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

2018 ◽  
Vol 19 (7) ◽  
pp. 2044 ◽  
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.

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

Cells ◽  
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.

scholarly journals Fibro-adipogenic progenitors in skeletal muscle homeostasis, regeneration and diseases

Open Biology ◽  
2021 ◽  
Vol 11 (12) ◽  
Author(s):  
Thomas Molina ◽  
Paul Fabre ◽  
Nicolas A. Dumont
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Muscle Regeneration ◽  
New Technologies ◽  
Cell Activity ◽  
Cellular Heterogeneity ◽  
Skeletal Muscle Regeneration ◽  
Acute Injury ◽  
Muscle Stem Cells ◽  
Muscle Homeostasis

Skeletal muscle possesses a remarkable regenerative capacity that relies on the activity of muscle stem cells, also known as satellite cells. The presence of non-myogenic cells also plays a key role in the coordination of skeletal muscle regeneration. Particularly, fibro-adipogenic progenitors (FAPs) emerged as master regulators of muscle stem cell function and skeletal muscle regeneration. This population of muscle resident mesenchymal stromal cells has been initially characterized based on its bi-potent ability to differentiate into fibroblasts or adipocytes. New technologies such as single-cell RNAseq revealed the cellular heterogeneity of FAPs and their complex regulatory network during muscle regeneration. In acute injury, FAPs rapidly enter the cell cycle and secrete trophic factors that support the myogenic activity of muscle stem cells. Conversely, deregulation of FAP cell activity is associated with the accumulation of fibrofatty tissue in pathological conditions such as muscular dystrophies and ageing. Considering their central role in skeletal muscle pathophysiology, the regulatory mechanisms of FAPs and their cellular and molecular crosstalk with muscle stem cells are highly investigated in the field. In this review, we summarize the current knowledge on FAP cell characteristics, heterogeneity and the cellular crosstalk during skeletal muscle homeostasis and regeneration. We further describe their role in muscular disorders, as well as different therapeutic strategies targeting these cells to restore muscle regeneration.

scholarly journals MON-710 ACVR1 Activation in Primary and iPS-Derived Human Skeletal Muscle Stem Cells Impairs Myogenic Transcriptional Signature and Function

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Emilie Barruet ◽  
Steven Garcia ◽  
Stanley Tamaki ◽  
Blanca M Morales ◽  
Jake Wu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Heterotopic Ossification ◽  
Satellite Cells ◽  
High Efficiency ◽  
Skeletal Muscle Regeneration ◽  
Type I ◽  
Muscle Repair ◽  
Mouse Muscle ◽  
Muscle Stem Cells

Abstract Developing optimal strategies for skeletal muscle regeneration and repair requires a detailed understanding of how these processes are regulated. The number of primary human satellite cells that can be obtained is usually extremely low, and may be impaired in disease of impaired skeletal muscle repair. One such condition is fibrodysplasia ossificans progressiva (FOP), a progressive disease characterized by massive heterotopic ossification in skeletal muscles and aberrant skeletal muscle repair after injury. FOP patients have activating mutations in the Activin A Type I receptor (ACVR1), a bone morphogenetic protein (BMP) receptor. Our overall hypothesis is that activated ACVR1 signaling caused by the ACVR1 R206H mutation incites inappropriate activation of human muscle stem cells (satellite cells, PAX7 expressing cells), causing loss of muscle cell fate and aberrant muscle repair. Since human satellite cells are difficult to obtain from live tissue donors, and injury can trigger heterotopic ossification, we created human induced pluripotent stem cell (iPSC)-derived muscle stem cells (iMuSCs) from FOP and control iPSC lines. We found that control and FOP iPSCs can differentiate into PAX7+ cells with high efficiency. Control and FOP iMuSCs can regenerate injured mouse muscle and form new human fibers, but both showed few PAX7 cells after transplant. Single cell RNA sequencing showed cell heterogeneity, and specific subsets of PAX7+ cells. FOP iMuSCs showed a chondrogenic/osteogenic signature (e.g COL1A1, DCN, OGN) with higher p38 pathway signaling activity. Skeletal muscle samples from autopsies of patients with FOP also showed increased expression of COL1A1. Additionally, we found that primary human FOP satellite cells can engraft and regenerate injured muscle, but with lower efficiency than control satellite cells. These studies used a novel iMuSC strategy to elucidate how increased ACVR1 activity affects human satellite cells function, and compare these iMuSCs to primary human satellite cells. These approaches will be useful to identify new therapeutic targets for conditions affecting skeletal muscle, and will improve our understanding of how muscle and bone interact in development and disease pathophysiology.

scholarly journals Zfp423 Regulates Skeletal Muscle Regeneration and Proliferation

2019 ◽  
Vol 39 (8) ◽  
Author(s):  
William N. Addison ◽  
Katherine C. Hall ◽  
Shoichiro Kokabu ◽  
Takuma Matsubara ◽  
Martin M. Fu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Muscle Regeneration ◽  
Affinity Purification ◽  
Skeletal Muscle Regeneration ◽  
Myoblast Differentiation ◽  
Muscle Stem Cells ◽  
Neuronal Precursors ◽  
A Cell ◽  
Skeletal Muscle Stem Cells

ABSTRACT Satellite cells (SCs) are skeletal muscle stem cells that proliferate in response to injury and provide myogenic precursors for growth and repair. Zfp423 is a transcriptional cofactor expressed in multiple immature cell populations, such as neuronal precursors, mesenchymal stem cells, and preadipocytes, where it regulates lineage allocation, proliferation, and differentiation. Here, we show that Zfp423 regulates myogenic progression during muscle regeneration. Zfp423 is undetectable in quiescent SCs but becomes expressed during SC activation. After expansion, Zfp423 is gradually downregulated as committed SCs terminally differentiate. Mice with satellite-cell-specific Zfp423 deletion exhibit severely impaired muscle regeneration following injury, with aberrant SC expansion, defective cell cycle exit, and failure to transition efficiently from the proliferative stage toward commitment. Consistent with a cell-autonomous role of Zfp423, shRNA-mediated knockdown of Zfp423 in myoblasts inhibits differentiation. Surprisingly, forced expression of Zfp423 in myoblasts induces differentiation into adipocytes and arrests myogenesis. Affinity purification of Zfp423 in myoblasts identified Satb2 as a nuclear partner of Zfp423 that cooperatively enhances Zfp423 transcriptional activity, which in turn affects myoblast differentiation. In conclusion, by controlling SC expansion and proliferation, Zfp423 is essential for muscle regeneration. Tight regulation of Zfp423 expression is essential for normal progression of muscle progenitors from proliferation to differentiation.

scholarly journals The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Anirban Roy ◽  
Meiricris Tomaz da Silva ◽  
Raksha Bhat ◽  
Kyle R Bohnert ◽  
Takao Iwawaki ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Ex Vivo ◽  
Skeletal Muscle Regeneration ◽  
Mdx Mice ◽  
Major Mechanism ◽  
Downstream Target ◽  
A Cell ◽  
The Unfolded Protein Response

Skeletal muscle regeneration is regulated by coordinated activation of multiple signaling pathways activated in both injured myofibers and satellite cells. The unfolded protein response (UPR) is a major mechanism that detects and alleviates protein-folding stresses in ER. However, the role of individual arms of the UPR in skeletal muscle regeneration remain less understood. In the present study, we demonstrate that IRE1α (also known as ERN1) and its downstream target, XBP1, are activated in skeletal muscle of mice upon injury. Myofiber-specific ablation of IRE1 or XBP1 in mice diminishes skeletal muscle regeneration that is accompanied with reduced number of satellite cells and their fusion to injured myofibers. Ex vivo cultures of myofiber explants demonstrate that ablation of IRE1α reduces the proliferative capacity of myofiber-associated satellite cells. Myofiber-specific deletion of IRE1α dampens Notch signaling and canonical NF-kB pathway in skeletal muscle of mice. Our results also demonstrate that targeted ablation of IRE1α reduces skeletal muscle regeneration in the mdx mice, a model of Duchenne muscular dystrophy. Collectively, our results reveal that the IRE1α-mediated signaling promotes muscle regeneration through augmenting the proliferation of satellite cells in a cell non-autonomous manner.

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

eLife ◽  
2018 ◽  
Vol 7 ◽  
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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