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Control of satellite cell function in muscle regeneration and its disruption in ageing

Abstract

Skeletal muscle contains a designated population of adult stem cells, called satellite cells, which are generally quiescent. In homeostasis, satellite cells proliferate only sporadically and usually by asymmetric cell division to replace myofibres damaged by daily activity and maintain the stem cell pool. However, satellite cells can also be robustly activated upon tissue injury, after which they undergo symmetric divisions to generate new stem cells and numerous proliferating myoblasts that later differentiate to muscle cells (myocytes) to rebuild the muscle fibre, thereby supporting skeletal muscle regeneration. Recent discoveries show that satellite cells have a great degree of population heterogeneity, and that their cell fate choices during the regeneration process are dictated by both intrinsic and extrinsic mechanisms. Extrinsic cues come largely from communication with the numerous distinct stromal cell types in their niche, creating a dynamically interactive microenvironment. This Review discusses the role and regulation of satellite cells in skeletal muscle homeostasis and regeneration. In particular, we highlight the cell-intrinsic control of quiescence versus activation, the importance of satellite cell–niche communication, and deregulation of these mechanisms associated with ageing. The increasing understanding of how satellite cells are regulated will help to advance muscle regeneration and rejuvenation therapies.

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Fig. 1: Quiescent satellite cells, heterogeneity and niche composition.
Fig. 2: Overview of basic mechanisms controlling satellite cell quiescence and activation.
Fig. 3: Epigenetic, metabolic and proteostatic effectors regulating satellite cell fate.
Fig. 4: Decline of satellite cells in ageing.

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Acknowledgements

The authors thank all reviewers for their insightful evaluation of and feedback for this Review. They also thank J. Neves for helpful comments on the manuscript. Furthermore, they thank many of their colleagues in the muscle regeneration field whose work inspired them for this Review. They regret that due to reference constraints, they could not cite all of the worthy articles on this subject. Work in the authors’ laboratory was supported in part by the Spanish MINECO (RTI2018-096068), ERC-AdG-741966, LaCaixa-HEALTH-HR17-00040, MDA, UPGRADE-H2020-825825, MWRF, FundacióLaMaratóTV3, AFM and DPP-Spain (P.M.-C). P.M.-C’s laboratories at Pompeu Fabra University and the Spanish National Center for Cardiovascular Research are recipients of grants from the María de Maeztu Units of Excellence programme to Pompeu Fabra University (MDM-2014-0370) and the Severo Ochoa Centers of Excellence programme to the Spanish National Center for Cardiovascular Research (SEV-2015-0505) for P.M.C. Work in the P.S.-V. laboratory was supported by the Fundação para a Ciência e Tecnologia Project (PTDC/MED-OUT/8010/2020), an EMBO installation grant (IG4448) and the ‘la Caixa’ Foundation for a junior leader fellowship (LCF/BQ/PI19/11690006) to P.S.-V. L.G.-P. was supported by an EMBO long-term fellowship (ALTF 420-2017), a Benjamin Pearl fellowship, and a CIHR fellowship (201910MFE-430959-284655).

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Correspondence to Pedro Sousa-Victor, Laura García-Prat or Pura Muñoz-Cánoves.

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Supplementary information

Glossary

Basal lamina

The inner layer of the basement membrane (composed of extracellular matrix proteins) that is adjacent to the muscle sarcolemma.

Hepatocyte growth factor (HGF) activator

(HGFA). A serine protease that activates HGF by converting it from a single chain to a heterodimeric form.

Duchenne muscular dystrophy

A genetic disorder characterized by progressive muscle degeneration and weakness due to a mutation in a gene coding for the protein dystrophin.

Myofibre type

The type of myosin expressed by each muscle fibre (myofibre) determines the myofibre type, which broadly categorizes them into types 1 and 2 myofibres, which in turn differ in the type of metabolism used for energy. Myofibres can be further subdivided into four types, identified by the expression of four myosin heavy chain (MyHC) isotypes: MyHC-2b, MyHC-2x, MyHC-2a and MyHC-1. Myofibres are also broadly classified as ‘slow-twitch‘ (type 1 MyHC) and ‘fast-twitch’ (type 2 MyHC) myofibres and differ in energy production: types 1 and 2a fibres primarily use oxidative metabolism, and types 2x and 2b myofibres primarily rely on glycolytic metabolism. These fibre types are dynamically interchangeable as an adaptation to alterations in muscle function and metabolism.

Asymmetric cell division

A process whereby the asymmetric inheritance of cellular components (for example, proteins, RNAs) during mitosis defines distinct fates for each daughter cell. This division mode is used by stem and progenitor cells in different tissues. Satellite cells in homeostasis usually undergo asymmetric cell division, which generates one self-renewing stem cell and one differentiating cell. By contrast, symmetric cell division occurs once satellite cells are activated and generates one type of cell (either two self-renewing stem cells or two differentiating cells).

CIP/KIP family of cell cycle inhibitors

Cyclin-dependent kinase (CDK)-interacting protein/kinase inhibitory protein family of cyclin-dependent kinase inhibitors, which bind both cyclin and CDK through a conserved amino-terminal domain. The family is composed of p21CIP1/WAF1, p27KIP1 and p57KIP2.

Schwann cells

Glial cells of the peripheral nervous system that surround axons of motor and sensory neurons and produce a myelin sheath.

Smooth muscle–mesenchymal cells

(SMMCs). A subpopulation of ITGA7+ cells identified in the skeletal muscle that are distinct from satellite cells and express markers of the mesenchymal and smooth muscle cell lineages.

FOXO

A subgroup of the forkhead family of transcription factors that orchestrate programmes of gene expression that regulate crucial cellular processes, including cell homeostasis, cell cycle progression, oxidative stress responses and metabolism and that share the characteristic of being regulated by the insulin–PI3K–AKT signalling pathway.

Calcitonin receptor

(CALCR). Seven-membrane-spanning domain G protein-coupled receptor that binds the peptide hormone calcitonin. It is involved in the maintenance of calcium homeostasis.

Tenocytes

Elongated fibroblast type tendon cells responsible for synthesis and turnover of tendon fibres and production of extracellular matrix components.

Syndecans

Single transmembrane domain proteoglycans with multiple heparan sulfate and chondroitin sulfate chains capable of interacting with multiple ligands and acting as co-receptors for G-protein-coupled receptors.

AMP-activated protein kinase

(AMPK). 5′-Adenosine monophosphate-activated protein kinase, a regulator of cellular energy homeostasis.

MYC

Transcription factor of the basic helix–loop–helix family encoded by the proto-oncogene MYC. It is constitutively expressed in several cancers and is associated with the promotion of cell proliferation.

E2F

Transcription factors, binding to the TTTCCCGC consensus sequence in target promoters, involved in the regulation of the cell cycle and DNA synthesis.

Dicer

An RNase III endonuclease that processes microRNA precursors into functional 21–23-nucleotode RNAs that are subsequently incorporated into the RNA-induced silencing complex.

Tristetraprolin

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

mRNA decay

A step in the process of gene expression (from gene to protein) consisting of the degradation or destruction of mRNA.

p38 mitogen-activated protein kinases

(MAPKs). A class of MAPKs (specific to the amino acids serine and threonine) that are responsive to stress stimuli. There are four isoforms of the p38 family of MAPKs (α, β, γ and δ), which have a key function in transducing extracellular signals from outside the cell into the nucleus, through a series of phosphorylation events, ultimately activating effectors of gene expression.

YAP

Yes-associated protein, a transcription factor that activates genes involved in cell proliferation and suppresses apoptotic genes. It also regulates genes in response to mechanotransduction. YAP is inhibited in the Hippo signalling pathway.

NAD+

Nicotinamide adenine dinucleotide (NAD), a coenzyme that is a hydrogen carrier central to metabolism, exists in two forms: an oxidized form (NAD+) and a reduced form (NADH). The main role of NAD+ in metabolism is the transfer of electrons from one molecule to another in redox reactions.

mTORC1

Mechanistic target of rapamycin complex 1, part of a protein complex that regulates protein synthesis in response to nutrients and metabolic products in the cell.

mTORC2

Mechanistic target of rapamycin complex 2, which is involved in the regulation of cell proliferation, survival and migration.

Unfolded protein response

A cellular stress response activated by the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum, aiming to restore normal function.

Dystrophin glycoprotein complex

A large multiprotein complex of the skeletal and cardiac muscle membrane, with both mechanically stabilizing and signalling roles in mediating interactions between the cytoskeleton, membrane and extracellular matrix. Mutations in dystrophin or additional dystrophin glycoprotein complex genes, the sarcoglycans, lead to muscular dystrophies.

Negative elongation factor

Protein complex that blocks transcription by pausing RNA polymerase II activity, preventing early transcript elongation.

Necroptosis

A programmed form of necrosis, or inflammatory cell death, usually associated with cellular damage or infiltration by pathogens. Receptor-interacting protein kinase 3 (RIP3K) is essential for necroptosis.

Gnai2

The gene encoding GTP-binding regulatory protein Gi α2 chain. It regulates proliferation and differentiation of several cell types, including satellite cells.

Neuromuscular junctions

(NMJs). The synapses between motor neurons and muscle fibres.

Regulatory T cells

(Treg cells). A subpopulation of T cells that modulate the function of other immune cells. They are identified by the expression of CD4, FOXP3 and CD25.

Senescence-associated secretory phenotype

Collection of secreted molecules derived from senescent cells that includes inflammatory cytokines, immune modulators, growth factors and proteases with paracrine action on surrounding cells.

Inflammageing

A state of low-grade chronic inflammation that develops in aged organisms.

Heterochronic parabiosis

An experimental procedure that combines two living organisms which are joined together surgically to develop a single, shared physiological system. In the context of ageing, when two animals of different ages are joined to test for systemic regulators of aspects of ageing or age-related diseases.

Yamanaka factors

OCT3/4, SOX2, KLF4 and MYC (OSKM factors) are a group of transcription factors identified by Yamanaka as capable of creating induced pluripotent stem cells.

Resistance training

A type of exercise where the muscles contract against an external resistance, promoting strength and hypertrophy.

Endurance training

A type of exercise that promotes adaptation of the skeletal muscle to aerobic metabolism, reflected by an increased oxidative capacity.

Genomic safe harbour

A genomic location where the integration of new genetic elements does not cause alterations of the host genome that pose risk to the cell, allowing the predictable function of the inserted transgenes.

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Sousa-Victor, P., García-Prat, L. & Muñoz-Cánoves, P. Control of satellite cell function in muscle regeneration and its disruption in ageing. Nat Rev Mol Cell Biol (2021). https://doi.org/10.1038/s41580-021-00421-2

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