scholarly journals Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3089
Author(s):  
Zsófia Budai ◽  
Nour Al-Zaeed ◽  
Péter Szentesi ◽  
Hajnalka Halász ◽  
László Csernoch ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Muscle Development ◽  
Tibialis Anterior Muscle ◽  
Transglutaminase 2 ◽  
Myoblast Fusion ◽  
Skeletal Muscle Regeneration ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Inflammatory Phenotype

Skeletal muscle regeneration is triggered by local inflammation and is accompanied by phagocytosis of dead cells at the injury site. Efferocytosis regulates the inflammatory program in macrophages by initiating the conversion of their inflammatory phenotype into the healing one. While pro-inflammatory cytokines induce satellite cell proliferation and differentiation into myoblasts, growth factors, such as GDF3, released by healing macrophages drive myoblast fusion and myotube growth. Therefore, improper efferocytosis may lead to impaired muscle regeneration. Transglutaminase 2 (TG2) is a versatile enzyme participating in efferocytosis. Here, we show that TG2 ablation did not alter the skeletal muscle weights or sizes but led to the generation of small size myofibers and to decreased grip force in TG2 null mice. Following cardiotoxin-induced injury, the size of regenerating fibers was smaller, and the myoblast fusion was delayed in the tibialis anterior muscle of TG2 null mice. Loss of TG2 did not affect the efferocytic capacity of muscle macrophages but delayed their conversion to Ly6C−CD206+, GDF3 expressing cells. Finally, TG2 promoted myoblast fusion in differentiating C2C12 myoblasts. These results indicate that TG2 expressed by both macrophages and myoblasts contributes to proper myoblast fusion, and its ablation leads to impaired muscle development and regeneration in mice.

scholarly journals Klf5 regulates muscle differentiation by directly targeting muscle-specific genes in cooperation with MyoD in mice

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Shinichiro Hayashi ◽  
Ichiro Manabe ◽  
Yumi Suzuki ◽  
Frédéric Relaix ◽  
Yumiko Oishi
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Myogenic Differentiation ◽  
Muscle Differentiation ◽  
Skeletal Muscle Regeneration ◽  
Biological Processes ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Acting In Concert

Krüppel-like factor 5 (Klf5) is a zinc-finger transcription factor that controls various biological processes, including cell proliferation and differentiation. We show that Klf5 is also an essential mediator of skeletal muscle regeneration and myogenic differentiation. During muscle regeneration after injury (cardiotoxin injection), Klf5 was induced in the nuclei of differentiating myoblasts and newly formed myofibers expressing myogenin in vivo. Satellite cell-specific Klf5 deletion severely impaired muscle regeneration, and myotube formation was suppressed in Klf5-deleted cultured C2C12 myoblasts and satellite cells. Klf5 knockdown suppressed induction of muscle differentiation-related genes, including myogenin. Klf5 ChIP-seq revealed that Klf5 binding overlaps that of MyoD and Mef2, and Klf5 physically associates with both MyoD and Mef2. In addition, MyoD recruitment was greatly reduced in the absence of Klf5. These results indicate that Klf5 is an essential regulator of skeletal muscle differentiation, acting in concert with myogenic transcription factors such as MyoD and Mef2.

scholarly journals Role of trophic factors in development and regeneration of skeletal muscles

2019 ◽  
Vol 75 (11) ◽  
pp. 6348-2019
Author(s):  
ANNA CIECIERSKA ◽  
TOMASZ SADKOWSKI ◽  
TOMASZ MOTYL
Keyword(s):  
Skeletal Muscle ◽  
Growth Factors ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Muscle Development ◽  
Biologically Active ◽  
Trophic Factors ◽  
Skeletal Muscle Regeneration ◽  
Surrounding Tissue ◽  
Proliferation And Differentiation

The process of skeletal muscle development is regulated by many biologically active factors, which are responsible for stimulating the proliferation and differentiation of muscle cells. Biologically active factors function in paracrine, autocrine and endocrine manner to control myogenesis. The main regulators include hormones, growth and differentiation factors, as well as cytokines. The process of skeletal muscle regeneration associated with the activation of satellite cells for their proliferation and differentiation requires the involvement of many growth factors secreted by the surrounding tissue, including inflammatory cells, blood vessels and damaged muscle fiber, as well as extracellular matrix. A number of trophic factors regulating the activity of satellite cells during muscle regeneration have been identified, e.g. fibroblast growth factors, transforming growth factors-β, insulin-like growth factors, hepatocyte growth factor, tumor necrosis factor-α, interleukin-6. These factors are responsible for maintaining a balance between the processes of proliferation and differentiation of satellite cells in order to restore the proper architecture and functioning of muscle tissue.

scholarly journals Phospholipase D1 facilitates second-phase myoblast fusion and skeletal muscle regeneration

2015 ◽  
Vol 26 (3) ◽  
pp. 506-517 ◽  
Author(s):  
Shuzhi Teng ◽  
David Stegner ◽  
Qin Chen ◽  
Tsunaki Hongu ◽  
Hiroshi Hasegawa ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Muscle Development ◽  
Myoblast Fusion ◽  
Skeletal Muscle Regeneration ◽  
Fusion Pore ◽  
Myoblast Differentiation ◽  
Second Phase ◽  
Genetic Ablation ◽  
Phospholipase D1

Myoblast differentiation and fusion is a well-orchestrated multistep process that is essential for skeletal muscle development and regeneration. Phospholipase D1 (PLD1) has been implicated in the initiation of myoblast differentiation in vitro. However, whether PLD1 plays additional roles in myoblast fusion and exerts a function in myogenesis in vivo remains unknown. Here we show that PLD1 expression is up-regulated in myogenic cells during muscle regeneration after cardiotoxin injury and that genetic ablation of PLD1 results in delayed myofiber regeneration. Myoblasts derived from PLD1-null mice or treated with PLD1-specific inhibitor are unable to form mature myotubes, indicating defects in second-phase myoblast fusion. Concomitantly, the PLD1 product phosphatidic acid is transiently detected on the plasma membrane of differentiating myocytes, and its production is inhibited by PLD1 knockdown. Exogenous lysophosphatidylcholine, a key membrane lipid for fusion pore formation, partially rescues fusion defect resulting from PLD1 inhibition. Thus these studies demonstrate a role for PLD1 in myoblast fusion during myogenesis in which PLD1 facilitates the fusion of mononuclear myocytes with nascent myotubes.

scholarly journals Conditional Deletion of Dicer in Adult Mice Impairs Skeletal Muscle Regeneration

2019 ◽  
Vol 20 (22) ◽  
pp. 5686 ◽  
Author(s):  
Satoshi Oikawa ◽  
Minjung Lee ◽  
Takayuki Akimoto
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Myogenic Differentiation ◽  
Tibialis Anterior Muscle ◽  
Critical Factor ◽  
Skeletal Muscle Regeneration ◽  
Small Noncoding Rnas ◽  
Adult Mice

Skeletal muscle has a remarkable regenerative capacity, which is orchestrated by multiple processes, including the proliferation, fusion, and differentiation of the resident stem cells in muscle. MicroRNAs (miRNAs) are small noncoding RNAs that mediate the translational repression or degradation of mRNA to regulate diverse biological functions. Previous studies have suggested that several miRNAs play important roles in myoblast proliferation and differentiation in vitro. However, their potential roles in skeletal muscle regeneration in vivo have not been fully established. In this study, we generated a mouse in which the Dicer gene, which encodes an enzyme essential in miRNA processing, was knocked out in a tamoxifen-inducible way (iDicer KO mouse) and determined its regenerative potential after cardiotoxin-induced acute muscle injury. Dicer mRNA expression was significantly reduced in the tibialis anterior muscle of the iDicer KO mice, whereas the expression of muscle-enriched miRNAs was only slightly reduced in the Dicer-deficient muscles. After cardiotoxin injection, the iDicer KO mice showed impaired muscle regeneration. We also demonstrated that the number of PAX7+ cells, cell proliferation, and the myogenic differentiation capacity of the primary myoblasts did not differ between the wild-type and the iDicer KO mice. Taken together, these data demonstrate that Dicer is a critical factor for muscle regeneration in vivo.

scholarly journals Tenogenic Contribution to Skeletal Muscle Regeneration: The Secretome of Scleraxis Overexpressing Mesenchymal Stem Cells Enhances Myogenic Differentiation In Vitro

2020 ◽  
Vol 21 (6) ◽  
pp. 1965
Author(s):  
Maximilian Strenzke ◽  
Paolo Alberton ◽  
Attila Aszodi ◽  
Denitsa Docheva ◽  
Elisabeth Haas ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Skeletal Muscles ◽  
Myogenic Differentiation ◽  
Muscular Contraction ◽  
Myoblast Fusion ◽  
Skeletal Muscle Regeneration ◽  
Potential Candidate ◽  
Musculoskeletal Tissue

Integrity of the musculoskeletal system is essential for the transfer of muscular contraction force to the associated bones. Tendons and skeletal muscles intertwine, but on a cellular level, the myotendinous junctions (MTJs) display a sharp transition zone with a highly specific molecular adaption. The function of MTJs could go beyond a mere structural role and might include homeostasis of this musculoskeletal tissue compound, thus also being involved in skeletal muscle regeneration. Repair processes recapitulate several developmental mechanisms, and as myotendinous interaction does occur already during development, MTJs could likewise contribute to muscle regeneration. Recent studies identified tendon-related, scleraxis-expressing cells that reside in close proximity to the MTJs and the muscle belly. As the muscle-specific function of these scleraxis positive cells is unknown, we compared the influence of two immortalized mesenchymal stem cell (MSC) lines—differing only by the overexpression of scleraxis—on myoblasts morphology, metabolism, migration, fusion, and alignment. Our results revealed a significant increase in myoblast fusion and metabolic activity when exposed to the secretome derived from scleraxis-overexpressing MSCs. However, we found no significant changes in myoblast migration and myofiber alignment. Further analysis of differentially expressed genes between native MSCs and scleraxis-overexpressing MSCs by RNA sequencing unraveled potential candidate genes, i.e., extracellular matrix (ECM) proteins, transmembrane receptors, or proteases that might enhance myoblast fusion. Our results suggest that musculotendinous interaction is essential for the development and healing of skeletal muscles.

scholarly journals Sox15 Is Required for Skeletal Muscle Regeneration

2004 ◽  
Vol 24 (19) ◽  
pp. 8428-8436 ◽  
Author(s):  
Heon-Jin Lee ◽  
Wolfgang Göring ◽  
Matthias Ochs ◽  
Christian Mühlfeld ◽  
Gerd Steding ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Fate ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Muscle Development ◽  
Myogenic Cell ◽  
Skeletal Muscle Regeneration ◽  
Term Survival ◽  
Differentiation Potential ◽  
Cell Lineages

ABSTRACT The Sox genes define a family of transcription factors that play a key role in the determination of cell fate during development. The preferential expression of the Sox15 in the myogenic precursor cells led us to suggest that the Sox15 is involved in the specification of myogenic cell lineages or in the regulation of the fusion of myoblasts to form myotubes during the development and regeneration of skeletal muscle. To identify the physiological function of Sox15 in mice, we disrupted the Sox15 by homologous recombination in mice. Sox15-deficient mice were born at expected ratios, were healthy and fertile, and displayed normal long-term survival rates. Histological analysis revealed the normal ultrastructure of myofibers and the presence of comparable amounts of satellite cells in the skeletal muscles of Sox15−/− animals compared to wild-type animals. These results exclude the role of Sox15 in the development of satellite cells. However, cultured Sox15−/− myoblasts displayed a marked delay in differentiation potential in vitro. Moreover, skeletal muscle regeneration in Sox15−/− mice was attenuated after application of a crush injury. These results suggest a requirement for Sox15 in the myogenic program. Expression analyses of the early myogenic regulated factors MyoD and Myf5 showed the downregulation of the MyoD and upregulation of the Myf5 in Sox15−/− myoblasts. These results show an increased proportion of the Myf5-positive cells and suggest a role for Sox15 in determining the early myogenic cell lineages during skeletal muscle development.

Plasmin activity is required for myogenesis in vitro and skeletal muscle regeneration in vivo

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2835-2844 ◽  
Author(s):  
Mònica Suelves ◽  
Roser López-Alemany ◽  
Frederic Lluı́s ◽  
Gloria Aniorte ◽  
Erika Serrano ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Myoblast Fusion ◽  
Skeletal Muscle Regeneration ◽  
Wild Type ◽  
Plasmin Activity ◽  
Type Plasminogen Activator ◽  
Deficient Mice

Abstract Plasmin, the primary fibrinolytic enzyme, has a broad substrate spectrum and is implicated in biologic processes dependent upon proteolytic activity, such as tissue remodeling and cell migration. Active plasmin is generated from proteolytic cleavage of the zymogen plasminogen (Plg) by urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). Here, we have investigated the role of plasmin in C2C12 myoblast fusion and differentiation in vitro, as well as in skeletal muscle regeneration in vivo, in wild-type and Plg-deficient mice. Wild-type mice completely repaired experimentally damaged skeletal muscle. In contrast, Plg−/− mice presented a severe regeneration defect with decreased recruitment of blood-derived monocytes and lymphocytes to the site of injury and persistent myotube degeneration. In addition, Plg-deficient mice accumulated fibrin in the degenerating muscle fibers; however, fibrinogen depletion of Plg-deficient mice resulted in a correction of the muscular regeneration defect. Because we found that uPA, but not tPA, was induced in skeletal muscle regeneration, and persistent fibrin deposition was also reproducible in uPA-deficient mice following injury, we propose that fibrinolysis by uPA-dependent plasmin activity plays a fundamental role in skeletal muscle regeneration. In summary, we identify plasmin as a critical component of the mammalian skeletal muscle regeneration process, possibly by preventing intramuscular fibrin accumulation and by contributing to the adequate inflammatory response after injury. Finally, we found that inhibition of plasmin activity with α2-antiplasmin resulted in decreased myoblast fusion and differentiation in vitro. Altogether, these studies demonstrate the requirement of plasmin during myogenesis in vitro and muscle regeneration in vivo.

scholarly journals The circular RNA circCPE regulates myoblast development by sponging miR-138

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wenxiu Ru ◽  
Ao Qi ◽  
Xuemei Shen ◽  
Binglin Yue ◽  
Xiaoyan Zhang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Proliferation ◽  
Muscle Regeneration ◽  
Noncoding Rna ◽  
Muscle Development ◽  
Circular Rna ◽  
Inhibitory Effect ◽  
Skeletal Muscle Regeneration ◽  
Bovine Muscle

Abstract Background Skeletal muscle development, a long-term and complex process, is controlled by a set of the myogenic genes. Circular RNAs (circRNAs), a class of noncoding RNA, have been shown to regulate various biological processes. Recent studies indicate circRNAs may be involved in myogenesis, but the role and regulatory mechanism of circRNAs in myogenesis is largely unknown. In the present study, circCPE was firstly found to promote the bovine myoblast proliferation and inhibit cell apoptosis and differentiation by influencing the expression of FOXC1 in a miR138-mediated manner. And in vivo experiments revealed that overexpression of circCPE attenuates skeletal muscle regeneration. Results We identified a novel circular RNA circCPE by analyzing circRNAs sequencing data of bovine muscle tissue. Sequencing verification, RNase R treatment and Actinomycin D treatment confirmed the circular nature of circCPE in bovine muscle. Functional assays showed that overexpression of circCPE could inhibit bovine myoblast apoptosis and differentiation, as well as facilitate cell proliferation. Moreover, in vivo experiments revealed that overexpression of circCPE attenuates skeletal muscle regeneration. In consideration of circRNA action as miRNAs sponge, we found that circCPE harbors miR-138 binding sites and absorbed miR-138. Mechanistically, the rescue experiments showed that the overexpression of circCPE can counteract the inhibitory effect of miR-138 on the cell proliferation and the accelerated effects on the differentiation and apoptosis. Subsequently, we found that circCPE sequester the inhibitory effect of miR-138 on FOXC1 so as to involve in myogenesis. Conclusions Collectively, we constructed a novel circCPE/miR-138/FOXC1 regulatory network in bovine myogenesis, which further provide stronger evidence that circRNA involved in muscle development acting as miRNA sponge.

scholarly journals Septin-7 is indispensable in skeletal muscle regeneration

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Andrea Telek ◽  
Janos Fodor ◽  
Nora Dobrosi ◽  
Laszlo Szabo ◽  
Monika Gönczi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Division ◽  
Mrna Expression ◽  
Muscle Regeneration ◽  
Tibialis Anterior ◽  
Tibialis Anterior Muscle ◽  
Critical Role ◽  
Skeletal Muscle Regeneration ◽  
The Right

Septins are considered as the fourth component of the cytoskeleton, with septin-7 isoform playing a critical role in myogenic cell division and fusion. Skeletal muscle regeneration is a highly orchestrated process that requires many steps, including proper cell division to achieve functional recovery. Here, the role of septin-7 was investigated in this complex process. To this end, muscle injury was induced in wild type BL6/C57 and septin-7–conditional (mer-Cre-mer) knock-down mice by in vivo BaCl2 injection to the left m. tibialis anterior muscle (TA) of the mice (the right m. tibialis anterior muscle was nontreated control). Mice were sacrificed 4 and 14 d later to reflect the early (monitored by PAX7 level) and late (monitored by myogenin level) phases of muscle regeneration. Western blotting was used to follow the changes of septin-7, PAX7, and myogenin expression at the protein level, while changes of mRNA were detected by qPCR. Morphological differences were visualized by HE staining. Levels of septin-7 protein increased 4 and 14 d after injury in BL6/C57 mice and mRNA expression of SEPT7 showed significant elevation both 4 and 14 d after injection in Cre+ mice only, considered to be a compensatory increase of mRNA expression of SEPT7 in order to ensure the appropriate regeneration process. Furthermore, up-regulation of septin-7 protein was more pronounced on day 14 in both Cre− and Cre+ mice, which may indicate its importance in the later phase of regeneration. Level of PAX7 and myogenin were also increased 4 and 14 d after injury in BL6/C57, Cre−, and Cre+ mice, respectively. Taken together, our data suggest the importance of septin-7 in skeletal muscle regeneration.

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