Role of trophic factors in development and regeneration of skeletal muscles

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.

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Sox15 Is Required for Skeletal Muscle Regeneration

Molecular and Cellular Biology ◽

10.1128/mcb.24.19.8428-8436.2004 ◽

2004 ◽

Vol 24 (19) ◽

pp. 8428-8436 ◽

Cited By ~ 48

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.

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Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice

Cells ◽

10.3390/cells10113089 ◽

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.

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Molecular Basis of Skeletal Muscle Regeneration

Canadian Journal of Applied Physiology ◽

10.1139/h96-014 ◽

1996 ◽

Vol 21 (3) ◽

pp. 155-184 ◽

Cited By ~ 60

Author(s):

Rebecca L. Chambers ◽

John C. McDermott

Keyword(s):

Skeletal Muscle ◽

Transcription Factors ◽

Growth Factors ◽

Satellite Cells ◽

Muscle Regeneration ◽

Myogenic Differentiation ◽

Skeletal Muscle Regeneration ◽

Regulatory Sequences ◽

Nuclear Factors ◽

Dna Regulatory Sequences

Skeletal muscle regeneration is a vital process with important implications for various muscle myopathies and adaptations to physiological overload. Few of the molecular regulatory proteins controlling this process have so far been identified. Several growth factors have defined effects on myogenic precursor cells and appear to also be involved during regeneration. In addition, factors that may be released by cells of the immune system may activate satellite cells during regeneration. Many of these growth factors are associated with signalling cascades which transmit information to the nucleus. The nuclear "receptors" that receive the incoming signals are transcription factors that interact with DNA regulatory sequences in order to modulate gene expression. Of the nuclear factors isolated so far, the immediate-early genes are associated with muscle precursor cell proliferation. This review aims to synthesize the extensive research on myogenic differentiation and relate this to research concerning the molecular regulation of skeletal muscle regeneration. Key words: satellite cells, growth factors, signal transduction, transcription factors, gene regulation, overload adaptation

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miR-21-5p Regulates the Proliferation and Differentiation of Skeletal Muscle Satellite Cells by Targeting KLF3 in Chicken

Genes ◽

10.3390/genes12060814 ◽

2021 ◽

Vol 12 (6) ◽

pp. 814

Author(s):

Donghao Zhang ◽

Jinshan Ran ◽

Jingjing Li ◽

Chunlin Yu ◽

Zhifu Cui ◽

...

Keyword(s):

Skeletal Muscle ◽

Satellite Cells ◽

Muscle Development ◽

Target Genes ◽

Cell Number ◽

Sequencing Data ◽

Proliferation Markers ◽

Muscle Satellite Cells ◽

Skeletal Muscle Satellite Cells ◽

Proliferation And Differentiation

The proliferation and differentiation of skeletal muscle satellite cells (SMSCs) play an important role in the development of skeletal muscle. Our previous sequencing data showed that miR-21-5p is one of the most abundant miRNAs in chicken skeletal muscle. Therefore, in this study, the spatiotemporal expression of miR-21-5p and its effects on skeletal muscle development of chickens were explored using in vitro cultured SMSCs as a model. The results in this study showed that miR-21-5p was highly expressed in the skeletal muscle of chickens. The overexpression of miR-21-5p promoted the proliferation of SMSCs as evidenced by increased cell viability, increased cell number in the proliferative phase, and increased mRNA and protein expression of proliferation markers including PCNA, CDK2, and CCND1. Moreover, it was revealed that miR-21-5p promotes the formation of myotubes by modulating the expression of myogenic markers including MyoG, MyoD, and MyHC, whereas knockdown of miR-21-5p showed the opposite result. Gene prediction and dual fluorescence analysis confirmed that KLF3 was one of the direct target genes of miR-21-5p. We confirmed that, contrary to the function of miR-21-5p, KLF3 plays a negative role in the proliferation and differentiation of SMSCs. Si-KLF3 promotes cell number and proliferation activity, as well as the cell differentiation processes. Our results demonstrated that miR-21-5p promotes the proliferation and differentiation of SMSCs by targeting KLF3. Collectively, the results obtained in this study laid a foundation for exploring the mechanism through which miR-21-5p regulates SMSCs.

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Satellite cells and skeletal muscle regeneration

British Journal of Surgery ◽

10.1002/bjs.1800530720 ◽

1966 ◽

Vol 53 (7) ◽

pp. 638-642 ◽

Cited By ~ 66

Author(s):

J. C. T. Church ◽

R. F. X. Noronha ◽

D. B. Allbrook

Keyword(s):

Skeletal Muscle ◽

Satellite Cells ◽

Muscle Regeneration ◽

Skeletal Muscle Regeneration

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The LIM domain protein nTRIP6 modulates the dynamics of myogenic differentiation

Scientific Reports ◽

10.1038/s41598-021-92331-8 ◽

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.

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

Cells ◽

10.3390/cells10113028 ◽

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.

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

eLife ◽

10.7554/elife.73215 ◽

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.

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The Potential Role of Insulin-Like Growth Factors in Skeletal Muscle Regeneration

Canadian Journal of Applied Physiology ◽

10.1139/h96-021 ◽

1996 ◽

Vol 21 (4) ◽

pp. 236-250 ◽

Cited By ~ 19

Author(s):

Jamie MacGregor ◽

Wade S. Parkhouse

Keyword(s):

Skeletal Muscle ◽

Growth Hormone ◽

Growth Factors ◽

Muscle Regeneration ◽

Potential Role ◽

Tissue Growth ◽

Skeletal Muscle Regeneration ◽

Tissue Type ◽

Insulin Like Growth Factors

The role of the insulin-like growth factors I and II (IGF-I and IGF-II), previously known as the somatomedins, in general growth and development of various tissues has been known for many years. Thought of exclusively as endocrine factors produced by the liver, and under the control of growth hormone, the somatomedins were known as the intermediaries by which growth hormone exerted its cellular effects during tissue growth and maturation. Eventually it was discovered that virtually every tissue type is capable of autocrine production of the IGFs, and their involvement in skeletal muscle tissue repair and regeneration became apparent. Recent advances in technology have allowed the characterisation of many of the different growth factors believed to play a role in muscle regeneration, and experimental manipulations of cells in culture have provided insight into the effects of the various growth factors on the myoblast. This paper explores the potential role of the IGFs in skeletal muscle regeneration. A critical role of IGF-II in terminal differentiation of proliferating muscle precurser cells following injury is proposed. Key words: growth factors, myogenesis, skeletal muscle regeneration

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MiR-27b Promotes Muscle Development by Inhibiting MDFI Expression

Cellular Physiology and Biochemistry ◽

10.1159/000489595 ◽

2018 ◽

Vol 46 (6) ◽

pp. 2271-2283 ◽

Cited By ~ 12

Author(s):

Lianjie Hou ◽

Jian Xu ◽

Yiren Jiao ◽

Huaqin Li ◽

Zhicheng Pan ◽

...

Keyword(s):

Skeletal Muscle ◽

Western Blot ◽

Satellite Cells ◽

Muscle Regeneration ◽

Muscle Injury ◽

Target Gene ◽

Muscle Development ◽

Muscle Satellite Cells ◽

Qrt Pcr

Background/Aims: Skeletal muscle plays an essential role in the body movement. However, injuries to the skeletal muscle are common. Lifelong maintenance of skeletal muscle function largely depends on preserving the regenerative capacity of muscle. Muscle satellite cells proliferation, differentiation, and myoblast fusion play an important role in muscle regeneration after injury. Therefore, understanding of the mechanisms associated with muscle development during muscle regeneration is essential for devising the alternative treatments for muscle injury in the future. Methods: Edu staining, qRT-PCR and western blot were used to evaluate the miR-27b effects on pig muscle satellite cells (PSCs) proliferation and differentiation in vitro. Then, we used bioinformatics analysis and dual-luciferase reporter assay to predict and confirm the miR-27b target gene. Finally, we elucidate the target gene function on muscle development in vitro and in vivo through Edu staining, qRT-PCR, western blot, H&E staining and morphological observation. Result: miR-27b inhibits PSCs proliferation and promotes PSCs differentiation. And the miR-27b target gene, MDFI, promotes PSCs proliferation and inhibits PSCs differentiation in vitro. Furthermore, interfering MDFI expression promotes mice muscle regeneration after injury. Conclusion: our results conclude that miR-27b promotes PSCs myogenesis by targeting MDFI. These results expand our understanding of muscle development mechanism in which miRNAs and genes work collaboratively in regulating skeletal muscle development. Furthermore, this finding has implications for obtaining the alternative treatments for patients with the muscle injury.

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