Borax-loaded injectable alginate hydrogels promote muscle regeneration in vivo after an injury

Plasminogen activators urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) are extracellular proteases involved in various tissue remodeling processes. A requirement for uPA activity in skeletal myogenesis was recently demonstrated in vitro. The role of plasminogen activators in skeletal muscle regeneration in vivo in wild-type, uPA-deficient, and tPA-deficient mice is investigated here. Wild-type and tPA−/− mice completely repaired experimentally damaged skeletal muscle. In contrast, uPA−/− mice had a severe regeneration defect, with decreased recruitment of blood-derived monocytes to the site of injury and with persistent myotube degeneration. In addition, uPA-deficient mice accumulated fibrin in the degenerating muscle fibers; however, the defibrinogenation of uPA-deficient mice resulted in a correction of the muscle regeneration defect. A similar severe regeneration deficit with persistent fibrin deposition was also reproducible in plasminogen-deficient mice after injury, suggesting that fibrinolysis by uPA-mediated plasminogen activation plays a fundamental role in skeletal muscle regeneration. In conclusion, the uPA-plasmin system is identified as a critical component of the mammalian skeletal muscle regeneration process, possibly because it prevents intramuscular fibrin accumulation and contributes to the adequate inflammatory response after injury. These studies demonstrate the requirement of an extracellular proteolytic cascade during muscle regeneration in vivo.

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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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Antifibrotic effects of suramin in injured skeletal muscle after laceration

Journal of Applied Physiology ◽

10.1152/japplphysiol.00915.2002 ◽

2003 ◽

Vol 95 (2) ◽

pp. 771-780 ◽

Cited By ~ 98

Author(s):

Yi-Sheng Chan ◽

Yong Li ◽

William Foster ◽

Takashi Horaguchi ◽

George Somogyi ◽

...

Keyword(s):

Skeletal Muscle ◽

Growth Factor ◽

Muscle Regeneration ◽

Sports Medicine ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Healing Process ◽

Muscle Injuries

Muscle injuries are very common in traumatology and sports medicine. Although muscle tissue can regenerate postinjury, the healing process is slow and often incomplete; complete recovery after skeletal muscle injury is hindered by fibrosis. Our studies have shown that decreased fibrosis could improve muscle healing. Suramin has been found to inhibit transforming growth factor (TGF)-β1 expression by competitively binding to the growth factor receptor. We conducted a series of tests to determine the antifibrotic effects of suramin on muscle laceration injuries. Our results demonstrate that suramin (50 μg/ml) can effectively decrease fibroblast proliferation and fibrotic-protein expression (α-smooth muscle actin) in vitro. In vivo, direct injection of suramin (2.5 mg) into injured murine muscle resulted in effective inhibition of muscle fibrosis and enhanced muscle regeneration, which led to efficient functional muscle recovery. These results support our hypothesis that prevention of fibrosis could enhance muscle regeneration, thereby facilitating more efficient muscle healing. This study could significantly contribute to the development of strategies to promote efficient muscle healing and functional recovery.

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Alginate Hydrogels for In Vivo Bone Regeneration: The Immune Competence of the Animal Model Matters

Tissue Engineering Part A ◽

10.1089/ten.tea.2019.0310 ◽

2020 ◽

Vol 26 (15-16) ◽

pp. 852-862 ◽

Cited By ~ 2

Author(s):

Daniela S. Garske ◽

Katharina Schmidt-Bleek ◽

Agnes Ellinghaus ◽

Anke Dienelt ◽

Luo Gu ◽

...

Keyword(s):

Animal Model ◽

Bone Regeneration ◽

Immune Competence ◽

Alginate Hydrogels

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Enhanced muscle regeneration in freshwater prawn Macrobrachium rosenbergii achieved through in vivo silencing of the myostatin gene

Journal of the World Aquaculture Society ◽

10.1111/jwas.12607 ◽

2019 ◽

Vol 50 (5) ◽

pp. 1026-1039 ◽

Cited By ~ 2

Author(s):

Sarasvathi P. Easwvaran ◽

Subha Bhassu ◽

Mary B. B. Maningas ◽

Rofina Y. Othman

Keyword(s):

Muscle Regeneration ◽

Macrobrachium Rosenbergii ◽

Freshwater Prawn ◽

Myostatin Gene

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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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Effects of the tetrahedral framework nucleic acids on the skeletal muscle regeneration in vitro and in vivo

Materials Chemistry Frontiers ◽

10.1039/d0qm00329h ◽

2020 ◽

Vol 4 (9) ◽

pp. 2731-2743

Author(s):

Yang Gao ◽

Tianxu Zhang ◽

Junyao Zhu ◽

Dexuan Xiao ◽

Mei Zhang ◽

...

Keyword(s):

Tissue Regeneration ◽

Muscle Regeneration ◽

Skeletal Muscle Regeneration ◽

Muscle Loss ◽

Degenerative Diseases ◽

Tetrahedral Framework ◽

Volumetric Muscle Loss ◽

Regeneration In Vitro

The challenges associated with muscle degenerative diseases and volumetric muscle loss (VML) emphasizes the prospects of muscle tissue regeneration.

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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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Intact satellite cells lead to remarkable protection against Smn gene defect in differentiated skeletal muscle

The Journal of Cell Biology ◽

10.1083/jcb.200210117 ◽

2003 ◽

Vol 161 (3) ◽

pp. 571-582 ◽

Cited By ~ 68

Author(s):

Sophie Nicole ◽

Benedicte Desforges ◽

Gaelle Millet ◽

Jeanne Lesbordes ◽

Carmen Cifuentes-Diaz ◽

...

Keyword(s):

Skeletal Muscle ◽

Satellite Cells ◽

Muscle Regeneration ◽

Motor Performance ◽

Muscular Atrophy ◽

Early Death ◽

Mutant Mice ◽

Mild Phenotype

Deletion of murine Smn exon 7, the most frequent mutation found in spinal muscular atrophy, has been directed to either both satellite cells, the muscle progenitor cells and fused myotubes, or fused myotubes only. When satellite cells were mutated, mutant mice develop severe myopathic process, progressive motor paralysis, and early death at 1 mo of age (severe mutant). Impaired muscle regeneration of severe mutants correlated with defect of myogenic precursor cells both in vitro and in vivo. In contrast, when satellite cells remained intact, mutant mice develop similar myopathic process but exhibit mild phenotype with median survival of 8 mo and motor performance similar to that of controls (mild mutant). High proportion of regenerating myofibers expressing SMN was observed in mild mutants compensating for progressive loss of mature myofibers within the first 6 mo of age. Then, in spite of normal contractile properties of myofibers, mild mutants develop reduction of muscle force and mass. Progressive decline of muscle regeneration process was no more able to counterbalance muscle degeneration leading to dramatic loss of myofibers. These data indicate that intact satellite cells remarkably improve the survival and motor performance of mutant mice suffering from chronic myopathy, and suggest a limited potential of satellite cells to regenerate skeletal muscle.

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