. Significant changes in its resident stem cells (i.e., satellite cells, SCs), differentiated cells (i.e., myofibers), and extracellular matrix cause a decline in tissue homeostasis, function, and regenerative capacity. Based on the conservation of aging across tissues and taking advantage of the relatively well-characterization of the myofibers and associated SCs, skeletal muscle emerged as an experimental system to study the decline in function and maintenance of old tissues and to explore rejuvenation strategies. In this review, we summarize the approaches for understanding the aging process and for assaying the success of rejuvenation that use skeletal muscle as the experimental system of choice. We further discuss (and exemplify with studies of skeletal muscle) how conflicting results might be due to variations in the techniques of stem cell isolation, differences in the assays of functional rejuvenation, or deciding on the numbers of replicates and experimental cohorts.

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Regulatory interactions between muscle and the immune system during muscle regeneration.

James G. Tidball, S Villalta (2010)

Recent discoveries reveal complex interactions between skeletal muscle and the immune system that regulate muscle regeneration. In this review, we evaluate evidence that indicates that the response of myeloid cells to muscle injury promotes muscle regeneration and growth. Acute perturbations of muscle activate a sequence of interactions between muscle and inflammatory cells. The initial inflammatory response is a characteristic Th1 inflammatory response, first dominated by neutrophils and subsequently by CD68(+) M1 macrophages. M1 macrophages can propagate the Th1 response by releasing proinflammatory cytokines and cause further tissue damage through the release of nitric oxide. Myeloid cells in the early Th1 response stimulate the proliferative phase of myogenesis through mechanisms mediated by TNF-alpha and IL-6; experimental prolongation of their presence is associated with delayed transition to the early differentiation stage of myogenesis. Subsequent invasion by CD163(+)/CD206(+) M2 macrophages attenuates M1 populations through the release of anti-inflammatory cytokines, including IL-10. M2 macrophages play a major role in promoting growth and regeneration; their absence greatly slows muscle growth following injury or modified use and inhibits muscle differentiation and regeneration. Chronic muscle injury leads to profiles of macrophage invasion and function that differ from acute injuries. For example, mdx muscular dystrophy yields invasion of muscle by M1 macrophages, but their early invasion is accompanied by a subpopulation of M2a macrophages. M2a macrophages are IL-4 receptor(+)/CD206(+) cells that reduce cytotoxicity of M1 macrophages. Subsequent invasion of dystrophic muscle by M2c macrophages is associated with progression of the regenerative phase in pathophysiology. Together, these findings show that transitions in macrophage phenotype are an essential component of muscle regeneration in vivo following acute or chronic muscle damage.

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The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus.

J J Jacobs, K. Kieboom, S. Marino … (1999)

The bmi-1 gene was first isolated as an oncogene that cooperates with c-myc in the generation of mouse lymphomas. We subsequently identified Bmi-1 as a transcriptional repressor belonging to the mouse Polycomb group. The Polycomb group comprises an important, conserved set of proteins that are required to maintain stable repression of specific target genes, such as homeobox-cluster genes, during development. In mice, the absence of bmi-1 expression results in neurological defects and severe proliferative defects in lymphoid cells, whereas bmi-1 overexpression induces lymphomas. Here we show that bmi-1-deficient primary mouse embryonic fibroblasts are impaired in progression into the S phase of the cell cycle and undergo premature senescence. In these fibroblasts and in bmi-1-deficient lymphocytes, the expression of the tumour suppressors p16 and p19Arf, which are encoded by ink4a, is raised markedly. Conversely, overexpression of bmi-1 allows fibroblast immortalization, downregulates expression of p16 and p19Arf and, in combination with H-ras, leads to neoplastic transformation. Removal of ink4a dramatically reduces the lymphoid and neurological defects seen in bmi-1-deficient mice, indicating that ink4a is a critical in vivo target for Bmi-1. Our results connect transcriptional repression by Polycomb-group proteins with cell-cycle control and senescence.

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Stem cell aging: mechanisms, regulators and therapeutic opportunities.

Juhyun Oh, Yang Lee, Amy J. Wagers (2014)

Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity. Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline. Here we explore key molecular pathways that are commonly perturbed as tissues and stem cells age and degenerate. We further consider experimental evidence both supporting and refuting the notion that modulation of these pathways per se can reverse aging phenotypes. Finally, we ask whether stem cell aging establishes an epigenetic 'memory' that is indelibly written or one that can be reset.

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Contributors

Irina M. Conboy:

ORCID: http://orcid.org/0000-0002-4276-0644

iconboy@berkeley.edu

Journal

Journal ID (nlm-ta): Skelet Muscle

Journal ID (iso-abbrev): Skelet Muscle

Title: Skeletal Muscle

Publisher: BioMed Central (London )

ISSN (Electronic): 2044-5040

Publication date (Electronic): 7 February 2020

Publication date PMC-release: 7 February 2020

Publication date Collection: 2020

Volume: 10

Electronic Location Identifier: 4

Affiliations

GRID grid.47840.3f, ISNI 0000 0001 2181 7878, Department of Bioengineering and QB3 Institute, , University of California, Berkeley, ; Berkeley, CA 94720-3220 USA

Author information

Jessy Etienne https://orcid.org/0000-0003-2173-6191

Irina M. Conboy http://orcid.org/0000-0002-4276-0644

Article

Publisher ID: 222

DOI: 10.1186/s13395-020-0222-1

PMC ID: 7007696

PubMed ID: 32033591

SO-VID: 1d4f6202-9fb4-4d5e-8452-7891d2c83015

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 6 August 2019

Date accepted : 12 January 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;

Award ID: NHLBI RO1

Funded by: National Institute of Biomedical Imaging and Bioengineering (US)

Award ID: NIBIB RO1

Funded by: Open Philanthropy

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ScienceOpen disciplines: Rheumatology

Keywords: aging,myogenesis,stem cells,niche,tissue repair,inflammation,signaling pathways,epigenome,satellite cells,rejuvenation

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ScienceOpen disciplines: Rheumatology

Keywords: aging, myogenesis, stem cells, niche, tissue repair, inflammation, signaling pathways, epigenome, satellite cells, rejuvenation

Skeletal muscle as an experimental model of choice to study tissue aging and rejuvenation

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Universal stem cells

Most cited references 170

Regulatory interactions between muscle and the immune system during muscle regeneration.

The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus.

Stem cell aging: mechanisms, regulators and therapeutic opportunities.

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