Fasting Induces a Highly Resilient Deep Quiescent State in Muscle Stem Cells via Ketone Body Signaling

Short-term fasting is beneficial for the regeneration of multiple tissue types. However, the effects of fasting on muscle regeneration are largely unknown. Here we report that fasting slows muscle repair both immediately after the conclusion of fasting as well as after multiple days of refeeding. We show that ketosis, either endogenously produced during fasting or a ketogenic diet, or exogenously administered, promotes a deep quiescent state in muscle stem cells(MuSCs). Although deep quiescent MuSCs are less poised to activate, slowing muscle regeneration, they have markedly improved survival when facing sources of cellular stress. Further, we show that ketone bodies, specifically b hydroxybutyrate, directly promote MuSC deep quiescence via a non-metabolic mechanism. We show that b-hydroxybutyrate functions as an HDAC inhibitor within MuSCs leading to acetylation and activation of an HDAC1 target protein p53. Finally, we demonstrate that p53 activation contributes to the deep quiescence and enhanced resilience observed during fasting.

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PPARγ Controls Ectopic Adipogenesis and Cross-Talks with Myogenesis During Skeletal Muscle Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms19072044 ◽

2018 ◽

Vol 19 (7) ◽

pp. 2044 ◽

Cited By ~ 11

Author(s):

Gabriele Dammone ◽

Sonia Karaz ◽

Laura Lukjanenko ◽

Carine Winkler ◽

Federico Sizzano ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Adipose Tissue ◽

Muscle Regeneration ◽

Ex Vivo ◽

Skeletal Muscle Regeneration ◽

Whole Body ◽

Muscle Repair ◽

Muscle Stem Cells ◽

Muscle Fat Infiltration

Skeletal muscle is a regenerative tissue which can repair damaged myofibers through the activation of tissue-resident muscle stem cells (MuSCs). Many muscle diseases with impaired regeneration cause excessive adipose tissue accumulation in muscle, alter the myogenic fate of MuSCs, and deregulate the cross-talk between MuSCs and fibro/adipogenic progenitors (FAPs), a bi-potent cell population which supports myogenesis and controls intra-muscular fibrosis and adipocyte formation. In order to better characterize the interaction between adipogenesis and myogenesis, we studied muscle regeneration and MuSC function in whole body Pparg null mice generated by epiblast-specific Cre/lox deletion (PpargΔ/Δ). We demonstrate that deletion of PPARγ completely abolishes ectopic muscle adipogenesis during regeneration and impairs MuSC expansion and myogenesis after injury. Ex vivo assays revealed that perturbed myogenesis in PpargΔ/Δ mice does not primarily result from intrinsic defects of MuSCs or from perturbed myogenic support from FAPs. The immune transition from a pro- to anti-inflammatory MuSC niche during regeneration is perturbed in PpargΔ/Δ mice and suggests that PPARγ signaling in macrophages can interact with ectopic adipogenesis and influence muscle regeneration. Altogether, our study demonstrates that a PPARγ-dependent adipogenic response regulates muscle fat infiltration during regeneration and that PPARγ is required for MuSC function and efficient muscle repair.

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Progressive and Coordinated Mobilization of the Skeletal Muscle Niche throughout Tissue Repair Revealed by Single-Cell Proteomic Analysis

Cells ◽

10.3390/cells10040744 ◽

2021 ◽

Vol 10 (4) ◽

pp. 744

Author(s):

Matthew Borok ◽

Nathalie Didier ◽

Francesca Gattazzo ◽

Teoman Ozturk ◽

Aurelien Corneau ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Stem Cell ◽

Muscle Regeneration ◽

Cell Types ◽

Skeletal Muscle Regeneration ◽

Muscle Repair ◽

Muscle Stem Cell ◽

Muscle Stem Cells ◽

Cell Lineages

Background: Skeletal muscle is one of the only mammalian tissues capable of rapid and efficient regeneration after trauma or in pathological conditions. Skeletal muscle regeneration is driven by the muscle satellite cells, the stem cell population in interaction with their niche. Upon injury, muscle fibers undergo necrosis and muscle stem cells activate, proliferate and fuse to form new myofibers. In addition to myogenic cell populations, interaction with other cell types such as inflammatory cells, mesenchymal (fibroadipogenic progenitors—FAPs, pericytes) and vascular (endothelial) lineages are important for efficient muscle repair. While the role of the distinct populations involved in skeletal muscle regeneration is well characterized, the quantitative changes in the muscle stem cell and niche during the regeneration process remain poorly characterized. Methods: We have used mass cytometry to follow the main muscle cell types (muscle stem cells, vascular, mesenchymal and immune cell lineages) during early activation and over the course of muscle regeneration at D0, D2, D5 and D7 compared with uninjured muscles. Results: Early activation induces a number of rapid changes in the proteome of multiple cell types. Following the induction of damage, we observe a drastic loss of myogenic, vascular and mesenchymal cell lineages while immune cells invade the damaged tissue to clear debris and promote muscle repair. Immune cells constitute up to 80% of the mononuclear cells 5 days post-injury. We show that muscle stem cells are quickly activated in order to form new myofibers and reconstitute the quiescent muscle stem cell pool. In addition, our study provides a quantitative analysis of the various myogenic populations during muscle repair. Conclusions: We have developed a mass cytometry panel to investigate the dynamic nature of muscle regeneration at a single-cell level. Using our panel, we have identified early changes in the proteome of stressed satellite and niche cells. We have also quantified changes in the major cell types of skeletal muscle during regeneration and analyzed myogenic transcription factor expression in satellite cells throughout this process. Our results highlight the progressive dynamic shifts in cell populations and the distinct states of muscle stem cells adopted during skeletal muscle regeneration. Our findings give a deeper understanding of the cellular and molecular aspects of muscle regeneration.

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Wnt4 from the Niche Controls the Mechano-Properties and Quiescent State of Muscle Stem Cells

Cell Stem Cell ◽

10.1016/j.stem.2019.08.007 ◽

2019 ◽

Vol 25 (5) ◽

pp. 654-665.e4 ◽

Cited By ~ 20

Author(s):

Susan Eliazer ◽

Jonathon M. Muncie ◽

Josef Christensen ◽

Xuefeng Sun ◽

Rebecca S. D’Urso ◽

...

Keyword(s):

Stem Cells ◽

Quiescent State ◽

Muscle Stem Cells

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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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