Regulation of muscle plasticity and trophism by fatty acids: A short review

Summary The skeletal muscle tissue has a remarkable ability to alter its plastic structural and functional properties after a harmful stimulus, regulating the expression of proteins in complex events such as muscle regeneration. In this context, considering that potential therapeutic agents have been widely studied, nutritional strategies have been investigated in order to improve the regenerative capacity of skeletal muscle. There is evidence of the modulatory action of fatty acids, such that oleic and linoleic acids, that are abundant in Western diets, on muscle function and trophism. Thus, fatty acids appear to be potential candidates to promote or impair the recovery of muscle mass and function during regeneration, since they modulate intracellular pathways that regulate myogenesis. This study is the first to describe and discuss the effect of fatty acids on muscle plasticity and trophism, with emphasis on skeletal muscle regeneration and in vitro differentiation of muscle cells.

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IL-4 and SDF-1 Increase Adipose Tissue-Derived Stromal Cell Ability to Improve Rat Skeletal Muscle Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms21093302 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3302

Author(s):

Małgorzata Zimowska ◽

Karolina Archacka ◽

Edyta Brzoska ◽

Joanna Bem ◽

Areta M. Czerwinska ◽

...

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Muscle Regeneration ◽

Structure And Function ◽

Skeletal Muscle Regeneration ◽

Stem Cell Markers ◽

Myogenic Factors ◽

And Function

Skeletal muscle regeneration depends on the satellite cells, which, in response to injury, activate, proliferate, and reconstruct damaged tissue. However, under certain conditions, such as large injuries or myopathies, these cells might not sufficiently support repair. Thus, other cell populations, among them adipose tissue-derived stromal cells (ADSCs), are tested as a tool to improve regeneration. Importantly, the pro-regenerative action of such cells could be improved by various factors. In the current study, we tested whether IL-4 and SDF-1 could improve the ability of ADSCs to support the regeneration of rat skeletal muscles. We compared their effect at properly regenerating fast-twitch EDL and poorly regenerating slow-twitch soleus. To this end, ADSCs subjected to IL-4 and SDF-1 were analyzed in vitro and also in vivo after their transplantation into injured muscles. We tested their proliferation rate, migration, expression of stem cell markers and myogenic factors, their ability to fuse with myoblasts, as well as their impact on the mass, structure and function of regenerating muscles. As a result, we showed that cytokine-pretreated ADSCs had a beneficial effect in the regeneration process. Their presence resulted in improved muscle structure and function, as well as decreased fibrosis development and a modulated immune response.

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ARHGEF3 regulates skeletal muscle regeneration and strength through autophagy

10.1101/2020.02.28.970756 ◽

2020 ◽

Author(s):

Jae-Sung You ◽

Nilmani Singh ◽

Adriana Reyes-Ordonez ◽

Nidhi Khanna ◽

Zehua Bao ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Regeneration ◽

Mammalian Target Of Rapamycin ◽

Akt Signaling ◽

Skeletal Muscle Regeneration ◽

Myoblast Differentiation ◽

Independent Manner ◽

And Function ◽

Old Mice

SummarySkeletal muscle regeneration is essential for restoring muscle function upon injury and for the maintenance of muscle health with aging. ARHGEF3, a Rho-specific GEF, negatively regulates myoblast differentiation via mammalian target of rapamycin complex 2 (mTORC2)-Akt signaling in a GEF-independent manner in vitro. Here, we investigated ARHGEF3’s role in skeletal muscle regeneration by creating ARHGEF3 KO mice. These mice exhibited no discernible phenotype under normal conditions. Upon injury, however, ARHGEF3 deficiency enhanced the mass, fiber size and function of regenerating muscles in both young and aged mice. Surprisingly, these effects were not mediated by mTORC2-Akt signaling, but by the GEF activity of ARHGEF3. Furthermore, ARHGEF3 KO promoted muscle regeneration through activation of autophagy, a process that is also critical for maintaining muscle strength. Accordingly, in old mice, ARHGEF3 depletion prevented muscle weakness by restoring autophagy flux. Collectively, our findings identify an unexpected link between ARHGEF3 and autophagy-related muscle pathophysiology.

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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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PEDF-derived peptide promotes skeletal muscle regeneration through its mitogenic effect on muscle progenitor cells

AJP Cell Physiology ◽

10.1152/ajpcell.00344.2014 ◽

2015 ◽

Vol 309 (3) ◽

pp. C159-C168 ◽

Cited By ~ 18

Author(s):

Tsung-Chuan Ho ◽

Yi-Pin Chiang ◽

Chih-Kuang Chuang ◽

Show-Li Chen ◽

Jui-Wen Hsieh ◽

...

Keyword(s):

Skeletal Muscle ◽

Cell Proliferation ◽

Cyclin D1 ◽

Satellite Cell ◽

Muscle Regeneration ◽

Muscle Fibers ◽

Skeletal Muscle Regeneration ◽

Satellite Cell Proliferation

In response injury, intrinsic repair mechanisms are activated in skeletal muscle to replace the damaged muscle fibers with new muscle fibers. The regeneration process starts with the proliferation of satellite cells to give rise to myoblasts, which subsequently differentiate terminally into myofibers. Here, we investigated the promotion effect of pigment epithelial-derived factor (PEDF) on muscle regeneration. We report that PEDF and a synthetic PEDF-derived short peptide (PSP; residues Ser93-Leu112) induce satellite cell proliferation in vitro and promote muscle regeneration in vivo. Extensively, soleus muscle necrosis was induced in rats by bupivacaine, and an injectable alginate gel was used to release the PSP in the injured muscle. PSP delivery was found to stimulate satellite cell proliferation in damaged muscle and enhance the growth of regenerating myofibers, with complete regeneration of normal muscle mass by 2 wk. In cell culture, PEDF/PSP stimulated C2C12 myoblast proliferation, together with a rise in cyclin D1 expression. PEDF induced the phosphorylation of ERK1/2, Akt, and STAT3 in C2C12 myoblasts. Blocking the activity of ERK, Akt, or STAT3 with pharmacological inhibitors attenuated the effects of PEDF/PSP on the induction of C2C12 cell proliferation and cyclin D1 expression. Moreover, 5-bromo-2′-deoxyuridine pulse-labeling demonstrated that PEDF/PSP stimulated primary rat satellite cell proliferation in myofibers in vitro. In summary, we report for the first time that PSP is capable of promoting the regeneration of skeletal muscle. The signaling mechanism involves the ERK, AKT, and STAT3 pathways. These results show the potential utility of this PEDF peptide for muscle regeneration.

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Conditional Deletion of Dicer in Adult Mice Impairs Skeletal Muscle Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms20225686 ◽

2019 ◽

Vol 20 (22) ◽

pp. 5686 ◽

Cited By ~ 2

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21061965 ◽

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.

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Dietary Flaxseed Mitigates Impaired Skeletal Muscle Regeneration: in Vivo, in Vitro and in Silico Studies

International Journal of Medical Sciences ◽

10.7150/ijms.13268 ◽

2016 ◽

Vol 13 (3) ◽

pp. 206-219 ◽

Cited By ~ 4

Author(s):

Felicia Carotenuto ◽

Alessandra Costa ◽

Maria Cristina Albertini ◽

Marco Bruno Luigi Rocchi ◽

Alexander Rudov ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Regeneration ◽

In Silico ◽

Skeletal Muscle Regeneration ◽

In Silico Studies

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Chlorella vulgaris Modulates Genes and Muscle-Specific microRNAs Expression to Promote Myoblast Differentiation in Culture

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/8394648 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 3

Author(s):

Nurhazirah Zainul Azlan ◽

Yasmin Anum Mohd Yusof ◽

Ekram Alias ◽

Suzana Makpol

Keyword(s):

Skeletal Muscle ◽

Chlorella Vulgaris ◽

Muscle Regeneration ◽

Human Skeletal Muscle ◽

The Elderly ◽

Myoblast Differentiation ◽

Gradual Decline ◽

Proliferation And Differentiation ◽

And Function

Background. Loss of skeletal muscle mass, strength, and function due to gradual decline in the regeneration of skeletal muscle fibers was observed with advancing age. This condition is known as sarcopenia. Myogenic regulatory factors (MRFs) are essential in muscle regeneration as its activation leads to the differentiation of myoblasts to myofibers. Chlorella vulgaris is a coccoid green eukaryotic microalga that contains highly nutritious substances and has been reported for its pharmaceutical effects. The aim of this study was to determine the effect of C. vulgaris on the regulation of MRFs and myomiRs expression in young and senescent myoblasts during differentiation in vitro. Methods. Human skeletal muscle myoblast (HSMM) cells were cultured and serial passaging was carried out to obtain young and senescent cells. The cells were then treated with C. vulgaris followed by differentiation induction. The expression of Pax7, MyoD1, Myf5, MEF2C, IGF1R, MYOG, TNNT1, PTEN, and MYH2 genes and miR-133b, miR-206, and miR-486 was determined in untreated and C. vulgaris-treated myoblasts on Days 0, 1, 3, 5, and 7 of differentiation. Results. The expression of Pax7, MyoD1, Myf5, MEF2C, IGF1R, MYOG, TNNT1, and PTEN in control senescent myoblasts was significantly decreased on Day 0 of differentiation (p<0.05). Treatment with C. vulgaris upregulated Pax7, Myf5, MEF2C, IGF1R, MYOG, and PTEN in senescent myoblasts (p<0.05) and upregulated Pax7 and MYOG in young myoblasts (p<0.05). The expression of MyoD1 and Myf5 in young myoblasts however was significantly decreased on Day 0 of differentiation (p<0.05). During differentiation, the expression of these genes was increased with C. vulgaris treatment. Further analysis on myomiRs expression showed that miR-133b, miR-206, and miR-486 were significantly downregulated in senescent myoblasts on Day 0 of differentiation which was upregulated by C. vulgaris treatment (p<0.05). During differentiation, the expression of miR-133b and miR-206 was significantly increased with C. vulgaris treatment in both young and senescent myoblasts (p<0.05). However, no significant change was observed on the expression of miR-486 with C. vulgaris treatment. Conclusions. C. vulgaris demonstrated the modulatory effects on the expression of MRFs and myomiRs during proliferation and differentiation of myoblasts in culture. These findings may indicate the beneficial effect of C. vulgaris in muscle regeneration during ageing thus may prevent sarcopenia in the elderly.

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Modulation of Caspase Activity Regulates Skeletal Muscle Regeneration and Function in Response to Vasopressin and Tumor Necrosis Factor

PLoS ONE ◽

10.1371/journal.pone.0005570 ◽

2009 ◽

Vol 4 (5) ◽

pp. e5570 ◽

Cited By ~ 27

Author(s):

Viviana Moresi ◽

Gisela Garcia-Alvarez ◽

Alessandro Pristerà ◽

Emanuele Rizzuto ◽

Maria C. Albertini ◽

...

Keyword(s):

Skeletal Muscle ◽

Tumor Necrosis Factor ◽

Muscle Regeneration ◽

Tumor Necrosis ◽

Skeletal Muscle Regeneration ◽

Caspase Activity ◽

And Function ◽

Necrosis Factor

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

Blood ◽

10.1182/blood.v99.8.2835 ◽

2002 ◽

Vol 99 (8) ◽

pp. 2835-2844 ◽

Cited By ~ 62

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.

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