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Molecular circuitry of stem cell fate in skeletal muscle regeneration, ageing and disease

Key Points

  • Satellite cell quiescence, activation and self-renewal are coordinated by extrinsic and intrinsic regulators.

  • Quiescent satellite cells are molecularly and functionally heterogeneous and have a unique transcriptional and epigenetic profile that distinguishes them from activated satellite cells.

  • Aged satellite cells misregulate intrinsic factors such as p38α/β MAPK, JAK–STAT and p16INK4A, leading to impairments in self-renewal and, eventually, conversion to a senescent state.

  • Local and systemic factors influence satellite cell fate decisions, and systemic delivery of youthful blood-borne factors can ameliorate some aspects of the ageing phenotype in skeletal muscle.

  • Dystrophin-deficiency directly misregulates satellite cell state and function, which further exacerbates symptoms of Duchenne muscular dystrophy (DMD).

Abstract

Satellite cells are adult myogenic stem cells that repair damaged muscle. The enduring capacity for muscle regeneration requires efficient satellite cell expansion after injury, their differentiation to produce myoblasts that can reconstitute damaged fibres and their self-renewal to replenish the muscle stem cell pool for subsequent rounds of injury and repair. Emerging studies indicate that misregulation of satellite cell fate and function can contribute to age-associated muscle dysfunction and influence the severity of muscle diseases, including Duchenne muscular dystrophy (DMD). It has also become apparent that satellite cell fate during muscle regeneration and ageing, and in the context of DMD, is governed by an intricate network of intrinsic and extrinsic regulators. Targeted manipulation of this network may offer unique opportunities for muscle regenerative medicine.

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Figure 1: Classical view of muscle myogenesis.
Figure 2: Emerging regulators of satellite cell quiescence, activation and self-renewal.
Figure 3: Intrinsic cell fate regulators are misregulated in aged and dystrophic satellite cells.

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Acknowledgements

The authors wish to thank all reviewers for their critical evaluation and their insightful feedback in preparing this manuscript. This work was supported in part by a Burroughs Wellcome Fund Postdoctoral fellowship Award and a T32 US National Institutes of Health (NIH) training grant (5T32DK007260-38) to A.E.A., and NIH RO1 ES024935 and R56 AG048917 to A.J.W. Content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Correspondence to Amy J. Wagers.

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A.J.W. is a consultant for Fate Therapeutics. A.J.W. is a co-inventor on patent applications relevant to the derivation, isolation, culture and genome modification of myogenic progenitors from muscle tissue or differentiated pluripotent cells.

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Glossary

Muscle sarcolemma

The outer cell membrane of a myofibre.

Basal lamina

The inner layer of the basement membrane, which is composed of extracellular matrix proteins and is adjacent to the muscle sarcolemma.

Satellite cell niche

A structural and growth factor-rich environment above the muscle sarcolemma but beneath the basal lamina, consisting of cellular and acellular components that support and regulate muscle satellite cells.

Fibro-adipogenic progenitors

(FAPs). A bipotent progenitor population that can adopt both fibrogenic and adipogenic cell fates, located in the interstitial space of muscle fibres.

Activation

A reversible state characterized by entry into the cell cycle, or transition to a proliferative state.

Quiescence

A reversible state characterized by withdrawal from the cell cycle or lack of proliferation.

PAX3

A member of the paired box protein family expressed in satellite cells in a few adult muscle groups, with a prominent role in embryonic myogenesis.

Somite

A division in the developing embryo consisting of paired blocks of paraxial mesoderm.

Myotome

The dorsal part of the somite in the developing embryo that gives rise to the skeletal muscle.

Cre recombinase-mediated lineage tracing

A molecular genetic technique used to trace each cell that has ever expressed a gene of interest, through gene-specific Cre-mediated recombination that leads to expression of a fluorescent reporter gene.

Active chromatin

Regions of the genome that are actively transcribed and are flanked by histone H3 trimethylation at Lys4 (H3K4me3).

mTORC1

The mammalian target of rapamycin complex 1. Part of a protein complex that controls protein synthesis by sensing nutrients, energy and metabolic products in the cell.

p38-α MAPK and p38-β MAPK

(p38α/β MAPK). Two isoforms of the p38 family of MAPKs, which has a seminal role in detecting extracellular signals from outside the cell and directing a cascade of phosphorylation events that activates downstream effectors and, ultimately, target gene expression.

Tristetraprolin

(TTP). An RNA-binding protein that binds the 3′ untranslated region of target RNAs, leading to their rapid decay through the recruitment of cytoplasmic RNA-degradation machinery.

Symmetric cell division

The partitioning of cellular components during cell division that leads to two daughter cells that are molecularly and functionally identical.

Asymmetric cell division

The partitioning of cellular components during cell division that leads to two daughter cells that are molecularly and functionally distinct.

Oxidative phosphorylation

(OXPHOS). A metabolic pathway in which mitochondria oxidize nutrients to form ATP.

Autophagic flux

A measurement that can be used to quantify cellular autophagic activity.

NAD+

The oxidized form of nicotinamide adenine dinucleotide (NAD), which can accept an electron, becoming reduced to its NADH form.

Sprouty 1

(SPRY1). A receptor Tyr kinase inhibitor that restricts entry to the cell cycle by abrogating cell signalling pathways such as the fibroblast growth factor receptor (FGFR) pathway.

Senescence

A cellular state induced by extensive proliferation, induction of oncogene expression, inflammatory signals or other stimuli, in which cells irreversibly exit the cell cycle.

Cyclin-dependent kinases

(CDKs). A family of kinases that regulate cell cycle transitions.

Gastrocnemius muscle

A skeletal muscle located at the back of the lower legs.

Heterochronic parabiosis

The surgical joining of the circulatory systems of a young and an old animal.

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Almada, A., Wagers, A. Molecular circuitry of stem cell fate in skeletal muscle regeneration, ageing and disease. Nat Rev Mol Cell Biol 17, 267–279 (2016). https://doi.org/10.1038/nrm.2016.7

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