Brief Report: Blockade of Notch Signaling in Muscle Stem Cells Causes Muscular Dystrophic Phenotype and Impaired Muscle Regeneration

The Pax7+ muscle stem cells (MuSCs) are essential for skeletal muscle homeostasis and muscle regeneration upon injury, while the molecular mechanisms underlying muscle stem cell fate determination and muscle regeneration are still not fully understood. N6-methyladenosine (m6A) RNA modification is catalyzed by METTL3 and plays important functions in posttranscriptional gene expression regulation and various biological processes. Here, we generated muscle stem cell-specific METTL3 conditional knockout mouse model and revealed that METTL3 knockout in muscle stem cells significantly inhibits the proliferation of muscle stem cells and blocks the muscle regeneration after injury. Moreover, knockin of METTL3 in muscle stem cells promotes the muscle stem cell proliferation and muscle regeneration in vivo. Mechanistically, METTL3-m6A-YTHDF1 axis regulates the mRNA translation of Notch signaling pathway. Our data demonstrated the important in vivo physiological function of METTL3-mediated m6A modification in muscle stem cells and muscle regeneration, providing molecular basis for the therapy of stem cell-related muscle diseases.

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The role of Pitx2 and Pitx3 in muscle stem cells gives new insights into P38α MAP kinase and redox regulation of muscle regeneration

eLife ◽

10.7554/elife.32991 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 15

Author(s):

Aurore L'honoré ◽

Pierre-Henri Commère ◽

Elisa Negroni ◽

Giorgia Pallafacchina ◽

Bertrand Friguet ◽

...

Keyword(s):

Stem Cells ◽

Map Kinase ◽

Satellite Cells ◽

Muscle Regeneration ◽

Redox Regulation ◽

Primary Cultures ◽

Rapid Expansion ◽

Skeletal Muscle Regeneration ◽

Muscle Stem Cells ◽

P38α Map Kinase

Skeletal muscle regeneration depends on satellite cells. After injury these muscle stem cells exit quiescence, proliferate and differentiate to regenerate damaged fibres. We show that this progression is accompanied by metabolic changes leading to increased production of reactive oxygen species (ROS). Using Pitx2/3 single and double mutant mice that provide genetic models of deregulated redox states, we demonstrate that moderate overproduction of ROS results in premature differentiation of satellite cells while high levels lead to their senescence and regenerative failure. Using the ROS scavenger, N-Acetyl-Cysteine (NAC), in primary cultures we show that a physiological increase in ROS is required for satellite cells to exit the cell cycle and initiate differentiation through the redox activation of p38α MAP kinase. Subjecting cultured satellite cells to transient inhibition of P38α MAP kinase in conjunction with NAC treatment leads to their rapid expansion, with striking improvement of their regenerative potential in grafting experiments.

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Skeletal Muscle Stem Cells for Muscle Regeneration

Methods in Molecular Biology - Animal Models for Stem Cell Therapy ◽

10.1007/978-1-4939-1453-1_20 ◽

2014 ◽

pp. 245-253 ◽

Cited By ~ 3

Author(s):

Johnny Kim ◽

Thomas Braun

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Muscle Regeneration ◽

Muscle Stem Cells ◽

Skeletal Muscle Stem Cells

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Satellite Cells CD44 Positive Drive Muscle Regeneration in Osteoarthritis Patients

Stem Cells International ◽

10.1155/2015/469459 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 13

Author(s):

Manuel Scimeca ◽

Elena Bonanno ◽

Eleonora Piccirilli ◽

Jacopo Baldi ◽

Alessandro Mauriello ◽

...

Keyword(s):

Electron Microscopy ◽

Stem Cells ◽

Transmission Electron Microscopy ◽

Satellite Cells ◽

Muscle Regeneration ◽

Bone Diseases ◽

Mineral Density ◽

Muscle Stem Cells ◽

Age Related ◽

Transmission Electron

Age-related bone diseases, such as osteoarthritis and osteoporosis, are strongly associated with sarcopenia and muscle fiber atrophy. In this study, we analyzed muscle biopsies in order to demonstrate that, in osteoarthritis patients, both osteophytes formation and regenerative properties of muscle stem cells are related to the same factors. In particular, thanks to immunohistochemistry, transmission electron microscopy, and immunogold labeling we investigated the role of BMP-2 in muscle stem cells activity. In patients with osteoarthritis both immunohistochemistry and transmission electron microscopy allowed us to note a higher number of CD44 positive satellite muscle cells forming syncytium. Moreover, the perinuclear and cytoplasmic expression of BMP-2 assessed byin situmolecular characterization of satellite cells syncytia suggest a very strict correlation between BMP-2 expression and muscle regeneration capability. Summing up, the higher BMP-2 expression in osteoarthritic patients could explain the increased bone mineral density as well as decreased muscle atrophy in osteoarthrosic patients. In conclusion, our results suggest that the control of physiological BMP-2 balance between bone and muscle tissues may be considered as a potential pharmacological target in bone-muscle related pathology.

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Erratum for the Research Article "Asymmetric division of clonal muscle stem cells coordinates muscle regeneration in vivo" by D. B. Gurevich, P. D. Nguyen, A. L. Siegel, O. V. Ehrlich, C. Sonntag, J. M. N. Phan, S. Berger, D. Ratnayake, L. Hersey, J. Berger, H. Verkade, T. E. Hall, P. D. Currie

Science ◽

10.1126/science.aah4673 ◽

2016 ◽

Vol 353 (6295) ◽

pp. aah4673-aah4673

Keyword(s):

Stem Cells ◽

Muscle Regeneration ◽

Asymmetric Division ◽

Muscle Stem Cells ◽

Research Article

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Lack of PKCθ Promotes Regenerative Ability of Muscle Stem Cells in Chronic Muscle Injury

International Journal of Molecular Sciences ◽

10.3390/ijms21030932 ◽

2020 ◽

Vol 21 (3) ◽

pp. 932 ◽

Cited By ~ 1

Author(s):

Piera Filomena Fiore ◽

Anna Benedetti ◽

Martina Sandonà ◽

Luca Madaro ◽

Marco De Bardi ◽

...

Keyword(s):

Stem Cells ◽

Muscle Regeneration ◽

Muscle Wasting ◽

Expression Level ◽

Acute Injury ◽

Mdx Mice ◽

Muscle Stem Cells ◽

Advanced Stages ◽

And Performance ◽

Dystrophic Mice

Duchenne muscular dystrophy (DMD) is a genetic disease characterized by muscle wasting and chronic inflammation, leading to impaired satellite cells (SCs) function and exhaustion of their regenerative capacity. We previously showed that lack of PKCθ in mdx mice, a mouse model of DMD, reduces muscle wasting and inflammation, and improves muscle regeneration and performance at early stages of the disease. In this study, we show that muscle regeneration is boosted, and fibrosis reduced in mdxθ−/− mice, even at advanced stages of the disease. This phenotype was associated with a higher number of Pax7 positive cells in mdxθ−/− muscle compared with mdx muscle, during the progression of the disease. Moreover, the expression level of Pax7 and Notch1, the pivotal regulators of SCs self-renewal, were upregulated in SCs isolated from mdxθ−/− muscle compared with mdx derived SCs. Likewise, the expression of the Notch ligands Delta1 and Jagged1 was higher in mdxθ−/− muscle compared with mdx. The expression level of Delta1 and Jagged1 was also higher in PKCθ−/− muscle compared with WT muscle following acute injury. In addition, lack of PKCθ prolonged the survival and sustained the differentiation of transplanted myogenic progenitors. Overall, our results suggest that lack of PKCθ promotes muscle repair in dystrophic mice, supporting stem cells survival and maintenance through increased Delta-Notch signaling.

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