It takes all kinds: heterogeneity among satellite cells and fibro-adipogenic progenitors during skeletal muscle regeneration

Development ◽  
2021 ◽  
Vol 148 (21) ◽  
Author(s):  
Brittany C. Collins ◽  
Gabrielle Kardon
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Regenerative Process ◽  
Skeletal Muscle Regeneration ◽  
Anatomical Location ◽  
Muscle Stem Cells ◽  
Functional Consequences ◽  
Transplantation Experiments ◽  
Complete Regeneration ◽  
Vertebrate Skeletal Muscle

ABSTRACT Vertebrate skeletal muscle is composed of multinucleate myofibers that are surrounded by muscle connective tissue. Following injury, muscle is able to robustly regenerate because of tissue-resident muscle stem cells, called satellite cells. In addition, efficient and complete regeneration depends on other cells resident in muscle – including fibro-adipogenic progenitors (FAPs). Increasing evidence from single-cell analyses and genetic and transplantation experiments suggests that satellite cells and FAPs are heterogeneous cell populations. Here, we review our current understanding of the heterogeneity of satellite cells, their myogenic derivatives and FAPs in terms of gene expression, anatomical location, age and timing during the regenerative process – each of which have potentially important functional consequences.

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.

Satellite cells and skeletal muscle regeneration

1966 ◽  
Vol 53 (7) ◽  
pp. 638-642 ◽  
Author(s):  
J. C. T. Church ◽  
R. F. X. Noronha ◽  
D. B. Allbrook
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Skeletal Muscle Regeneration

scholarly journals The LIM domain protein nTRIP6 modulates the dynamics of myogenic differentiation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tannaz Norizadeh Abbariki ◽  
Zita Gonda ◽  
Denise Kemler ◽  
Pavel Urbanek ◽  
Tabea Wagner ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Myogenic Differentiation ◽  
Skeletal Muscle Regeneration ◽  
Temporal Control ◽  
Lim Domain ◽  
Lim Domain Protein ◽  
Domain Protein

AbstractThe process of myogenesis which operates during skeletal muscle regeneration involves the activation of muscle stem cells, the so-called satellite cells. These then give rise to proliferating progenitors, the myoblasts which subsequently exit the cell cycle and differentiate into committed precursors, the myocytes. Ultimately, the fusion of myocytes leads to myofiber formation. Here we reveal a role for the transcriptional co-regulator nTRIP6, the nuclear isoform of the LIM-domain protein TRIP6, in the temporal control of myogenesis. In an in vitro model of myogenesis, the expression of nTRIP6 is transiently up-regulated at the transition between proliferation and differentiation, whereas that of the cytosolic isoform TRIP6 is not altered. Selectively blocking nTRIP6 function results in accelerated early differentiation followed by deregulated late differentiation and fusion. Thus, the transient increase in nTRIP6 expression appears to prevent premature differentiation. Accordingly, knocking out the Trip6 gene in satellite cells leads to deregulated skeletal muscle regeneration dynamics in the mouse. Thus, dynamic changes in nTRIP6 expression contributes to the temporal control of myogenesis.

scholarly journals Acid Sphingomyelinase Controls Early Phases of Skeletal Muscle Regeneration by Shaping the Macrophage Phenotype

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3028
Author(s):  
Paulina Roux-Biejat ◽  
Marco Coazzoli ◽  
Pasquale Marrazzo ◽  
Silvia Zecchini ◽  
Ilaria Di Renzo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Acid Sphingomyelinase ◽  
Skeletal Muscle Regeneration ◽  
Sphingolipid Metabolism ◽  
M2 Macrophages ◽  
Macrophage Phenotype ◽  
M1 Macrophages ◽  
Early Phases

Skeletal muscle regeneration is a complex process involving crosstalk between immune cells and myogenic precursor cells, i.e., satellite cells. In this scenario, macrophage recruitment in damaged muscles is a mandatory step for tissue repair since pro-inflammatory M1 macrophages promote the activation of satellite cells, stimulating their proliferation and then, after switching into anti-inflammatory M2 macrophages, they prompt satellite cells’ differentiation into myotubes and resolve inflammation. Here, we show that acid sphingomyelinase (ASMase), a key enzyme in sphingolipid metabolism, is activated after skeletal muscle injury induced in vivo by the injection of cardiotoxin. ASMase ablation shortens the early phases of skeletal muscle regeneration without affecting satellite cell behavior. Of interest, ASMase regulates the balance between M1 and M2 macrophages in the injured muscles so that the absence of the enzyme reduces inflammation. The analysis of macrophage populations indicates that these events depend on the altered polarization of M1 macrophages towards an M2 phenotype. Our results unravel a novel role of ASMase in regulating immune response during muscle regeneration/repair and suggest ASMase as a supplemental therapeutic target in conditions of redundant inflammation that impairs muscle recovery.

scholarly journals Skeletal muscle regeneration is altered in the R6/2 mouse model of Huntington's disease

2022 ◽  
Author(s):  
Sanzana Hoque ◽  
Marie Sjogren ◽  
Valerie Allamand ◽  
Kinga Gawlik ◽  
Naomi Franke ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Muscle Damage ◽  
Satellite Cell ◽  
Mouse Models ◽  
Satellite Cells ◽  
Muscle Fibers ◽  
Cag Repeat ◽  
Skeletal Muscle Regeneration

Huntington's disease (HD) is caused by CAG repeat expansion in the huntingtin (HTT) gene. Skeletal muscle wasting alongside central pathology is a well-recognized phenomenon seen in patients with HD and HD mouse models. HD muscle atrophy progresses with disease and affects prognosis and quality of life. Satellite cells, progenitors of mature skeletal muscle fibers, are essential for proliferation, differentiation, and repair of muscle tissue in response to muscle injury or exercise. In this study, we aim to investigate the effect of mutant HTT on the differentiation and regeneration capacity of HD muscle by employing in vitro mononuclear skeletal muscle cell isolation and in vivo acute muscle damage model in R6/2 mice. We found that, similar to R6/2 adult mice, neonatal R6/2 mice also exhibit a significant reduction in myofiber width and morphological changes in gastrocnemius and soleus muscles compared to WT mice. Cardiotoxin (CTX)-induced acute muscle damage in R6/2 and WT mice showed that the Pax7+ satellite cell pool was dampened in R6/2 mice at 4 weeks post-injection, and R6/2 mice exhibited an altered inflammatory profile in response to acute damage. Our results suggest that, in addition to the mutant HTT degenerative effects in mature muscle fibers, expression of mutant HTT in satellite cells might alter developmental and regenerative processes to contribute to the progressive muscle mass loss in HD. Taken together, the results presented here encourage further studies evaluating the underlying mechanisms of satellite cell dysfunction in HD mouse models.

scholarly journals MORPHOLOGICAL CHARACTERISTICS OF POSTTRAUMATIC SKELETAL MUSCLE REGENERATION AFTER EXPERIMENTAL BLAST INJURY

2015 ◽  
Vol 14 (4) ◽  
pp. 17-24 ◽  
Author(s):  
N. G. Vengerovich ◽  
I. A. Shperling ◽  
Yu. V. Yurkevich ◽  
O. O. Vladimirova ◽  
I. I. Alekseyeva ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Morphological Analysis ◽  
Morphological Characteristics ◽  
Blast Injury ◽  
Regenerative Process ◽  
Lower Limbs ◽  
Skeletal Muscle Regeneration ◽  
Musculoskeletal Tissue ◽  
Histological Characteristics

The research objective was a morphological analysis of posttraumatic regeneration of musculoskeletal tissue in rats after experimental blast injury with field simulation of remote musculocutaneous injury of lower limbs. Wound process was evaluated visually and by histological characteristics of injury zones. This research helped to deepen understanding of details of regenerative process of blast musculocutaneous injury and formation of regenerating muscular and connective tissue of skeletal muscle in rats

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.

scholarly journals Abcg2 labels multiple cell types in skeletal muscle and participates in muscle regeneration

2011 ◽  
Vol 195 (1) ◽  
pp. 147-163 ◽  
Author(s):  
Michelle J. Doyle ◽  
Sheng Zhou ◽  
Kathleen Kelly Tanaka ◽  
Addolorata Pisconti ◽  
Nicholas H. Farina ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Side Population ◽  
Cell Types ◽  
Lineage Tracing ◽  
Skeletal Muscle Regeneration ◽  
Genetic Lineage ◽  
Multiple Cell ◽  
A Minor

Skeletal muscle contains progenitor cells (satellite cells) that maintain and repair muscle. It also contains muscle side population (SP) cells, which express Abcg2 and may participate in muscle regeneration or may represent a source of satellite cell replenishment. In Abcg2-null mice, the SP fraction is lost in skeletal muscle, although the significance of this loss was previously unknown. We show that cells expressing Abcg2 increased upon injury and that muscle regeneration was impaired in Abcg2-null mice, resulting in fewer centrally nucleated myofibers, reduced myofiber size, and fewer satellite cells. Additionally, using genetic lineage tracing, we demonstrate that the progeny of Abcg2-expressing cells contributed to multiple cell types within the muscle interstitium, primarily endothelial cells. After injury, Abcg2 progeny made a minor contribution to regenerated myofibers. Furthermore, Abcg2-labeled cells increased significantly upon injury and appeared to traffic to muscle from peripheral blood. Together, these data suggest an important role for Abcg2 in positively regulating skeletal muscle regeneration.

scholarly journals Satellite Cell Depletion Disrupts Transcriptional Coordination and Muscle Adaptation to Exercise

Function ◽  
2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Davis A Englund ◽  
Vandré C Figueiredo ◽  
Cory M Dungan ◽  
Kevin A Murach ◽  
Bailey D Peck ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Gene Networks ◽  
Wheel Running ◽  
Skeletal Muscle Regeneration ◽  
Rna Seq ◽  
Muscle Adaptation ◽  
Hypertrophic Growth ◽  
Adaptation To Exercise

Abstract Satellite cells are required for postnatal development, skeletal muscle regeneration across the lifespan, and skeletal muscle hypertrophy prior to maturity. Our group has aimed to address whether satellite cells are required for hypertrophic growth in mature skeletal muscle. Here, we generated a comprehensive characterization and transcriptome-wide profiling of skeletal muscle during adaptation to exercise in the presence or absence of satellite cells in order to identify distinct phenotypes and gene networks influenced by satellite cell content. We administered vehicle or tamoxifen to adult Pax7-DTA mice and subjected them to progressive weighted wheel running (PoWeR). We then performed immunohistochemical analysis and whole-muscle RNA-seq of vehicle (SC+) and tamoxifen-treated (SC−) mice. Further, we performed single myonuclear RNA-seq to provide detailed information on how satellite cell fusion affects myonuclear transcription. We show that while skeletal muscle can mount a robust hypertrophic response to PoWeR in the absence of satellite cells, growth, and adaptation are ultimately blunted. Transcriptional profiling reveals several gene networks key to muscle adaptation are altered in the absence of satellite cells.

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