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| Open AccessGli1 marks a sentinel muscle stem cell population for muscle regeneration
Adult skeletal muscle regeneration is mainly driven by muscle stem cells (MuSCs), which are highly heterogeneous. Here, the authors found that a population of MuSCs, marked by Gli1 expression, is key contributor to muscle regeneration.
- Jiayin Peng
- , Lili Han
- & Yun Zhao
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Article
| Open AccessATF3 induction prevents precocious activation of skeletal muscle stem cell by regulating H2B expression
Muscle regeneration relies on activation and expansion of skeletal muscle stem cells. Here, authors show that ATF3 induction prevents precocious activation of skeletal muscle stem cells by binding and promoting the transcription of Histone2B.
- Suyang Zhang
- , Feng Yang
- & Huating Wang
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Article
| Open AccessClearance of defective muscle stem cells by senolytics restores myogenesis in myotonic dystrophy type 1
Muscle stem cells drive muscle regeneration and are affected in myotonic dystrophy type 1. Here, the authors demonstrate that some muscle stem cells show signs of senescence in myotonic dystrophy type 1 and administer senolytics to eliminate these defective cells and restore myogenesis.
- Talita C. Conte
- , Gilberto Duran-Bishop
- & Nicolas A. Dumont
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Article
| Open AccessMethionine adenosyltransferase2A inhibition restores metabolism to improve regenerative capacity and strength of aged skeletal muscle
Aged myoblasts suffer from impaired glycolysis and insulin resistance, but increase methionine catabolism, possibly to meet energetic demands. Here, authors show that inhibiting methionine metabolism via NANOG reprogramming or MAT2A inhibition restores the function and regeneration capacity of aged muscle.
- Nika Rajabian
- , Izuagie Ikhapoh
- & Stelios T. Andreadis
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Article
| Open AccessTranscriptional reprogramming of skeletal muscle stem cells by the niche environment
Aging leads to significant alteration in the gene expression of muscle stem cells. In vivo exposure of muscle stem cells from aged mice to a young niche environment restores the expression of a significant portion of age-altered genes in mice.
- Felicia Lazure
- , Rick Farouni
- & Vahab D. Soleimani
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Article
| Open AccessMuscle 4EBP1 activation modifies the structure and function of the neuromuscular junction in mice
The group of Shih-Yin Tsai observed age-associated neuromuscular junction structural instability in male but not female mice which is driven by dysregulation of mTOR complex 1 activity. Genetic activation of the downstream phosphorylation target 4EBP1 in the muscle remodeled the neuromuscular junction and enhanced synaptic transmission.
- Seok-Ting J. Ang
- , Elisa M. Crombie
- & Shih-Yin Tsai
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Article
| Open AccessGLI3 regulates muscle stem cell entry into GAlert and self-renewal
Primary cilia regulate the processing of the GLI transcription factors and Hedgehog signaling. Here, the authors show that cilia-related GLI3 controls both the quiescence-to-activation transition and self-renewal in muscle stem cells.
- Caroline E. Brun
- , Marie-Claude Sincennes
- & Michael A. Rudnicki
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Article
| Open AccessPrimary cilia on muscle stem cells are critical to maintain regenerative capacity and are lost during aging
Repair of muscle damage requires muscle stem cells, which lose regenerative capacity with aging. Here, the authors show that a sensory organelle, the primary cilium, is critical for muscle stem cell proliferation during regeneration and lost with aging.
- Adelaida R. Palla
- , Keren I. Hilgendorf
- & Helen M. Blau
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Article
| Open AccessCPEB1 directs muscle stem cell activation by reprogramming the translational landscape
Skeletal muscle stem cells are actively maintained in quiescence, but can activate quickly upon extrinsic stimulation. Here the authors show that CPEB1 promotes muscle stem cell activation by reprogramming the translational landscape.
- Wenshu Zeng
- , Lu Yue
- & Tom H. Cheung
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Article
| Open AccessMyoD is a 3D genome structure organizer for muscle cell identity
Pioneer transcription factors (TFs) have been proposed to act as protein anchors to orchestrate cell type-specific 3D genome architecture. MyoD is a pioneer TF for myogenic lineage specification. Here the authors provide further support for the role of MyoD in 3D genome architecture in muscle stem cells by comparing MyoD knockout and wild-type mice.
- Ruiting Wang
- , Fengling Chen
- & Dahai Zhu
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Article
| Open AccessResolvin-D2 targets myogenic cells and improves muscle regeneration in Duchenne muscular dystrophy
Glucocorticoids delay muscle wasting in Duchenne Muscular Dystrophy by reducing inflammation; but also have harmful side effects. Here, the authors show that Resolvin-D2 is more effective than glucocorticoids in mitigating muscular dystrophy in mouse models, due to its ability to dampen inflammation and target myogenic cells to improve muscle regeneration.
- Junio Dort
- , Zakaria Orfi
- & Nicolas A. Dumont
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Article
| Open AccessThe transcription factor NF-Y participates to stem cell fate decision and regeneration in adult skeletal muscle
Satellite cells represent myogenic stem cells that allow the homeostasis and repair of adult skeletal muscle. Here the authors report that the transcription factor NF-Y is expressed in satellite cells and is important for their maintenance and proper myogenic differentiation.
- Giovanna Rigillo
- , Valentina Basile
- & Carol Imbriano
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Article
| Open Accessp107 mediated mitochondrial function controls muscle stem cell proliferative fates
The connection between cell cycle, metabolic state and mitochondrial activity is unclear. Here, the authors show that p107 represses mitochondrial transcription and ATP output in response to glycolytic byproducts, causing metabolic control of the cell cycle rate in myogenic progenitors.
- Debasmita Bhattacharya
- , Vicky Shah
- & Anthony Scimè
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Article
| Open AccessTranslational control by DHX36 binding to 5′UTR G-quadruplex is essential for muscle stem-cell regenerative functions
Skeletal muscle stem cells (or satellite cells, SCs) are normally quiescent but activate and expand in response to injury. Here the authors show that induction of DHX36 helicase during SC activation promotes mRNA translation by binding to 5′UTR mRNA G-quadruplexes (rG4) in targets including Gnai2 and unwinding them.
- Xiaona Chen
- , Jie Yuan
- & Huating Wang
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Article
| Open AccessUnexpected contribution of fibroblasts to muscle lineage as a mechanism for limb muscle patterning
The dogma is that limb muscle cells originate from somite, while connective tissue fibroblasts derive from lateral plate mesoderm. Here the authors identify a fibroblast population that undergoes myoblast conversion in response to BMP and contributes nuclei to myotubes at the myotendinous junction.
- Joana Esteves de Lima
- , Cédrine Blavet
- & Delphine Duprez
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Article
| Open AccessAcetylation of PAX7 controls muscle stem cell self-renewal and differentiation potential in mice
The acetyltransferase MYST1 stimulated by acetyl-CoA, and the deacetylase SIRT2 stimulated by NAD+, regulate PAX7 acetylation in muscle stem cells, which in turn, regulates stem cell self-renewal and regeneration following injury in mouse skeletal muscle.
- Marie-Claude Sincennes
- , Caroline E. Brun
- & Michael A. Rudnicki
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Article
| Open AccessIn vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche
Short term systemic expression of the reprogramming factors Oct-3/4, Sox2, Klf4, c-Myc (OSKM) rejuvenates aging cells and promotes tissue regeneration. Here the authors show that myofiber-specific expression of OSKM accelerates muscle regeneration by reducing secretion of muscle stem cell quiescence promoting Wnt4.
- Chao Wang
- , Ruben Rabadan Ros
- & Juan Carlos Izpisua Belmonte
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Article
| Open AccessVPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics
Insulin resistance and lower muscle strength in relation to mass are hallmarks of type 2 diabetes. Here, the authors report alterations in muscle stem cells from individuals with type 2 diabetes that may contribute to these phenotypes through VPS39 mediated effects on autophagy and epigenetics.
- Cajsa Davegårdh
- , Johanna Säll
- & Charlotte Ling
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Article
| Open AccessTGFβ signalling acts as a molecular brake of myoblast fusion
Fusion of myoblasts is essential for muscle development and repair, but the molecular mechanism underlying this process remains unclear. Here, the authors show, using chicken embryos as a model, that TGFβ signalling inhibits fusion via a receptor complementation mechanism, and indicate the involvement of endocytic degradation of activated receptors in modulation of this process.
- Julie Melendez
- , Daniel Sieiro
- & Christophe Marcelle
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Article
| Open AccessTGFβ signaling curbs cell fusion and muscle regeneration
The fusion of muscle progenitor cells to form syncytial myofibers is required for skeletal muscle development and regeneration. Here, the authors describe a novel and specific molecular regulation of muscle cell fusion driven by transforming growth factor beta (TGFβ) signaling.
- Francesco Girardi
- , Anissa Taleb
- & Fabien Le Grand
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Review Article
| Open AccessPerspectives on skeletal muscle stem cells
Skeletal muscle has a remarkable regenerative capacity, which can largely be attributed to resident muscle stem cells (MuSCs). Here, the authors review the molecular mechanisms regulating MuSC quiescence, activation and proliferation, how these processes are regulated by the stem cell niche, and the role of MuSCs in neuromuscular diseases.
- F. Relaix
- , M. Bencze
- & Taglietti V.
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Article
| Open AccessMuscle progenitor specification and myogenic differentiation are associated with changes in chromatin topology
Chromatin structure and topology play important roles in the regulation of gene expression. Here the authors study the spatio-temporal re-organization of promoter-enhancer interactions in pluripotent ES and skeletal muscle stem cells and the corresponding impact on gene expression as a consequence of myogenic commitment and differentiation.
- Nan Zhang
- , Julen Mendieta-Esteban
- & Brian David Dynlacht
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Article
| Open AccessInhibition of inflammatory CCR2 signaling promotes aged muscle regeneration and strength recovery after injury
Chronic inflammation is a feature of age-related regenerative decline in skeletal muscles, but how it directly affects resident muscle stem cell fate and function is unclear. Here, the authors show that Ccr2 signaling in muscle stem cell derived progenitors represses terminal myogenic differentiation, and that targeting Ccr2 on aged myogenic progenitors rejuvenates aged skeletal muscle healing and function.
- Roméo S. Blanc
- , Jacob G. Kallenbach
- & Joe V. Chakkalakal
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Article
| Open AccessLong noncoding RNA SAM promotes myoblast proliferation through stabilizing Sugt1 and facilitating kinetochore assembly
Long noncoding RNA SAM (Sugt1 associated muscle) is upregulated in the proliferating myoblast cells. Here the authors investigate SAM knockout mice and suggest that SAM binds and stabilizes Sugt1, a co-chaperone protein that regulates kinetochore assembly.
- Yuying Li
- , Jie Yuan
- & Huating Wang
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Article
| Open AccessHuman muscle-derived CLEC14A-positive cells regenerate muscle independent of PAX7
Skeletal muscle stem cells express the transcription factor Pax7. Here, the authors isolate, from human muscle, cells that are positive for the endothelial marker CLEC14A and show that despite not expressing pax7, these cells regenerate muscle and contribute to the muscle stem cell niche when transplanted into mice.
- Andreas Marg
- , Helena Escobar
- & Simone Spuler
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Article
| Open AccessThe transcription factor Slug represses p16Ink4a and regulates murine muscle stem cell aging
Muscle regeneration depends on self-renewal of muscle stem cells but how this is regulated on aging is unclear. Here, the authors identify Slug as regulating p16Ink4a in quiescent muscle stem cells, and when Slug expression reduces in aged stem cells, p16Ink4a accumulates, causing regenerative defects.
- Pei Zhu
- , Chunping Zhang
- & Wen-Shu Wu
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Article
| Open AccessThe Stat3-Fam3a axis promotes muscle stem cell myogenic lineage progression by inducing mitochondrial respiration
Induction of mitochondrial oxidative respiration is required for stem cell differentiation, but the mechanisms underlying this process are poorly understood. Here, the authors report that Stat3 promotes muscle stem cell differentiation by stimulating mitochondrial respiration via Fam3a.
- David Sala
- , Thomas J. Cunningham
- & Alessandra Sacco
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Article
| Open AccessZEB1 protects skeletal muscle from damage and is required for its regeneration
Following muscle damage, an inflammatory response is associated to activation of satellite cells, which drive muscle repair. Here, the authors show that upregulation of Zeb1 in macrophages and muscle fibres regulates inflammation, and also show a role for Zeb1 in maintenance of satellite cell quiescence.
- Laura Siles
- , Chiara Ninfali
- & Antonio Postigo
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Article
| Open AccessIslr regulates canonical Wnt signaling-mediated skeletal muscle regeneration by stabilizing Dishevelled-2 and preventing autophagy
“Satellite cells are crucial for skeletal muscle regeneration. Here the authors show that immunoglobulin superfamily containing leucine-rich repeat (Islr) promotes skeletal muscle regeneration via a mechanism involving Dishevelled-2 stabilization in satellite cells and protection from autophagy.
- Kuo Zhang
- , Yuying Zhang
- & Qingyong Meng
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Article
| Open AccessSpatiotemporal regulation of the GPCR activity of BAI3 by C1qL4 and Stabilin-2 controls myoblast fusion
Myoblast fusion is an essential step in muscle growth and regeneration, and is regulated by the G-protein coupled receptor (GPCR) BAI3. Here Hamoud et al. show that the GPCR activity of BAI3 is spatiotemporally regulated during myoblast fusion, and identify C1qL4 and Stabilin-2 as, respectively, negative and positive regulators of its activity.
- Noumeira Hamoud
- , Viviane Tran
- & Jean-François Côté
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Article
| Open AccessInduction of muscle stem cell quiescence by the secreted niche factor Oncostatin M
The factors that mediate quiescence of muscle stem cells are unknown. The authors show that Oncostatin M is produced by skeletal muscle, suppresses stem cell proliferation, and that its deletion in muscle results in stem cell depletion and impaired muscle regeneration following injury in mice.
- Srinath C. Sampath
- , Srihari C. Sampath
- & Helen M. Blau
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Article
| Open AccessHistone H3.3 sub-variant H3mm7 is required for normal skeletal muscle regeneration
Incorporation of histone H3 variant H3.3 into chromatin regulates transcription. Here the authors find that H3.3 sub-variant H3mm7 is required for skeletal muscle regeneration and that H3mm7 nucleosomes are unstable and exhibit higher mobility, with H3mm7 promoting open chromatin around promoters.
- Akihito Harada
- , Kazumitsu Maehara
- & Yasuyuki Ohkawa
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Article
| Open AccessBasal lamina remodeling at the skeletal muscle stem cell niche mediates stem cell self-renewal
Extracellular matrix (ECM) remodelling is thought to have effects on muscle stem cells that support muscle homeostasis. Here the authors show ECM remodeling controls satellite cell self-renewal through deposition of laminin-α1 into the satellite cell niche.
- Shantisree Sandeepani Rayagiri
- , Daniele Ranaldi
- & Anne-Gaëlle Borycki
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Article
| Open AccessSomatic mutagenesis in satellite cells associates with human skeletal muscle aging
Aging skeletal muscle shows declining numbers and activity of satellite cells. Here, Franco et al. show that in satellite cells of the human leg muscle vastus lateralis, somatic mutations accumulate with age and that these mutations become enriched in exons and promoters of genes involved in muscle function.
- Irene Franco
- , Anna Johansson
- & Maria Eriksson
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Article
| Open AccessActivin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva
Fibrodysplasia ossificans progressiva is a severe disorder characterized by heterotopic ossification, and is caused by mutations in ACVR1. Here, the authors show that expression of mutant ACVR1 in fibro/adipogenic progenitors recapitulates disease progression, and that this can be halted by systemic inhibition of activin A in mice.
- John B. Lees-Shepard
- , Masakazu Yamamoto
- & David J. Goldhamer
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Article
| Open AccessLsd1 regulates skeletal muscle regeneration and directs the fate of satellite cells
Satellite cells can differentiate both into myocytes and brown adipocytes. Here, the authors show that the histone demethylase Lsd1 prevents adipogenic differentiation of satellite cells by repressing expression of Glis1, and that its ablation changes satellite cell fate towards brown adipocytes and delays muscle regeneration in mice.
- Milica Tosic
- , Anita Allen
- & Roland Schüle
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Article
| Open AccessComplement C3a signaling facilitates skeletal muscle regeneration by regulating monocyte function and trafficking
Regeneration of skeletal muscle is accompanied by a transitory inflammatory phase. Here the authors show that the complement C3 component is activated following muscle injury, and signals through the alternative complement pathway to regulate immune cell infiltration and muscle regeneration.
- Congcong Zhang
- , Chunxiao Wang
- & Jie Du
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Article
| Open AccessMyD88 promotes myoblast fusion in a cell-autonomous manner
Myoblast fusion is essential for skeletal muscle development and regeneration. Here the authors show that MyD88 is upregulated during myogenesis and during muscle growth, signals via the NF-κB and Wnt pathways, and that its expression modulates myoblast fusion and myofiber size in mice.
- Sajedah M. Hindi
- , Jonghyun Shin
- & Ashok Kumar
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Article
| Open AccessMicroRNAs promote skeletal muscle differentiation of mesodermal iPSC-derived progenitors
Mesodermal iPSC-derived progenitors (MiPs) can regenerate both skeletal and cardiac muscle. Here, the authors show that a microRNA cocktail stimulates skeletal muscle differentiation and that human MiPs can engraft into striated muscle in mice.
- Giorgia Giacomazzi
- , Bryan Holvoet
- & Maurilio Sampaolesi
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Article
| Open AccessSilencing Nfix rescues muscular dystrophy by delaying muscle regeneration
Strategies aimed at promoting muscle regeneration to treat muscular dystrophy have met with limited success. Here the authors show instead that delaying muscle regeneration, by ablation of the transcription factor Nfix, ameliorates muscular dystrophy in mice.
- Giuliana Rossi
- , Chiara Bonfanti
- & Graziella Messina
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Article
| Open AccessMacrophage-released ADAMTS1 promotes muscle stem cell activation
Satellite cells are crucial for growth and regeneration of skeletal muscle. Here the authors show that in response to muscle injury, macrophages secrete Adamts1, which induces satellite cell activation by modulating Notch1 signaling.
- Hongqing Du
- , Chung-Hsuan Shih
- & Brian J. Feldman
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Article
| Open AccessBioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss
Volumetric muscle loss leads to functional muscle impairment, and current stem cell-based treatments show limited efficacy. Here, the authors generate a stem cell scaffold, implant it in mice, and show that an exercise regimen enhances innervation and restoration of muscle function in mice.
- Marco Quarta
- , Melinda Cromie
- & Thomas A. Rando
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Article
| Open AccessThe microprotein Minion controls cell fusion and muscle formation
Cellular fusion is essential for skeletal muscle development. Here the authors identify Minion as a microprotein required for myoblast fusion and skeletal muscle formation, and show that co-expression of Minion and Myomaker is sufficient to induce cytoskeletal rearrangement and cell fusion even in non-muscle cells.
- Qiao Zhang
- , Ajay A. Vashisht
- & Srihari C. Sampath
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Article
| Open AccessMyomerger induces fusion of non-fusogenic cells and is required for skeletal muscle development
Cellular fusion is fundamental for skeletal muscle development. Here the authors show that myomerger is expressed in myoblasts, is essential for myoblast fusion in mice, and in co-operation with myomaker confers fusogenic ability to non-fusogenic cells.
- Malgorzata E. Quinn
- , Qingnian Goh
- & Douglas P. Millay
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Article
| Open AccessPten is necessary for the quiescence and maintenance of adult muscle stem cells
Pten is known to regulate haematopoietic stem cell functions. Here the authors show that Ptenalteration of Notch signalling has stage-specific muscle regenerative functions in muscle stem cells by preventing premature differentiation of quiescent cells and enhancing the self-renewal of activated cells.
- Feng Yue
- , Pengpeng Bi
- & Shihuan Kuang
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Article
| Open AccessPraja1 E3 ubiquitin ligase promotes skeletal myogenesis through degradation of EZH2 upon p38α activation
In skeletal muscle progenitors, EZH2 maintains myogenic genes in a repressed state, but during differentiation its levels are reduced via unknown mechanisms. Here the authors show that during myogenesis, p38α kinase phosphorylates EZH2 and targets it for degradation by the ubiquitin ligase PRAJA1.
- Silvia Consalvi
- , Arianna Brancaccio
- & Daniela Palacios
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Article
| Open AccessThe transcription factor Prox1 is essential for satellite cell differentiation and muscle fibre-type regulation
Skeletal muscle has remarkable adaptive and regenerative capacity. Here the authors show that the transcription factor Prox1 is necessary for maintenance of slow muscle fibre types via activation of NFAT signalling, and for myoblast differentiation via cross-talk with the Notch signalling pathway.
- Riikka Kivelä
- , Ida Salmela
- & Kari Alitalo
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Article
| Open AccessPrmt5 is a regulator of muscle stem cell expansion in adult mice
Skeletal muscle satellite cells are important for muscle regeneration, but their regulatory mechanisms are largely unknown. Here the authors identify arginine methyltransferase Prmt5 as a key regulator of satellite cell maintenance and function in adult mice, and show that Prmt5 acts mainly but not exclusively on the cell cycle inhibitor p21.
- Ting Zhang
- , Stefan Günther
- & Thomas Braun
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Article |
Muscle stem cells contribute to myofibres in sedentary adult mice
Skeletal muscle satellite cells are muscle stem cells believed to contribute only to regenerating myofibres. Here Keefe et al. show that in adult sedentary mice satellite cells continue to fuse with uninjured myofibres, but they are not globally required for the maintenance of aging muscles.
- Alexandra C. Keefe
- , Jennifer A. Lawson
- & Gabrielle Kardon