Journal articles on the topic 'Muscle regeneration'
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1
Kami, Katsuya, and Emiko Senba. "In Vivo Activation of STAT3 Signaling in Satellite Cells and Myofibers in Regenerating Rat Skeletal Muscles." Journal of Histochemistry & Cytochemistry 50, no. 12 (December 2002): 1579–89. http://dx.doi.org/10.1177/002215540205001202.
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Although growth factors and cytokines play critical roles in skeletal muscle regeneration, intracellular signaling molecules that are activated by these factors in regenerating muscles have been not elucidated. Several lines of evidence suggest that leukemia inhibitory factor (LIF) is an important cytokine for the proliferation and survival of myoblasts in vitro and acceleration of skeletal muscle regeneration. To elucidate the role of LIF signaling in regenerative responses of skeletal muscles, we examined the spatial and temporal activation patterns of an LIF-associated signaling molecule, the signal transducer and activator transcription 3 (STAT3) proteins in regenerating rat skeletal muscles induced by crush injury. At the early stage of regeneration, activated STAT3 proteins were first detected in the nuclei of activated satellite cells and then continued to be activated in proliferating myoblasts expressing both PCNA and MyoD proteins. When muscle regeneration progressed, STAT3 signaling was no longer activated in differentiated myoblasts and myotubes. In addition, activation of STAT3 was also detected in myonuclei within intact sarcolemmas of surviving myofibers that did not show signs of necrosis. These findings suggest that activation of STAT3 signaling is an important molecular event that induces the successful regeneration of injured skeletal muscles.
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Gulati, Adarshk. "Pattern of skeletal muscle regeneration after reautotransplantation of regenerated muscle." Development 92, no. 1 (March 1, 1986): 1–10. http://dx.doi.org/10.1242/dev.92.1.1.
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Autotransplantation of rat extensor digitorum longus muscle results in initial myofibre degeneration and subsequent regeneration from precursor myosatellite cells. To determine what effect a reinjury would have on the regenerative response, in the present,study, once transplanted and regenerated muscles were reinjured by reautotransplantion. In rats, four weeks after initial transplantation, when the regeneration was complete, the extensor digitorum longus muscle was transplanted again and the pattern of regeneration in reautotransplanted and once auto transplanted muscles was compared. Muscles were analysed 2, 4, 7, 14 and 30 days after autotransplantation and reautotransplantation. Both autotransplanted and reautotransplanted muscles underwent degeneration and regeneration; however, the pattern of regeneration in these two transplants was quite different. In autotransplants, a thin myogenic zone, marked by activated myoblasts, was first seen at 4 days. By 7 days the width of myogenic zone increased but still many degenerating myofibres were present in the central region of the muscle. By 14 days the muscle was filled with regenerated myotubes and myofibres. The reautotransplanted muscles underwent similar regenerative events; however, the rate of regeneration was considerably faster. The myogenic zone was apparent as early as 2 days and was much larger at 4 days, and by 7 days the entire muscle was filled with regenerated myotubes and myofibres which matured at later time intervals. Furthermore, the decrease in muscle weight in reautotransplanted muscles was not as much as that seen after autotransplantation. These findings reveal that not only is skeletal muscle capable of regeneration after a second injury, but the rate of this regeneration is much faster. This increased rate and recovery may be due to a conditioning effect of the first injury.
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Carlsen, R. C., D. Kerlin, and S. D. Gray. "Regeneration and revascularization of a nerve-intact skeletal muscle graft in the spontaneously hypertensive rat." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 270, no. 1 (January 1, 1996): R153—R161. http://dx.doi.org/10.1152/ajpregu.1996.270.1.r153.
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Skeletal muscles in hypertensive subjects develop an increased resistance to insulin that reduces their ability to incorporate glucose and synthesize glycogen. Insulin is an anabolic hormone in muscle, and muscle insulin receptors bind the growth factor, insulin-like growth factor I (IGF-I), an important contributor to muscle development and regeneration. An increase in insulin resistance in hypertensive subjects might produce muscle atrophy and weakness or limit regenerative growth after injury. Regenerative muscle growth was assessed in 24-to 26-wk-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats by subjecting extensor digitorum longus (EDL), an ankle flexor, to a nerve-intact graft procedure. The procedure produces extensive muscle fiber and capillary degeneration, but has little effect on the muscle nerve. Muscle morphology and contractile function were examined in intact and regenerating EDL at 21, 42, and 63 days postgraft. Muscle revascularization was assessed histologically at the same time points. Severe established hypertension did not prevent the reestablishment of a structurally normal capillary network in injured muscles. SHR muscle fiber regeneration and maturation, however, were significantly depressed compared with WKY grafts. The reduced regenerative recovery of SHR EDL in adult animals with severe hypertension does not appear to be due to a failure to restore the muscle nerve or capillary network, but may reflect a reduced anabolic response to insulin or IGF-I.
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Zimowska, Małgorzata, Karolina Archacka, Edyta Brzoska, Joanna Bem, Areta M. Czerwinska, Iwona Grabowska, Paulina Kasprzycka, et al. "IL-4 and SDF-1 Increase Adipose Tissue-Derived Stromal Cell Ability to Improve Rat Skeletal Muscle Regeneration." International Journal of Molecular Sciences 21, no. 9 (May 7, 2020): 3302. http://dx.doi.org/10.3390/ijms21093302.
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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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Banerji, Christopher R. S., Don Henderson, Rabi N. Tawil, and Peter S. Zammit. "Skeletal muscle regeneration in facioscapulohumeral muscular dystrophy is correlated with pathological severity." Human Molecular Genetics 29, no. 16 (August 3, 2020): 2746–60. http://dx.doi.org/10.1093/hmg/ddaa164.
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Abstract Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant myopathy characterized by slowly progressive skeletal muscle weakness and wasting. While a regenerative response is often provoked in many muscular dystrophies, little is known about whether a regenerative response is regularly elicited in FSHD muscle, prompting this study. For comparison, we also examined the similarly slowly progressing myotonic dystrophy type 2 (DM2). To first investigate regeneration at the transcriptomic level, we used the 200 human gene Hallmark Myogenesis list. This myogenesis biomarker was elevated in FSHD and control healthy myotubes compared to their myoblast counterparts, so is higher in myogenic differentiation. The myogenesis biomarker was also elevated in muscle biopsies from most independent FSHD, DM2 or Duchenne muscular dystrophy (DMD) studies compared to control biopsies, and on meta-analysis for each condition. In addition, the myogenesis biomarker was a robust binary discriminator of FSHD, DM2 and DMD from controls. We also analysed muscle regeneration at the protein level by immunolabelling muscle biopsies for developmental myosin heavy chain. Such immunolabelling revealed one or more regenerating myofibres in 76% of FSHD muscle biopsies from quadriceps and 91% from tibialis anterior. The mean proportion of regenerating myofibres per quadriceps biopsy was 0.48%, significantly less than 1.72% in the tibialis anterior. All DM2 muscle biopsies contained regenerating myofibres, with a mean of 1.24% per biopsy. Muscle regeneration in FSHD was correlated with the pathological hallmarks of fibre size variation, central nucleation, fibrosis and necrosis/regeneration/inflammation. In summary, the regenerative response in FSHD muscle biopsies correlates with the severity of pathology.
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Dadgar, Sherry, Zuyi Wang, Helen Johnston, Akanchha Kesari, Kanneboyina Nagaraju, Yi-Wen Chen, D. Ashley Hill, et al. "Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy." Journal of Cell Biology 207, no. 1 (October 13, 2014): 139–58. http://dx.doi.org/10.1083/jcb.201402079.
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We sought to determine the mechanisms underlying failure of muscle regeneration that is observed in dystrophic muscle through hypothesis generation using muscle profiling data (human dystrophy and murine regeneration). We found that transforming growth factor β–centered networks strongly associated with pathological fibrosis and failed regeneration were also induced during normal regeneration but at distinct time points. We hypothesized that asynchronously regenerating microenvironments are an underlying driver of fibrosis and failed regeneration. We validated this hypothesis using an experimental model of focal asynchronous bouts of muscle regeneration in wild-type (WT) mice. A chronic inflammatory state and reduced mitochondrial oxidative capacity are observed in bouts separated by 4 d, whereas a chronic profibrotic state was seen in bouts separated by 10 d. Treatment of asynchronously remodeling WT muscle with either prednisone or VBP15 mitigated the molecular phenotype. Our asynchronous regeneration model for pathological fibrosis and muscle wasting in the muscular dystrophies is likely generalizable to tissue failure in chronic inflammatory states in other regenerative tissues.
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Launay, Thierry, Philippe Noirez, Gillian Butler-Browne, and Onnik Agbulut. "Expression of slow myosin heavy chain during muscle regeneration is not always dependent on muscle innervation and calcineurin phosphatase activity." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 290, no. 6 (June 2006): R1508—R1514. http://dx.doi.org/10.1152/ajpregu.00486.2005.
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In the literature, there is an ambiguity as to the respective roles played by calcineurin phosphatase activity (CPA) and muscle innervation in the reestablishment of the slow-twitch muscle phenotype after muscle regeneration in different species. In this study, we wanted to determine the role of calcineurin and muscle innervation on the appearance and maintenance of the slow phenotype during mouse muscle regeneration. The pattern of myosin expression and CPA was analyzed in adult ( n = 15), regenerating ( n = 45) and denervated-regenerating ( n = 32) slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles. Moreover, in a second group of denervated-regenerating mice ( n = 9), the animals were treated with a calcineurin inhibitor. Regeneration was induced by injection of cardiotoxin and in the denervated-regenerating group, denervation was carried out by cutting the sciatic nerve before the administration of cardiotoxin. In innervated-regenerating soleus muscle, CPA increased continuously after 10 days postinjury and by 21 days, there was a 3.5-fold increase in CPA compared with adult basal level, whereas in innervated-regenerating EDL muscle, CPA remained unchanged. Moreover, our results show that in denervated-regenerating muscles, the MyHC profile was identical in spite of the functional differences inherent in these muscles. In long-term denervated-regenerating muscles, a slow muscle phenotype was reexpressed both in the presence or absence of calcineurin inhibitor. Our results show that although in innervated-regenerating mouse muscle, the appearance of a slow phenotype is correlated with a peak of CPA, in denervated-regenerating muscles, a slow phenotype is triggered and maintained in a calcineurin- and nerve-independent manner.
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Zullo, Letizia, Matteo Bozzo, Alon Daya, Alessio Di Clemente, Francesco Paolo Mancini, Aram Megighian, Nir Nesher, et al. "The Diversity of Muscles and Their Regenerative Potential across Animals." Cells 9, no. 9 (August 19, 2020): 1925. http://dx.doi.org/10.3390/cells9091925.
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Cells with contractile functions are present in almost all metazoans, and so are the related processes of muscle homeostasis and regeneration. Regeneration itself is a complex process unevenly spread across metazoans that ranges from full-body regeneration to partial reconstruction of damaged organs or body tissues, including muscles. The cellular and molecular mechanisms involved in regenerative processes can be homologous, co-opted, and/or evolved independently. By comparing the mechanisms of muscle homeostasis and regeneration throughout the diversity of animal body-plans and life cycles, it is possible to identify conserved and divergent cellular and molecular mechanisms underlying muscle plasticity. In this review we aim at providing an overview of muscle regeneration studies in metazoans, highlighting the major regenerative strategies and molecular pathways involved. By gathering these findings, we wish to advocate a comparative and evolutionary approach to prompt a wider use of “non-canonical” animal models for molecular and even pharmacological studies in the field of muscle regeneration.
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Anderson, Judy E., Laura M. McIntosh, Andrea N. Moor (neé Pernitsky), and Zipora Yablonka–Reuveni. "Levels of MyoD Protein Expression Following Injury of mdx and Normal Limb Muscle Are Modified by Thyroid Hormone." Journal of Histochemistry & Cytochemistry 46, no. 1 (January 1998): 59–67. http://dx.doi.org/10.1177/002215549804600108.
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Thyroid hormone (T3) affects muscle development and muscle regeneration. It also interacts with the muscle regulatory gene MyoD in culture and affects myoblast proliferation. We studied the localization of MyoD protein using a well-characterized polyclonal antibody for immunohistochemistry. Relative numbers of myogenic precursor cells per field were identified by their MyoD expression during muscle regeneration in normal and mdx dystrophic mice, with particular reference to the expression in mononuclear cells and myotubes at various T3 levels. In regeneration by normal muscles, relatively few MyoD+ nuclei per field were present in mononuclear cells of euthyroid and hypothyroid mice. MyoD staining of mononuclear cell nuclei was approximately doubled in fields of regenerating muscles of normal hyperthyroid compared to euthyroid mice, and was observed in precursors that appeared to be aligned before fusion into myotubes. In mdx regenerating muscle, twofold more mononuclear cells positive for MyoD were present in all three treatment groups compared to normal muscles regenerating under the same conditions. Localization was similar to the pattern in normal euthyroid mice. However, in muscles regenerating in hyperthyroid mdx mice, both mononuclear cell nuclei and centrally located nuclei in a subpopulation (about 15%) of new myotubes formed after the crush injury were intensely stained for MyoD protein. The changes observed are consistent with reports on T3-induced alteration of muscle repair, and propose a link between MyoD regulation and the accelerated differentiation during regeneration under high T3 conditions.
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Rahman, Fasih Ahmad, Sarah Anne Angus, Kyle Stokes, Phillip Karpowicz, and Matthew Paul Krause. "Impaired ECM Remodeling and Macrophage Activity Define Necrosis and Regeneration Following Damage in Aged Skeletal Muscle." International Journal of Molecular Sciences 21, no. 13 (June 27, 2020): 4575. http://dx.doi.org/10.3390/ijms21134575.
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Regenerative capacity of skeletal muscle declines with age, the cause of which remains largely unknown. We investigated extracellular matrix (ECM) proteins and their regulators during early regeneration timepoints to define a link between aberrant ECM remodeling, and impaired aged muscle regeneration. The regeneration process was compared in young (three month old) and aged (18 month old) C56BL/6J mice at 3, 5, and 7 days following cardiotoxin-induced damage to the tibialis anterior muscle. Immunohistochemical analyses were performed to assess regenerative capacity, ECM remodeling, and the macrophage response in relation to plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), and ECM protein expression. The regeneration process was impaired in aged muscle. Greater intracellular and extramyocellular PAI-1 expression was found in aged muscle. Collagen I was found to accumulate in necrotic regions, while macrophage infiltration was delayed in regenerating regions of aged muscle. Young muscle expressed higher levels of MMP-9 early in the regeneration process that primarily colocalized with macrophages, but this expression was reduced in aged muscle. Our results indicate that ECM remodeling is impaired at early time points following muscle damage, likely a result of elevated expression of the major inhibitor of ECM breakdown, PAI-1, and consequent suppression of the macrophage, MMP-9, and myogenic responses.
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Coulton, G. R., B. Rogers, P. Strutt, M. J. Skynner, and D. J. Watt. "In situ localisation of single-stranded DNA breaks in nuclei of a subpopulation of cells within regenerating skeletal muscle of the dystrophic mdx mouse." Journal of Cell Science 102, no. 3 (July 1, 1992): 653–62. http://dx.doi.org/10.1242/jcs.102.3.653.
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Degeneration of muscle fibres during the early stages of Duchenne Muscular Dystrophy (DMD) is accompanied by muscle fibre regeneration where cell division and myoblast fusion to form multinucleate myotubes within the lesions appear to recapitulate the events of normal muscle development. The mechanisms that govern the expression of genes regulating differentiation of myoblasts in regenerating skeletal muscle are of great interest for the development of future therapies designed to stimulate muscle regeneration. We show here that single-stranded breaks in DNA are localised in nuclei, using an exogenously applied medium containing labelled deoxynucleotides and the Klenow fragment of DNA polymerase I. The nuclei of a sub-population of cells lying in the inflammatory infiltrate of lesions in the skeletal muscle of the muscular dystrophic mouse (mdx), a genetic homologue of DMD, were labelled in this fashion. By contrast, labelled cells were completely absent from the muscles of normal non-myopathic animals (C57BL/10) and non-lesioned areas of mdx muscles. Cells expressing the muscle-specific regulatory gene, myogenin, were also found within mononucleate cells and myotubes within similar mdx muscle lesions. While we cannot yet say that the cells labelled by the DNA polymerase reaction are in fact differentiating, they were found only in significant numbers within mdx muscle lesions where new muscle fibres appear, providing strong circumstantial evidence that they are intimately associated with the regenerative process. Using a range of nucleases and different DNA polymerases, we show that the DNA polymerase-labelling reaction observed was DNA-dependent and most probably due to infilling of naturally occurring single-stranded gaps in DNA. Since the regenerative process in human Duchenne Muscular Dystrophy is apparently less effective than that seen in mdx mice, continued study of single-stranded DNA breaks may help to elucidate further the mechanisms controlling the expression of genes that characterise the myogenic process during skeletal muscle regeneration. Such findings might be applied in the development of future therapies designed to stimulate muscle regeneration in human dystrophies.
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Pernitsky, A. N., L. M. McIntosh, and J. E. Anderson. "Hyperthyroidism impairs early repair in normal but not dystrophic mdx mouse tibialis anterior muscle. An in vivo study." Biochemistry and Cell Biology 74, no. 3 (May 1, 1996): 315–24. http://dx.doi.org/10.1139/o96-034.
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The effect of hyperthyroidism on muscle repair was examined in mdx and control mice injected with triiodothyronine (T3) for 4 weeks. On day 24 of treatment, the right tibialis anterior (TA) muscle was crush-injured; 3 days later, mice received intraperitoneal [3H]thymidine to label newly synthesized DNA. One day later, muscles from both limbs were removed to study the severity of dystrophy (uncrushed muscle) and the regeneration response (crushed muscle). In uncrushed TA muscle, the area of active dystrophy (fiber damage and infiltration as a proportion of muscle cross-sectional area) was reduced by half after T3 treatment. Uncrushed muscle fiber diameter was lower in T3-treated control muscles. In crushed muscles, the diameter of new myotubes was larger in mdx mice than in controls and was reduced after T3 treatment in control regenerating muscle. In the same muscles, developmental myosin heavy chain was present in new myotubes and in small numbers of mononuclear cells (possibly differentiating myoblasts) near new myotubes and surviving fibers. Myotube density in the regenerating muscles was not changed by T3 treatment, although the number of myotube nuclei per field was decreased in control and increased in mdx T3-treated mice. Results extend previous reports of T3 effects on dystrophy and the strain difference in muscle precursor cell (mpc) proliferation. The results also suggest the hypothesis that excess T3 affects muscle regeneration either by reducing mpc proliferation or by increasing mpc fusion early in regeneration in control and mdx muscle.Key words: hypothyroid, muscle regeneration, crush injury, proliferation, mdx mouse.
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Zhang, Lidan, Akiyoshi Uezumi, Takayuki Kaji, Kazutake Tsujikawa, Ditte Caroline Andersen, Charlotte Harken Jensen, and So-ichiro Fukada. "Expression and Functional Analyses of Dlk1 in Muscle Stem Cells and Mesenchymal Progenitors during Muscle Regeneration." International Journal of Molecular Sciences 20, no. 13 (July 3, 2019): 3269. http://dx.doi.org/10.3390/ijms20133269.
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Delta like non-canonical Notch ligand 1 (Dlk1) is a paternally expressed gene which is also known as preadipocyte factor 1 (Pref−1). The accumulation of adipocytes and expression of Dlk1 in regenerating muscle suggests a correlation between fat accumulation and Dlk1 expression in the muscle. Additionally, mice overexpressing Dlk1 show increased muscle weight, while Dlk1-null mice exhibit decreased body weight and muscle mass, indicating that Dlk1 is a critical factor in regulating skeletal muscle mass during development. The muscle regeneration process shares some features with muscle development. However, the role of Dlk1 in regeneration processes remains controversial. Here, we show that mesenchymal progenitors also known as adipocyte progenitors exclusively express Dlk1 during muscle regeneration. Eliminating developmental effects, we used conditional depletion models to examine the specific roles of Dlk1 in muscle stem cells or mesenchymal progenitors. Unexpectedly, deletion of Dlk1 in neither the muscle stem cells nor the mesenchymal progenitors affected the regenerative ability of skeletal muscle. In addition, fat accumulation was not increased by the loss of Dlk1. Collectively, Dlk1 plays essential roles in muscle development, but does not greatly impact regeneration processes and adipogenic differentiation in adult skeletal muscle regeneration.
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Rosero Salazar, D. H., P. L. Carvajal Monroy, F. A. D. T. G. Wagener, and J. W. Von den Hoff. "Orofacial Muscles: Embryonic Development and Regeneration after Injury." Journal of Dental Research 99, no. 2 (November 1, 2019): 125–32. http://dx.doi.org/10.1177/0022034519883673.
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Orofacial congenital defects such as cleft lip and/or palate are associated with impaired muscle regeneration and fibrosis after surgery. Also, other orofacial reconstructions or trauma may end up in defective muscle regeneration and fibrosis. The aim of this review is to discuss current knowledge on the development and regeneration of orofacial muscles in comparison to trunk and limb muscles. The orofacial muscles include the tongue muscles and the branchiomeric muscles in the lower face. Their main functions are chewing, swallowing, and speech. All orofacial muscles originate from the mesoderm of the pharyngeal arches under the control of cranial neural crest cells. Research in vertebrate models indicates that the molecular regulation of orofacial muscle development is different from that of trunk and limb muscles. In addition, the regenerative ability of orofacial muscles is lower, and they develop more fibrosis than other skeletal muscles. Therefore, specific approaches need to be developed to stimulate orofacial muscle regeneration. Regeneration may be stimulated by growth factors such fibroblast growth factors and hepatocyte growth factor, while fibrosis may be reduced by targeting the transforming growth factor β1 (TGFβ1)/myofibroblast axis. New approaches that combine these 2 aspects will improve the surgical treatment of orofacial muscle defects.
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Wang, Yanjie, Jianqiang Lu, and Yujian Liu. "Skeletal Muscle Regeneration in Cardiotoxin-Induced Muscle Injury Models." International Journal of Molecular Sciences 23, no. 21 (November 2, 2022): 13380. http://dx.doi.org/10.3390/ijms232113380.
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Skeletal muscle injuries occur frequently in daily life and exercise. Understanding the mechanisms of regeneration is critical for accelerating the repair and regeneration of muscle. Therefore, this article reviews knowledge on the mechanisms of skeletal muscle regeneration after cardiotoxin-induced injury. The process of regeneration is similar in different mouse strains and is inhibited by aging, obesity, and diabetes. Exercise, microcurrent electrical neuromuscular stimulation, and mechanical loading improve regeneration. The mechanisms of regeneration are complex and strain-dependent, and changes in functional proteins involved in the processes of necrotic fiber debris clearance, M1 to M2 macrophage conversion, SC activation, myoblast proliferation, differentiation and fusion, and fibrosis and calcification influence the final outcome of the regenerative activity.
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Pizza, Francis X., and Kole H. Buckley. "Regenerating Myofibers after an Acute Muscle Injury: What Do We Really Know about Them?" International Journal of Molecular Sciences 24, no. 16 (August 8, 2023): 12545. http://dx.doi.org/10.3390/ijms241612545.
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Injury to skeletal muscle through trauma, physical activity, or disease initiates a process called muscle regeneration. When injured myofibers undergo necrosis, muscle regeneration gives rise to myofibers that have myonuclei in a central position, which contrasts the normal, peripheral position of myonuclei. Myofibers with central myonuclei are called regenerating myofibers and are the hallmark feature of muscle regeneration. An important and underappreciated aspect of muscle regeneration is the maturation of regenerating myofibers into a normal sized myofiber with peripheral myonuclei. Strikingly, very little is known about processes that govern regenerating myofiber maturation after muscle injury. As knowledge of myofiber formation and maturation during embryonic, fetal, and postnatal development has served as a foundation for understanding muscle regeneration, this narrative review discusses similarities and differences in myofiber maturation during muscle development and regeneration. Specifically, we compare and contrast myonuclear positioning, myonuclear accretion, myofiber hypertrophy, and myofiber morphology during muscle development and regeneration. We also discuss regenerating myofibers in the context of different types of myofiber necrosis (complete and segmental) after muscle trauma and injurious contractions. The overall goal of the review is to provide a framework for identifying cellular and molecular processes of myofiber maturation that are unique to muscle regeneration.
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Marsh, Daniel R., David S. Criswell, James A. Carson, and Frank W. Booth. "Myogenic regulatory factors during regeneration of skeletal muscle in young, adult, and old rats." Journal of Applied Physiology 83, no. 4 (October 1, 1997): 1270–75. http://dx.doi.org/10.1152/jappl.1997.83.4.1270.
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Marsh, Daniel R., David S. Criswell, James A. Carson, and Frank W. Booth. Myogenic regulatory factors during regeneration of skeletal muscle in young, adult, and old rats. J. Appl. Physiol. 83(4): 1270–1275, 1997.—Myogenic factor mRNA expression was examined during muscle regeneration after bupivacaine injection in Fischer 344/Brown Norway F1 rats aged 3, 18, and 31 mo of age (young, adult, and old, respectively). Mass of the tibialis anterior muscle in the young rats had recovered to control values by 21 days postbupivacaine injection but in adult and old rats remained 40% less than that of contralateral controls at 21 and 28 days of recovery. During muscle regeneration, myogenin mRNA was significantly increased in muscles of young, adult, and old rats 5 days after bupivacaine injection. Subsequently, myogenin mRNA levels in young rat muscle decreased to postinjection control values by day 21 but did not return to control values in 28-day regenerating muscles of adult and old rats. The expression of MyoD mRNA was also increased in muscles at day 5 of regeneration in young, adult, and old rats, decreased to control levels by day 14 in young and adult rats, and remained elevated in the old rats for 28 days. In summary, either a diminished ability to downregulate myogenin and MyoD mRNAs in regenerating muscle occurs in old rat muscles, or the continuing myogenic effort includes elevated expression of these mRNAs.
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Karra, Ravi, Matthew J. Foglia, Wen-Yee Choi, Christine Belliveau, Paige DeBenedittis, and Kenneth D. Poss. "Vegfaa instructs cardiac muscle hyperplasia in adult zebrafish." Proceedings of the National Academy of Sciences 115, no. 35 (August 13, 2018): 8805–10. http://dx.doi.org/10.1073/pnas.1722594115.
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During heart development and regeneration, coronary vascularization is tightly coupled with cardiac growth. Although inhibiting vascularization causes defects in the innate regenerative response of zebrafish to heart injury, angiogenic signals are not known to be sufficient for triggering regeneration events. Here, by using a transgenic reporter strain, we found that regulatory sequences of the angiogenic factor vegfaa are active in epicardial cells of uninjured animals, as well as in epicardial and endocardial tissue adjacent to regenerating muscle upon injury. Additionally, we find that induced cardiac overexpression of vegfaa in zebrafish results in overt hyperplastic thickening of the myocardial wall, accompanied by indicators of angiogenesis, epithelial-to-mesenchymal transition, and cardiomyocyte regeneration programs. Unexpectedly, vegfaa overexpression in the context of cardiac injury enabled ectopic cardiomyogenesis but inhibited regeneration at the site of the injury. Our findings identify Vegfa as one of a select few known factors sufficient to activate adult cardiomyogenesis, while also illustrating how instructive factors for heart regeneration require spatiotemporal control for efficacy.
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Danieli-Betto, Daniela, Samantha Peron, Elena Germinario, Marika Zanin, Guglielmo Sorci, Susanna Franzoso, Dorianna Sandonà, and Romeo Betto. "Sphingosine 1-phosphate signaling is involved in skeletal muscle regeneration." American Journal of Physiology-Cell Physiology 298, no. 3 (March 2010): C550—C558. http://dx.doi.org/10.1152/ajpcell.00072.2009.
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Sphingosine 1-phosphate (S1P) is a bioactive lipid known to control cell growth that was recently shown to act as a trophic factor for skeletal muscle, reducing the progress of denervation atrophy. The aim of this work was to investigate whether S1P is involved in skeletal muscle fiber recovery (regeneration) after myotoxic injury induced by bupivacaine. The postnatal ability of skeletal muscle to grow and regenerate is dependent on resident stem cells called satellite cells. Immunofluorescence analysis demonstrated that S1P-specific receptors S1P1 and S1P3 are expressed by quiescent satellite cells. Soleus muscles undergoing regeneration following injury induced by intramuscular injection of bupivacaine exhibited enhanced expression of S1P1 receptor, while S1P3 expression progressively decreased to adult levels. S1P2 receptor was absent in quiescent cells but was transiently expressed in the early regenerating phases only. Administration of S1P (50 μM) at the moment of myotoxic injury caused a significant increase of the mean cross-sectional area of regenerating fibers in both rat and mouse. In separate experiments designed to test the trophic effects of S1P, neutralization of endogenous circulating S1P by intraperitoneal administration of anti-S1P antibody attenuated fiber growth. Use of selective modulators of S1P receptors indicated that S1P1 receptor negatively and S1P3 receptor positively modulate the early phases of regeneration, whereas S1P2 receptor appears to be less important. The present results show that S1P signaling participates in the regenerative processes of skeletal muscle.
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Bohnert, Kathryn L., Mary K. Hastings, David R. Sinacore, Jeffrey E. Johnson, Sandra E. Klein, Jeremy J. McCormick, Paul Gontarz, and Gretchen A. Meyer. "Skeletal Muscle Regeneration in Advanced Diabetic Peripheral Neuropathy." Foot & Ankle International 41, no. 5 (February 14, 2020): 536–48. http://dx.doi.org/10.1177/1071100720907035.
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Background: Decreased lean muscle mass in the lower extremity in diabetic peripheral neuropathy (DPN) is thought to contribute to altered joint loading, immobility, and disability. However, the mechanism behind this loss is unknown and could derive from a reduction in size of myofibers (atrophy), destruction of myofibers (degeneration), or both. Degenerative changes require participation of muscle stem (satellite) cells to regenerate lost myofibers and restore lean mass. Determining the degenerative state and residual regenerative capacity of DPN muscle will inform the utility of regeneration-targeted therapeutic strategies. Methods: Biopsies were acquired from 2 muscles in 12 individuals with and without diabetic neuropathy undergoing below-knee amputation surgery. Biopsies were subdivided for histological analysis, transcriptional profiling, and satellite cell isolation and culture. Results: Histological analysis revealed evidence of ongoing degeneration and regeneration in DPN muscles. Transcriptional profiling supports these findings, indicating significant upregulation of regeneration-related pathways. However, regeneration appeared to be limited in samples exhibiting the most severe structural pathology as only extremely small, immature regenerated myofibers were found. Immunostaining for satellite cells revealed a significant decrease in their relative frequency only in the subset with severe pathology. Similarly, a reduction in fusion in cultured satellite cells in this group suggests impairment in regenerative capacity in severe DPN pathology. Conclusion: DPN muscle exhibited features of degeneration with attempted regeneration. In the most severely pathological muscle samples, regeneration appeared to be stymied and our data suggest that this may be partly due to intrinsic dysfunction of the satellite cell pool in addition to extrinsic structural pathology (eg, nerve damage). Clinical Relevance: Restoration of DPN muscle function for improved mobility and physical activity is a goal of surgical and rehabilitation clinicians. Identifying myofiber degeneration and compromised regeneration as contributors to dysfunction suggests that adjuvant cell-based therapies may improve clinical outcomes.
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Kohno, Shohei, Yui Yamashita, Tomoki Abe, Katsuya Hirasaka, Motoko Oarada, Ayako Ohno, Shigetada Teshima-Kondo, et al. "Unloading stress disturbs muscle regeneration through perturbed recruitment and function of macrophages." Journal of Applied Physiology 112, no. 10 (May 15, 2012): 1773–82. http://dx.doi.org/10.1152/japplphysiol.00103.2012.
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Skeletal muscle is one of the most sensitive tissues to mechanical loading, and unloading inhibits the regeneration potential of skeletal muscle after injury. This study was designed to elucidate the specific effects of unloading stress on the function of immunocytes during muscle regeneration after injury. We examined immunocyte infiltration and muscle regeneration in cardiotoxin (CTX)-injected soleus muscles of tail-suspended (TS) mice. In CTX-injected TS mice, the cross-sectional area of regenerating myofibers was smaller than that of weight-bearing (WB) mice, indicating that unloading delays muscle regeneration following CTX-induced skeletal muscle damage. Delayed infiltration of macrophages into the injured skeletal muscle was observed in CTX-injected TS mice. Neutrophils and macrophages in CTX-injected TS muscle were presented over a longer period at the injury sites compared with those in CTX-injected WB muscle. Disturbance of activation and differentiation of satellite cells was also observed in CTX-injected TS mice. Further analysis showed that the macrophages in soleus muscles were mainly Ly-6C-positive proinflammatory macrophages, with high expression of tumor necrosis factor-α and interleukin-1β, indicating that unloading causes preferential accumulation and persistence of proinflammatory macrophages in the injured muscle. The phagocytic and myotube formation properties of macrophages from CTX-injected TS skeletal muscle were suppressed compared with those from CTX-injected WB skeletal muscle. We concluded that the disturbed muscle regeneration under unloading is due to impaired macrophage function, inhibition of satellite cell activation, and their cooperation.
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Kent, Karla S., Joanne Pearce, Christine Gee, and C. K. Govind. "Regenerative fidelity in the paired claw closer muscles of lobsters." Canadian Journal of Zoology 67, no. 6 (June 1, 1989): 1573–77. http://dx.doi.org/10.1139/z89-223.
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The paired claws in the lobster Homarus americanus are bilaterally asymmetric, consisting of a major (crusher) and a minor (cutter) claw. The fiber composition of the claw closer muscles is correspondingly asymmetric: the cutter muscle has predominantly fast fibers with a small ventral slow band, whereas the crusher muscle has 100% slow fibers. Loss of the paired claws results in regeneration of new ones, which resemble their predecessors in external morphology and in the fiber composition of the closer muscle. Such regenerative fidelity prevails even when the paired claws and closer muscles are symmetric and of the cutter type, and even when they have undergone two successive cycles of limb loss and regeneration. Therefore the type of closer muscle and the configuration of the paired claws is not altered by loss and regeneration.
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Endo, Yori, Charles Hwang, Yuteng Zhang, Ronald Neppl, Shailesh Argawal, and Indranil Sinah. "AGING-RELATED VEGF IMPAIRS MUSCLE REGENERATION." Innovation in Aging 6, Supplement_1 (November 1, 2022): 409. http://dx.doi.org/10.1093/geroni/igac059.1608.
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Abstract Purpose Aging is associated with frailty, a parameter that correlates with mortality and loss of muscle mass. The molecular mechanisms behind aging-associated impairment of muscle regeneration remain incompletely understood. We hypothesized VEGF-A with known role in angiogenesis and muscle progenitor differentiation to regulate regeneration in aged skeletal muscle. Methods Young C57BL/6 (10 weeks old) and old C57BL/6 mice (24 months old) were subjected to muscle cryoinjury to induce regeneration. Quantifications of cross-sectional area (CSA) of regenerating myofibers were performed. Tibialis anterior muscle lysates was used for quantifying VEGF-A. To evaluate the role of VEGF in muscle regeneration, a similar experiment was performed on VEGFlo mice with a 75% decrease in VEGF-A activity and littermate controls. ML228, a hypoxia signaling activator that increases VEGF-A levels, was injected into young and old mice as well as VEGFlo and littermate controls. Results Old mice exhibited marked reduction in the VEGF-A protein levels and regenerating myofiber CSA on DPI 10 (1250 vs. 833μm2, p<.001). Similarly, VEGFlo mice exhibited significantly smaller regenerating fiber CSA as compared to littermate controls on DPI 10 (541 vs. 238μm2, p=.0011). Pharmacological augmentation of VEGFA using ML228 increased muscle VEGF levels by 2 folds and skeletal muscle regeneration in both old mice (25% increase in regenerating fiber CSA, p<.01) and VEGFlo (20% increase in regenerating fiber CSA, p<.01) mice, but not young or littermate controls. Conclusions Muscle regeneration declines with aging in correlation with loss of VEGFA levels within skeletal muscle. Supplementation of VEGFA represents a therapeutic target for sarcopenia.
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Church, Jarrod E., Stefan M. Gehrig, Annabel Chee, Timur Naim, Jennifer Trieu, Glenn K. McConell, and Gordon S. Lynch. "Early functional muscle regeneration after myotoxic injury in mice is unaffected by nNOS absence." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 301, no. 5 (November 2011): R1358—R1366. http://dx.doi.org/10.1152/ajpregu.00096.2011.
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Nitric oxide (NO) is an important signaling molecule produced in skeletal muscle primarily via the neuronal subtype of NO synthase (NOS1, or nNOS). While many studies have reported NO production to be important in muscle regeneration, none have examined the contribution of nNOS-derived NO to functional muscle regeneration (i.e., restoration of the muscle's ability to produce force) after acute myotoxic injury. In the present study, we tested the hypothesis that genetic deletion of nNOS would impair functional muscle regeneration after myotoxic injury in nNOS−/− mice. We found that nNOS−/− mice had lower body mass, lower muscle mass, and smaller myofiber cross-sectional area and that their tibialis anterior (TA) muscles produced lower absolute tetanic forces than those of wild-type littermate controls but that normalized or specific force was identical between the strains. In addition, muscles from nNOS−/− mice were more resistant to fatigue than those of wild-type littermates ( P < 0.05). To determine whether deletion of nNOS affected muscle regeneration, TA muscles from nNOS−/− mice and wild-type littermates were injected with the myotoxin notexin to cause complete fiber degeneration, and muscle structure and function were assessed at 7 and 10 days postinjury. Myofiber cross-sectional area was lower in regenerating nNOS−/− mice than wild-type controls at 7 and 10 days postinjury; however, contrary to our original hypothesis, no difference in force-producing capacity of the TA muscle was evident between the two groups at either time point. Our findings reveal that nNOS is not essential for functional muscle regeneration after acute myotoxic damage.
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Hosaka, Yukio, Toshifumi Yokota, Yuko Miyagoe-Suzuki, Katsutoshi Yuasa, Michihiro Imamura, Ryoichi Matsuda, Takaaki Ikemoto, Shuhei Kameya, and Shin'ichi Takeda. "α1-Syntrophin–deficient skeletal muscle exhibits hypertrophy and aberrant formation of neuromuscular junctions during regeneration." Journal of Cell Biology 158, no. 6 (September 9, 2002): 1097–107. http://dx.doi.org/10.1083/jcb.200204076.
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α1-Syntrophin is a member of the family of dystrophin-associated proteins; it has been shown to recruit neuronal nitric oxide synthase and the water channel aquaporin-4 to the sarcolemma by its PSD-95/SAP-90, Discs-large, ZO-1 homologous domain. To examine the role of α1-syntrophin in muscle regeneration, we injected cardiotoxin into the tibialis anterior muscles of α1-syntrophin–null (α1syn−/−) mice. After the treatment, α1syn−/− muscles displayed remarkable hypertrophy and extensive fiber splitting compared with wild-type regenerating muscles, although the untreated muscles of the mutant mice showed no gross histological change. In the hypertrophied muscles of the mutant mice, the level of insulin-like growth factor-1 transcripts was highly elevated. Interestingly, in an early stage of the regeneration process, α1syn−/− mice showed remarkably deranged neuromuscular junctions (NMJs), accompanied by impaired ability to exercise. The contractile forces were reduced in α1syn−/− regenerating muscles. Our results suggest that the lack of α1-syntrophin might be responsible in part for the muscle hypertrophy, abnormal synapse formation at NMJs, and reduced force generation during regeneration of dystrophin-deficient muscle, all of which are typically observed in the early stages of Duchenne muscular dystrophy patients.
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Kirk, S. P., M. A. Whittle, J. M. Oldham, P. M. Dobbie, and J. J. Bass. "GH regulation of the Type 2 IGF receptor in regenerating skeletal muscle of rats." Journal of Endocrinology 149, no. 1 (April 1996): 81–91. http://dx.doi.org/10.1677/joe.0.1490081.
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Abstract GH enhances skeletal muscle growth, and IGF-II peptide is highly expressed during regeneration. We have therefore investigated the effect of GH administration on IGF-II binding and expression in regenerating rat skeletal muscle using the techniques of receptor autoradiography and in situ hybridisation. Notexin, a myotoxin, was injected into the right M. biceps femoris (day 0), causing affected fibres to undergo necrosis followed by rapid regeneration. Animals were administered either GH (200 μg/100 g body weight) or saline vehicle daily. Contralateral muscles were used as regeneration controls. GH administration during regeneration resulted in significant increases in body weight, and damaged and undamaged muscle weights (P<0·001). IGF-II expression, which was examined in regenerating fibres, survivor fibres and undamaged fibres, varied according to tissue type (P< 0·001). Specifically, IGF-II expression in regenerating fibres was elevated relative to control and survivor fibres after day 3 (P<0·05), with a peak on day 9 (P<0·001). GH did not affect IGF-II message levels. 125I-IGF-II binding in regenerating muscle was examined in the same fibre types as well as in connective tissue. 125I-IGF-II binding in regenerating fibres was higher (P<0·001) than in other tissue types on day 5. GH administration increased 125I-IGF-II binding in all damaged muscle tissues on day 5 (P<0·001, regenerating fibres; P<0·01, others). We believe that this shows for the first time an effect of GH on the Type 2 IGF receptor in regenerating skeletal muscle. Journal of Endocrinology (1996) 149, 81–91
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Contreras-Shannon, Verónica, Oscar Ochoa, Sara M. Reyes-Reyna, Dongxu Sun, Joel E. Michalek, William A. Kuziel, Linda M. McManus, and Paula K. Shireman. "Fat accumulation with altered inflammation and regeneration in skeletal muscle of CCR2−/− mice following ischemic injury." American Journal of Physiology-Cell Physiology 292, no. 2 (February 2007): C953—C967. http://dx.doi.org/10.1152/ajpcell.00154.2006.
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Chemokines recruit inflammatory cells to sites of injury, but the role of the CC chemokine receptor 2 (CCR2) during regenerative processes following ischemia is poorly understood. We studied injury, inflammation, perfusion, capillary formation, monocyte chemotactic protein-1 (MCP-1) levels, muscle regeneration, fat accumulation, and transcription factor activation in hindlimb muscles of CCR2−/− and wild-type (WT) mice following femoral artery excision (FAE). In both groups, muscle injury and restoration of vascular perfusion were similar. Nevertheless, edema and neutrophil accumulation were significantly elevated in CCR2−/− compared with WT mice at day 1 post-FAE and fewer macrophages were present at day 3. MCP-1 levels in post-ischemic calf muscle of CCR2−/− animals were significantly elevated over baseline through 14 days post-FAE and were higher than WT mice at days 1, 7, and 14. In addition, CCR2−/− mice exhibited impaired muscle regeneration, decreased muscle fiber size, and increased intermuscular adipocytes with similar capillaries/mm2 postinjury. Finally, the transcription factors, MyoD and signal transducers of and activators of transcription-3 (STAT3), were significantly increased above baseline but did not differ significantly between groups at any time point post-FAE. These findings suggest that increases in MCP-1, and possibly, MyoD and STAT3, may modulate molecular signaling in CCR2−/− mice during inflammatory and regenerative events. Furthermore, alterations in neutrophil and macrophage recruitment in CCR2−/− mice may critically alter the normal progression of downstream regenerative events in injured skeletal muscle and may direct myogenic precursor cells in the regenerating milieu toward an adipogenic phenotype.
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Morawin, Barbara, and Agnieszka Zembroń-Łacny. "Role of endocrine factors and stem cells in skeletal muscle regeneration." Postępy Higieny i Medycyny Doświadczalnej 75 (June 2, 2021): 371–84. http://dx.doi.org/10.5604/01.3001.0014.9125.
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The process of reconstructing damaged skeletal muscles involves degeneration, inflammatory and immune responses, regeneration and reorganization, which are regulated by a number of immune-endocrine factors affecting muscle cells and satellite cells (SCs). One of these molecules is testosterone (T), which binds to the androgen receptor (AR) to initiate the expression of the muscle isoform of insulin-like growth factor 1 (IGF-1Ec). The interaction between T and IGF-1Ec stimulates the growth and regeneration of skeletal muscles by inhibiting apoptosis, enhancement of SCs proliferation and myoblasts differentiation. As a result of sarcopenia, muscle dystrophy or wasting diseases, the SCs population is significantly reduced. Regular physical exercise attenuates a decrease in SCs count, and thus elevates the regenerative potential of muscles in both young and elderly people. One of the challenges of modern medicine is the application of SCs and extracellular matrix scaffolds in regenerative and molecular medicine, especially in the treatment of degenerative diseases and post-traumatic muscle reconstruction. The aim of the study is to present current information on the molecular and cellular mechanisms of skeletal muscle regenera,tion, the role of testosterone and growth factors in the activation of SCs and the possibility of their therapeutic use in stimulating the reconstruction of damaged muscle fibers.
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Oikawa, Satoshi, Minjung Lee, and Takayuki Akimoto. "Conditional Deletion of Dicer in Adult Mice Impairs Skeletal Muscle Regeneration." International Journal of Molecular Sciences 20, no. 22 (November 13, 2019): 5686. http://dx.doi.org/10.3390/ijms20225686.
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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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Hara, Mie, Shinsuke Yuasa, Kenichiro Shimoji, Takeshi Onizuka, Nozomi Hayashiji, Yohei Ohno, Takahide Arai, et al. "G-CSF influences mouse skeletal muscle development and regeneration by stimulating myoblast proliferation." Journal of Experimental Medicine 208, no. 4 (March 21, 2011): 715–27. http://dx.doi.org/10.1084/jem.20101059.
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After skeletal muscle injury, neutrophils, monocytes, and macrophages infiltrate the damaged area; this is followed by rapid proliferation of myoblasts derived from muscle stem cells (also called satellite cells). Although it is known that inflammation triggers skeletal muscle regeneration, the underlying molecular mechanisms remain incompletely understood. In this study, we show that granulocyte colony-stimulating factor (G-CSF) receptor (G-CSFR) is expressed in developing somites. G-CSFR and G-CSF were expressed in myoblasts of mouse embryos during the midgestational stage but not in mature myocytes. Furthermore, G-CSFR was specifically but transiently expressed in regenerating myocytes present in injured adult mouse skeletal muscle. Neutralization of endogenous G-CSF with a blocking antibody impaired the regeneration process, whereas exogenous G-CSF supported muscle regeneration by promoting the proliferation of regenerating myoblasts. Furthermore, muscle regeneration was markedly impaired in G-CSFR–knockout mice. These findings indicate that G-CSF is crucial for skeletal myocyte development and regeneration and demonstrate the importance of inflammation-mediated induction of muscle regeneration.
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Stupka, Nicole, Jonathan D. Schertzer, Rhonda Bassel-Duby, Eric N. Olson, and Gordon S. Lynch. "Calcineurin-Aα activation enhances the structure and function of regenerating muscles after myotoxic injury." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 293, no. 2 (August 2007): R686—R694. http://dx.doi.org/10.1152/ajpregu.00612.2006.
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Calcineurin signaling is essential for successful muscle regeneration. Although calcineurin inhibition compromises muscle repair, it is not known whether calcineurin activation can enhance muscle repair after injury. Tibialis anterior (TA) muscles from adult wild-type (WT) and transgenic mice overexpressing the constitutively active calcineurin-Aα transgene under the control of the mitochondrial creatine kinase promoter (MCK-CnAα*) were injected with the myotoxic snake venom Notexin to destroy all muscle fibers. The TA muscle of the contralateral limb served as the uninjured control. Muscle structure was assessed at 5 and 9 days postinjury, and muscle function was tested in situ at 9 days postinjury. Calcineurin stimulation enhanced muscle regeneration and altered levels of myoregulatory factors (MRFs). Recovery of myofiber size and force-producing capacity was hastened in injured muscles of MCK-CnAα* mice compared with control. Myogenin levels were greater 5 days postinjury and myocyte enhancer factor 2a (MEF2a) expression was greater 9 days postinjury in muscles of MCK-CnAα* mice compared with WT mice. Higher MEF2a expression in regenerating muscles of MCK-CnAα* mice 9 days postinjury may be related to an increase of slow fiber genes. Calcineurin activation in uninjured and injured TA muscles slowed muscle contractile properties, reduced fatigability, and enhanced force recovery after 4 min of intermittent maximal stimulation. Therefore, calcineurin activation can confer structural and functional benefits to regenerating skeletal muscles, which may be mediated in part by differential expression of MRFs.
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Takagi, Ryo, Naoto Fujita, Takamitsu Arakawa, Shigeo Kawada, Naokata Ishii, and Akinori Miki. "Influence of icing on muscle regeneration after crush injury to skeletal muscles in rats." Journal of Applied Physiology 110, no. 2 (February 2011): 382–88. http://dx.doi.org/10.1152/japplphysiol.01187.2010.
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The influence of icing on muscle regeneration after crush injury was examined in the rat extensor digitorum longus. After the injury, animals were randomly divided into nonicing and icing groups. In the latter, ice packs were applied for 20 min. Due to the icing, degeneration of the necrotic muscle fibers and differentiation of satellite cells at early stages of regeneration were retarded by ∼1 day. In the icing group, the ratio of regenerating fibers showing central nucleus at 14 days after the injury was higher, and cross-sectional area of the muscle fibers at 28 days was evidently smaller than in the nonicing group. Besides, the ratio of collagen fibers area at 14 and 28 days after the injury in the icing group was higher than in the nonicing group. These findings suggest that icing applied soon after the injury not only considerably retarded muscle regeneration but also induced impairment of muscle regeneration along with excessive collagen deposition. Macrophages were immunohistochemically demonstrated at the injury site during degeneration and early stages of regeneration. Due to icing, chronological changes in the number of macrophages and immunohistochemical expression of transforming growth factor (TGF)-β1 and IGF-I were also retarded by 1 to 2 days. Since it has been said that macrophages play important roles not only for degeneration, but also for muscle regeneration, the influence of icing on macrophage activities might be closely related to a delay in muscle regeneration, impairment of muscle regeneration, and redundant collagen synthesis.
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Kuang, Shihuan, Feng Yue, and Stephanie Oprescu. "193 Single Cell RNA-sequencing Reveals a Role of Lipid Metabolism in Muscle Satellite Cells." Journal of Animal Science 99, Supplement_3 (October 8, 2021): 104–5. http://dx.doi.org/10.1093/jas/skab235.189.
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Abstract Single Cell RNA-sequencing (scRNA-seq) is a powerful technique to deconvolute gene expression of various subset of cells intermingled within a complex tissue, such as the skeletal muscle. We first used scRNA-seq to understand dynamics of cell populations and their gene expression during muscle regeneration in murine limb muscles. This leads to the identification of a subset of satellite cells (the resident stem cells of skeletal muscles) with immune gene signatures in regenerating muscles. Next, we used scRNA-seq to examine gene expression dynamics of satellite cells at various status: quiescence, activation, proliferation, differentiation and self-renewal. This analysis uncovers stage-dependent changes in expression of genes related to lipid metabolism. Further analyses lead to the discovery of previously unappreciated dynamics of lipid droplets in satellite cells; and demonstrate that the abundance of the lipid droplets in newly divided satellite daughter cells is linked to cell fate segregation into differentiation versus self-renewal. Perturbation of lipid droplet dynamics through blocking lipolysis disrupts cell fate homeostasis and impairs muscle regeneration. Finally, we show that lipid metabolism regulates the function of satellite cells through two mechanisms. On one hand, lipid metabolism functions as an energy source through fatty acid oxidation (FAO), and blockage of FAO reduces energy production that is critical for satellite cell function. On the other hand, lipid metabolism generates bioactive molecules that influence signaling transduction and gene expression. In this scenario, lipid metabolism and FAO regulate the intracellular levels of acetyl-coA and selective acetylation of PAX7, a pivotal transcriptional factor underlying function of satellite cells. These results together reveal for the first time a critical role of lipid metabolism and lipid droplet dynamics in muscle satellite cell fate determination and regenerative function; and underscore a potential role of dietary fatty acids in satellite cell-dependent muscle development, growth and regeneration.
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Barton, Elisabeth R., Linda Morris, Antonio Musaro, Nadia Rosenthal, and H. Lee Sweeney. "Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice." Journal of Cell Biology 157, no. 1 (April 1, 2002): 137–48. http://dx.doi.org/10.1083/jcb.200108071.
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Duchenne muscular dystrophy is an X-linked degenerative disorder of muscle caused by the absence of the protein dystrophin. A major consequence of muscular dystrophy is that the normal regenerative capacity of skeletal muscle cannot compensate for increased susceptibility to damage, leading to repetitive cycles of degeneration–regeneration and ultimately resulting in the replacement of muscle fibers with fibrotic tissue. Because insulin-like growth factor I (IGF-I) has been shown to enhance muscle regeneration and protein synthetic pathways, we asked whether high levels of muscle-specific expression of IGF-I in mdx muscle could preserve muscle function in the diseased state. In transgenic mdx mice expressing mIgf-I (mdx:mIgf+/+), we showed that muscle mass increased by at least 40% leading to similar increases in force generation in extensor digitorum longus muscles compared with those from mdx mice. Diaphragms of transgenic mdx:mIgf+/+ exhibited significant hypertrophy and hyperplasia at all ages observed. Furthermore, the IGF-I expression significantly reduced the amount of fibrosis normally observed in diaphragms from aged mdx mice. Decreased myonecrosis was also observed in diaphragms and quadriceps from mdx:mIgf+/+ mice when compared with age-matched mdx animals. Finally, signaling pathways associated with muscle regeneration and protection against apoptosis were significantly elevated. These results suggest that a combination of promoting muscle regenerative capacity and preventing muscle necrosis could be an effective treatment for the secondary symptoms caused by the primary loss of dystrophin.
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Brenner, H. R., A. Herczeg, and C. R. Slater. "Synapse-specific expression of acetylcholine receptor genes and their products at original synaptic sites in rat soleus muscle fibres regenerating in the absence of innervation." Development 116, no. 1 (September 1, 1992): 41–53. http://dx.doi.org/10.1242/dev.116.1.41.
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To test the hypothesis that synaptic basal lamina can induce synapse-specific expression of acetylcholine receptor (AChR) genes, we examined the levels mRNA for the alpha- and epsilon-subunits of the AChR in regenerating rat soleus muscles up to 17 days of regeneration. Following destruction of all muscle fibres and their nuclei by exposure to venom of the Australian tiger snake, new fibres regenerated within the original basal lamina sheaths. Northern blots showed that original mRNA was lost during degeneration. Early in regeneration, both alpha- and epsilon-subunit mRNAs were present throughout the muscle fibres but in situ hybridization showed them to be concentrated primarily at original synaptic sites, even when the nerve was absent during regeneration. A similar concentration was seen in denervated regenerating muscles kept active by electrical stimulation and in muscles frozen 41–44 hours after venom injection to destroy all cells in the synaptic region of the muscle. Acetylcholine-gated ion channels with properties similar to those at normal neuromuscular junctions were concentrated at original synaptic sites on denervated stimulated muscles. Taken together, these findings provide strong evidence that factors that induce the synapse-specific expression of AChR genes are stably bound to synaptic basal lamina.
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Hirano, Kotaro, Masaki Tsuchiya, Akifumi Shiomi, Seiji Takabayashi, Miki Suzuki, Yudai Ishikawa, Yuya Kawano, et al. "The mechanosensitive ion channel PIEZO1 promotes satellite cell function in muscle regeneration." Life Science Alliance 6, no. 2 (November 29, 2022): e202201783. http://dx.doi.org/10.26508/lsa.202201783.
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Muscle satellite cells (MuSCs), myogenic stem cells in skeletal muscles, play an essential role in muscle regeneration. After skeletal muscle injury, quiescent MuSCs are activated to enter the cell cycle and proliferate, thereby initiating regeneration; however, the mechanisms that ensure successful MuSC division, including chromosome segregation, remain unclear. Here, we show that PIEZO1, a calcium ion (Ca2+)-permeable cation channel activated by membrane tension, mediates spontaneous Ca2+influx to control the regenerative function of MuSCs. Our genetic engineering approach in mice revealed that PIEZO1 is functionally expressed in MuSCs and thatPiezo1deletion in these cells delays myofibre regeneration after injury. These results are, at least in part, due to a mitotic defect in MuSCs. Mechanistically, this phenotype is caused by impaired PIEZO1-Rho signalling during myogenesis. Thus, we provide the first concrete evidence that PIEZO1, a bona fide mechanosensitive ion channel, promotes proliferation and regenerative functions of MuSCs through precise control of cell division.
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Sommerland, H., M. Ullman, E. Jennische, A. Skottner, and A. Oldfors. "Muscle regeneration." Acta Neuropathologica 78, no. 3 (1989): 264–69. http://dx.doi.org/10.1007/bf00687756.
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Clow, Charlene, and Bernard J. Jasmin. "Brain-derived Neurotrophic Factor Regulates Satellite Cell Differentiation and Skeltal Muscle Regeneration." Molecular Biology of the Cell 21, no. 13 (July 2010): 2182–90. http://dx.doi.org/10.1091/mbc.e10-02-0154.
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In adult skeletal muscle, brain-derived neurotrophic factor (BDNF) is expressed in myogenic progenitors known as satellite cells. To functionally address the role of BDNF in muscle satellite cells and regeneration in vivo, we generated a mouse in which BDNF is specifically depleted from skeletal muscle cells. For comparative purposes, and to determine the specific role of muscle-derived BDNF, we also examined muscles of the complete BDNF−/− mouse. In both models, expression of the satellite cell marker Pax7 was significantly decreased. Furthermore, proliferation and differentiation of primary myoblasts was abnormal, exhibiting delayed induction of several markers of differentiation as well as decreased myotube size. Treatment with exogenous BDNF protein was sufficient to rescue normal gene expression and myotube size. Because satellite cells are responsible for postnatal growth and repair of skeletal muscle, we next examined whether regenerative capacity was compromised. After injury, BDNF-depleted muscle showed delayed expression of several molecular markers of regeneration, as well as delayed appearance of newly regenerated fibers. Recovery of wild-type BDNF levels was sufficient to restore normal regeneration. Together, these findings suggest that BDNF plays an important role in regulating satellite cell function and regeneration in vivo, particularly during early stages.
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Liu, Qi, Su Pan, Shijie Liu, Sui Zhang, James T. Willerson, James F. Martin, and Richard A. F. Dixon. "Suppressing Hippo signaling in the stem cell niche promotes skeletal muscle regeneration." Stem Cells 39, no. 6 (February 18, 2021): 737–49. http://dx.doi.org/10.1002/stem.3343.
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Abstract Lack of blood flow to the lower extremities in peripheral arterial disease causes oxygen and nutrient deprivation in ischemic skeletal muscles, leading to functional impairment. Treatment options for muscle regeneration in this scenario are lacking. Here, we selectively targeted the Hippo pathway in myofibers, which provide architectural support for muscle stem cell niches, to facilitate functional muscle recovery in ischemic extremities by promoting angiogenesis, neovascularization, and myogenesis. We knocked down the core Hippo pathway component, Salvador (SAV1), by using an adeno-associated virus 9 (AAV9) vector expressing a miR30-based triple short-hairpin RNA (shRNA), controlled by a muscle-specific promoter. In a mouse hindlimb-ischemia model, AAV9 SAV1 shRNA administration in ischemic muscles induced nuclear localization of the Hippo effector YAP, accelerated perfusion restoration, and increased exercise endurance. Intravascular lectin labeling of the vasculature revealed enhanced angiogenesis. Using 5-ethynyl-2′-deoxyuridine to label replicating cellular DNA in vivo, we found SAV1 knockdown concurrently increased paired box transcription factor Pax7+ muscle satellite cell and CD31+ endothelial cell proliferation in ischemic muscles. To further study Hippo suppression in skeletal muscle regeneration, we used a cardiotoxin-induced muscle damage model in adult (12-15 weeks old) and aged mice (26-month old). Two weeks after delivery of AAV9 SAV1 shRNA into injured muscles, the distribution of regenerative myofibers shifted toward a larger cross-sectional area and increased capillary density compared with mice receiving AAV9 control. Together, these findings suggest our approach may have clinical promise in regenerative therapy for leg ischemia and muscle injury.
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Slack, J. M. W., C. W. Beck, C. Gargioli, and B. Christen. "Cellular and molecular mechanisms of regeneration in Xenopus." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 359, no. 1445 (May 29, 2004): 745–51. http://dx.doi.org/10.1098/rstb.2004.1463.
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We have employed transgenic methods combined with embryonic grafting to analyse the mechanisms of regeneration in Xenopus tadpoles. The Xenopus tadpole tail contains a spinal cord, notochord and segmented muscles, and all tissues are replaced when the tail regenerates after amputation. We show that there is a refractory period of very low regenerative ability in the early tadpole stage. Tracing of cell lineage with the use of single tissue transgenic grafts labelled with green fluorescent protein (GFP) shows that there is no de-differentiation and no metaplasia during regeneration. The spinal cord, notochord and muscle all regenerate from the corresponding tissue in the stump; in the case of the muscle the satellite cells provide the material for regeneration. By using constitutive or dominant negative gene products, induced under the control of a heat shock promoter, we show that the bone morphogenetic protein (BMP) and Notch signalling pathways are both essential for regeneration. BMP is upstream of Notch and has an independent effect on regeneration of muscle. The Xenopus limb bud will regenerate completely at the early stages but regenerative ability falls during digit differentiation. We have developed a procedure for making tadpoles in which one hindlimb is transgenic and the remainder wild-type. This has been used to introduce various gene products expected to prolong the period of regenerative capacity, but none has so far been successful.
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Ge, Yejing, Ai-Luen Wu, Christine Warnes, Jianming Liu, Chongben Zhang, Hideki Kawasome, Naohiro Terada, Marni D. Boppart, Christopher J. Schoenherr, and Jie Chen. "mTOR regulates skeletal muscle regeneration in vivo through kinase-dependent and kinase-independent mechanisms." American Journal of Physiology-Cell Physiology 297, no. 6 (December 2009): C1434—C1444. http://dx.doi.org/10.1152/ajpcell.00248.2009.
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Rapamycin-sensitive signaling is required for skeletal muscle differentiation and remodeling. In cultured myoblasts, the mammalian target of rapamycin (mTOR) has been reported to regulate differentiation at different stages through distinct mechanisms, including one that is independent of mTOR kinase activity. However, the kinase-independent function of mTOR remains controversial, and no in vivo studies have examined those mTOR myogenic mechanisms previously identified in vitro. In this study, we find that rapamycin impairs injury-induced muscle regeneration. To validate the role of mTOR with genetic evidence and to probe the mechanism of mTOR function, we have generated and characterized transgenic mice expressing two mutants of mTOR under the control of human skeletal actin (HSA) promoter: rapamycin-resistant (RR) and RR/kinase-inactive (RR/KI). Our results show that muscle regeneration in rapamycin-administered mice is restored by RR-mTOR expression. In the RR/KI-mTOR mice, nascent myofiber formation during the early phase of regeneration proceeds in the presence of rapamycin, but growth of the regenerating myofibers is blocked by rapamycin. Igf2 mRNA levels increase drastically during early regeneration, which is sensitive to rapamycin in wild-type muscles but partially resistant to rapamycin in both RR- and RR/KI-mTOR muscles, consistent with mTOR regulation of Igf2 expression in a kinase-independent manner. Furthermore, systemic ablation of S6K1, a target of mTOR kinase, results in impaired muscle growth but normal nascent myofiber formation during regeneration. Therefore, mTOR regulates muscle regeneration through kinase-independent and kinase-dependent mechanisms at the stages of nascent myofiber formation and myofiber growth, respectively.
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Liu, Juan, Dominik Saul, Kai Oliver Böker, Jennifer Ernst, Wolfgang Lehman, and Arndt F. Schilling. "Current Methods for Skeletal Muscle Tissue Repair and Regeneration." BioMed Research International 2018 (2018): 1–11. http://dx.doi.org/10.1155/2018/1984879.
Full textAbstract:
Skeletal muscle has the capacity of regeneration after injury. However, for large volumes of muscle loss, this regeneration needs interventional support. Consequently, muscle injury provides an ongoing reconstructive and regenerative challenge in clinical work. To promote muscle repair and regeneration, different strategies have been developed within the last century and especially during the last few decades, including surgical techniques, physical therapy, biomaterials, and muscular tissue engineering as well as cell therapy. Still, there is a great need to develop new methods and materials, which promote skeletal muscle repair and functional regeneration. In this review, we give a comprehensive overview over the epidemiology of muscle tissue loss, highlight current strategies in clinical treatment, and discuss novel methods for muscle regeneration and challenges for their future clinical translation.
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Milewska, Marta, and Katarzyna Grzelkowska-Kowalczyk. "Role of proinflammatory cytokines and growth factors in skeletal muscle regeneration." Medycyna Weterynaryjna 72, no. 8 (2016): 472–78. http://dx.doi.org/10.21521/mw.5551.
Full textAbstract:
Skeletal muscle healing after injury can be divided into three distinct but overlapping phases. The destruction phase is characterized by rupture followed by necrosis of muscle fibers, formation of hematoma and inflammatory reaction. During the repair phase a necrotic tissue is phagocyted by macrophages, muscle fibers are regenerating and connective tissue scars are formed. The remodeling phase concerns the period when regenerating muscle fibers mature, scar contraction and reorganization occurs and the muscle recovers its functional efficiency. Proinflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and growth factors (FGF, IGF, TGF-β, HGF) play a critical role in all phases of muscle repair. Moreover, chemokines expressed at early stages of myogenesis can regulate the survival and proliferation of myoblasts. Chemokines expressed in vivo in muscle cells can directly influence myogenesis, but can also act in a paracrine manner by recruiting the immune cells (macrophages) to injured skeletal muscles, which is crucial for the regeneration process. Identification of molecules regulating myogenesis, like cytokines, chemokines and growth factors, contributes to the exploration of molecular mechanisms that can improve muscle regeneration after injury, diseases, surgery and increase the effectiveness of cell transplantation.
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Ribchester, R. R. "Co‐existence and elimination of convergent motor nerve terminals in reinnervated and paralysed adult rat skeletal muscle." Journal of Physiology 466, no. 1 (July 1993): 421–41. http://dx.doi.org/10.1113/jphysiol.1993.sp019728.
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1. Experiments were carried out to determine whether neuromuscular synapse elimination can occur in skeletal muscle in the complete absence of conducted neural activity, using reinnervation of partially denervated adult muscle as a paradigm. Partially denervated rat lumbrical muscles were paralysed with a nerve conduction block applied to the sciatic nerve during regeneration of injured sural nerve motor axons. Both intact (lateral plantar nerve) and regenerating motor axons converging on the same muscle fibres were therefore inactive. 2. Paralysed muscles expressed prolonged twitch contractions, low tetanus‐to‐twitch ratios, prolonged synaptic potentials and marked post‐tetanic potentiation of frequency of miniature endplate potentials compared with control muscles and neuromuscular junctions. 3. Isometric tension and intracellular recording data suggest that regenerating axons reinnervated more muscle fibres in paralysed muscles than in controls. A greater proportion of muscle fibres was polyneuronally innervated in the paralysed muscles, but significant numbers of muscle fibres acquired a mononeuronal innervation by regenerated, inactive motor nerve terminals. 4. The data suggest that muscle paralysis enhances the regeneration of motor axons when they grow into partially denervated muscles, but activity‐independent competition may also be important in the mechanism of synapse elimination at neuromuscular junctions. The data further imply that when nerve endings expressing identical patterns of activity converge on a postsynaptic cell, Hebbian rules may not be sufficient to predict the outcome of the competition, contrary to specific postulates of the neurotrophic theory of development and maintenance of neural connections.
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CIECIERSKA, ANNA, TOMASZ SADKOWSKI, and TOMASZ MOTYL. "Role of satellite cells in growth and regeneration of skeletal muscles." Medycyna Weterynaryjna 75, no. 11 (2019): 6349–2019. http://dx.doi.org/10.21521/mw.6349.
Full textAbstract:
Postnatal growth and regeneration capacity of skeletal muscles is dependent mainly on adult muscle stem cells called satellite cells. Satellite cells are quiescent mononucleated cells that are normally located outside the sarcolemma within the basal lamina of the muscle fiber. Their activation, which results from injury, is manifested by mobilization, proliferation, differentiation and, ultimately, fusion into new muscle fibers. The satellite cell pool is responsible for the remarkable regenerative capacity of skeletal muscles. Moreover, these cells are capable of self-renewal and can give rise to myogenic progeny.
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Rebalka, Irena A., Cynthia M. F. Monaco, Nina E. Varah, Thorsten Berger, Donna M. D’souza, Sarah Zhou, Tak W. Mak, and Thomas J. Hawke. "Loss of the adipokine lipocalin-2 impairs satellite cell activation and skeletal muscle regeneration." American Journal of Physiology-Cell Physiology 315, no. 5 (November 1, 2018): C714—C721. http://dx.doi.org/10.1152/ajpcell.00195.2017.
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Lipocalin-2 (LCN2) is an adipokine previously described for its contribution to numerous processes, including innate immunity and energy metabolism. LCN2 has also been demonstrated to be an extracellular matrix (ECM) regulator through its association with the ECM protease matrix metalloproteinase-9 (MMP-9). With the global rise in obesity and the associated comorbidities related to increasing adiposity, it is imperative to gain an understanding of the cross talk between adipose tissue and other metabolic tissues, such as skeletal muscle. Given the function of LCN2 on the ECM in other tissues and the importance of matrix remodeling in skeletal muscle regeneration, we examined the localization and expression of LCN2 in uninjured and regenerating wild-type skeletal muscle and assessed the impact of LCN2 deletion (LCN2−/−) on skeletal muscle repair following cardiotoxin injury. Though LCN2 was minimally present in uninjured skeletal muscle, its expression was increased significantly at 1 and 2 days postinjury, with expression present in Pax7-positive satellite cells. Although satellite cell content was unchanged, the ability of quiescent satellite cells to become activated was significantly impaired in LCN2−/− skeletal muscles. Skeletal muscle regeneration was also significantly compromised as evidenced by decreased embryonic myosin heavy chain expression and smaller regenerating myofiber areas. Consistent with a role for LCN2 in MMP-9 regulation, regenerating muscle also displayed a significant increase in fibrosis and lower ( P = 0.07) MMP-9 activity in LCN2−/− mice at 2 days postinjury. These data highlight a novel role for LCN2 in muscle regeneration and suggest that changes in adipokine expression can significantly impact skeletal muscle repair.
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Grabowska, Iwona, Malgorzata Zimowska, Karolina Maciejewska, Zuzanna Jablonska, Anna Bazga, Michal Ozieblo, Wladyslawa Streminska, Joanna Bem, Edyta Brzoska, and Maria Ciemerych. "Adipose Tissue-Derived Stromal Cells in Matrigel Impact the Regeneration of Severely Damaged Skeletal Muscles." International Journal of Molecular Sciences 20, no. 13 (July 5, 2019): 3313. http://dx.doi.org/10.3390/ijms20133313.
Full textAbstract:
In case of large injuries of skeletal muscles the pool of endogenous stem cells, i.e., satellite cells, might be not sufficient to secure proper regeneration. Such failure in reconstruction is often associated with loss of muscle mass and excessive formation of connective tissue. Therapies aiming to improve skeletal muscle regeneration and prevent fibrosis may rely on the transplantation of different types of stem cell. Among such cells are adipose tissue-derived stromal cells (ADSCs) which are relatively easy to isolate, culture, and manipulate. Our study aimed to verify applicability of ADSCs in the therapies of severely injured skeletal muscles. We tested whether 3D structures obtained from Matrigel populated with ADSCs and transplanted to regenerating mouse gastrocnemius muscles could improve the regeneration. In addition, ADSCs used in this study were pretreated with myoblasts-conditioned medium or anti-TGFβ antibody, i.e., the factors modifying their ability to proliferate, migrate, or differentiate. Analyses performed one week after injury allowed us to show the impact of 3D cultured control and pretreated ADSCs at muscle mass and structure, as well as fibrosis development immune response of the injured muscle.
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Musarò, Antonio. "The Basis of Muscle Regeneration." Advances in Biology 2014 (July 9, 2014): 1–16. http://dx.doi.org/10.1155/2014/612471.
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Muscle regeneration recapitulates many aspects of embryonic myogenesis and is an important homeostatic process of the adult skeletal muscle, which, after development, retains the capacity to regenerate in response to appropriate stimuli, activating the muscle compartment of stem cells, namely, satellite cells, as well as other precursor cells. Moreover, significant evidence suggests that while stem cells represent an important determinant for tissue regeneration, a “qualified” environment is necessary to guarantee and achieve functional results. It is therefore plausible that the loss of control over these cell fate decisions could lead to a pathological transdifferentiation, leading to pathologic defects in the regenerative process. This review provides an overview about the general aspects of muscle development and discusses the cellular and molecular aspects that characterize the five interrelated and time-dependent phases of muscle regeneration, namely, degeneration, inflammation, regeneration, remodeling, and maturation/functional repair.
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Bondesen, Brenda A., Stephen T. Mills, Kristy M. Kegley, and Grace K. Pavlath. "The COX-2 pathway is essential during early stages of skeletal muscle regeneration." American Journal of Physiology-Cell Physiology 287, no. 2 (August 2004): C475—C483. http://dx.doi.org/10.1152/ajpcell.00088.2004.
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Skeletal muscle regeneration comprises several overlapping cellular processes, including inflammation and myogenesis. Prostaglandins (PGs) may regulate muscle regeneration, because they modulate inflammation and are involved in various stages of myogenesis in vitro. PG synthesis is catalyzed by different isoforms of cyclooxygenase (COX), which are inhibited by nonsteroidal anti-inflammatory drugs. Although experiments employing nonsteroidal anti-inflammatory drugs have implicated PGs in tissue repair, how PGs regulate muscle regeneration remains unclear, and the potentially distinct roles of different COX isoforms have not been investigated. To address these questions, a localized freeze injury was induced in the tibialis anterior muscles of mice chronically treated with either a COX-1- or COX-2-selective inhibitor (SC-560 and SC-236, respectively), starting before injury. The size of regenerating myofibers was analyzed at time points up to 5 wk after injury and found to be decreased by SC-236 and in COX-2−/− muscles, but unaffected by SC-560. In contrast, SC-236 had no effect on myofiber growth when administered starting 7 days after injury. The attenuation of myofiber growth by SC-236 treatment and in COX-2−/− muscles is associated with decreases in the number of myoblasts and intramuscular inflammatory cells at early times after injury. Together, these data suggest that COX-2-dependent PG synthesis is required during early stages of muscle regeneration and thus raise caution about the use of COX-2-selective inhibitors in patients with muscle injury or disease.
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Pereira, T., P. A. S. Armada-da Silva, I. Amorim, A. Rêma, A. R. Caseiro, A. Gärtner, M. Rodrigues, et al. "Effects of Human Mesenchymal Stem Cells Isolated from Wharton’s Jelly of the Umbilical Cord and Conditioned Media on Skeletal Muscle Regeneration Using a Myectomy Model." Stem Cells International 2014 (2014): 1–16. http://dx.doi.org/10.1155/2014/376918.
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Skeletal muscle has good regenerative capacity, but the extent of muscle injury and the developed fibrosis might prevent complete regeneration. Thein vivoapplication of human mesenchymal stem cells (HMSCs) of the umbilical cord and the conditioned media (CM) where the HMSCs were cultured and expanded, associated with different vehicles to induce muscle regeneration, was evaluated in a rat myectomy model. Two commercially available vehicles and a spherical hydrogel developed by our research group were used. The treated groups obtained interesting results in terms of muscle regeneration, both in the histological and in the functional assessments. A less evident scar tissue, demonstrated by collagen type I quantification, was present in the muscles treated with HMSCs or their CM. In terms of the histological evaluation performed by ISO 10993-6 scoring, it was observed that HMSCs apparently have a long-term negative effect, since the groups treated with CM presented better scores. CM could be considered an alternative to thein vivotransplantation of these cells, as it can benefit from the local tissue response to secreted molecules with similar results in terms of muscular regeneration. Searching for an optimal vehicle might be the key point in the future of skeletal muscle tissue engineering.