scholarly journals miR-24:Prdx6 interactions regulate oxidative stress and viability of myogenic progenitors during ageing

2021 ◽  
Author(s):  
Ana Soriano-Arroquia ◽  
John Gostage ◽  
David Bardell ◽  
Eugene McCloskey ◽  
Ilaria Bellantuono ◽  
...  
Keyword(s):  
Cell Viability ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Protective Mechanism ◽  
Compensatory Mechanism ◽  
Differentiation Potential ◽  
Myogenic Potential ◽  
Early Stages ◽  
Old Mice

ABSTRACTmicroRNAs regulate a myriad of physiological processes, including skeletal muscle regeneration and homeostasis. During ageing, changes in muscle fibre microenvironment contribute to the capability of satellite cells to regenerate the muscle in response to injury and loading stressors. In this study, we isolated murine satellite cells and primary myogenic progenitors from mice and humans to demonstrate that the microRNA miR-24-3p and its target peroxiredoxin 6 (Prdx6) play an important role in muscle regeneration during ageing, regulating satellite cell viability and their differentiation potential. Our results show upregulation of miR-24 during early stages of muscle regeneration in vivo in adult mice, suggesting a potential role of miR-24 at the early stages of muscle injury. On contrary, miR-24 was downregulated during regeneration of muscle of old mice. miR-24 was also downregulated, whereas its target gene Prdx6 was upregulated, in satellite cells isolated from old mice. miR-24 consistently regulated viability and myogenic potential of myogenic progenitors from both humans and old mice, suggesting that changes in miR-24 levels during ageing may contribute to defective early stages of muscle regeneration during ageing through affecting satellite cell viability and myogenic potential. This regulation likely occurs via miR-24 counteracting the generation of reactive oxygen species through Prdx6 de-repression in primary myogenic progenitors isolated from humans and old mice. We propose that downregulation of miR-24 in muscle of old mice following injury may be a protective mechanism against elevated ROS levels to maintain satellite cell viability and myogenic potential, acting through Prdx6 upregulation. However, as miR-24 is a regulator of p16 and p21, this downregulation may lead to increased satellite cell senescence, therefore representing an age-related failed compensatory mechanism.

scholarly journals Inflamma-miR-21 Negatively Regulates Myogenesis during Ageing

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 345 ◽  
Author(s):  
Maria Borja-Gonzalez ◽  
Jose C. Casas-Martinez ◽  
Brian McDonagh ◽  
Katarzyna Goljanek-Whysall
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Muscle Hypertrophy ◽  
Myogenic Potential ◽  
Age Related ◽  
Primary Myoblasts ◽  
Muscle Homeostasis ◽  
Old Mice

Ageing is associated with disrupted redox signalling and increased circulating inflammatory cytokines. Skeletal muscle homeostasis depends on the balance between muscle hypertrophy, atrophy and regeneration, however during ageing this balance is disrupted. The molecular pathways underlying the age-related decline in muscle regenerative potential remain elusive. microRNAs are conserved robust gene expression regulators in all tissues including skeletal muscle. Here, we studied satellite cells from adult and old mice to demonstrate that inhibition of miR-21 in satellite cells from old mice improves myogenesis. We determined that increased levels of proinflammatory cytokines, TNFα and IL6, as well as H2O2, increased miR-21 expression in primary myoblasts, which in turn resulted in their decreased viability and myogenic potential. Inhibition of miR-21 function rescued the decreased size of myotubes following TNFα or IL6 treatment. Moreover, we demonstrated that miR-21 could inhibit myogenesis in vitro via regulating IL6R, PTEN and FOXO3 signalling. In summary, upregulation of miR-21 in satellite cells and muscle during ageing may occur in response to elevated levels of TNFα and IL6, within satellite cells or myofibrillar environment contributing to skeletal muscle ageing and potentially a disease-related decline in potential for muscle regeneration.

scholarly journals MLL1 is required for PAX7 expression and satellite cell self-renewal in mice

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Gregory C. Addicks ◽  
Caroline E. Brun ◽  
Marie-Claude Sincennes ◽  
John Saber ◽  
Christopher J. Porter ◽  
...  
Keyword(s):  
Satellite Cell ◽  
Satellite Cells ◽  
Transcriptional Activation ◽  
Cell Activation ◽  
Target Genes ◽  
Cell Function ◽  
Skeletal Muscle Regeneration ◽  
Differentiation Potential ◽  
Self Renewal

Abstract PAX7 is a paired-homeobox transcription factor that specifies the myogenic identity of muscle stem cells and acts as a nodal factor by stimulating proliferation while inhibiting differentiation. We previously found that PAX7 recruits the H3K4 methyltransferases MLL1/2 to epigenetically activate target genes. Here we report that in the absence of Mll1, myoblasts exhibit reduced H3K4me3 at both Pax7 and Myf5 promoters and reduced Pax7 and Myf5 expression. Mll1-deficient myoblasts fail to proliferate but retain their differentiation potential, while deletion of Mll2 had no discernable effect. Re-expression of PAX7 in committed Mll1 cKO myoblasts restored H3K4me3 enrichment at the Myf5 promoter and Myf5 expression. Deletion of Mll1 in satellite cells reduced satellite cell proliferation and self-renewal, and significantly impaired skeletal muscle regeneration. Pax7 expression was unaffected in quiescent satellite cells but was markedly downregulated following satellite cell activation. Therefore, MLL1 is required for PAX7 expression and satellite cell function in vivo. Furthermore, PAX7, but not MLL1, is required for Myf5 transcriptional activation in committed myoblasts.

scholarly journals Sox15 Is Required for Skeletal Muscle Regeneration

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

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

scholarly journals Loss of myogenic potential and fusion capacity of muscle stem cells isolated from contractured muscle in children with cerebral palsy

2018 ◽  
Vol 315 (2) ◽  
pp. C247-C257 ◽  
Author(s):  
Andrea A. Domenighetti ◽  
Margie A. Mathewson ◽  
Rajeswari Pichika ◽  
Lydia A. Sibley ◽  
Leyna Zhao ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Cerebral Palsy ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Skeletal Muscles ◽  
Muscle Stem Cells ◽  
Myogenic Potential ◽  
Myotube Formation ◽  
The Brain

Cerebral palsy (CP) is the most common cause of pediatric neurodevelopmental and physical disability in the United States. It is defined as a group of motor disorders caused by a nonprogressive perinatal insult to the brain. Although the brain lesion is nonprogressive, there is a progressive, lifelong impact on skeletal muscles, which are shorter, spastic, and may develop debilitating contractures. Satellite cells are resident muscle stem cells that are indispensable for postnatal growth and regeneration of skeletal muscles. Here we measured the myogenic potential of satellite cells isolated from contractured muscles in children with CP. When compared with typically developing (TD) children, satellite cell-derived myoblasts from CP differentiated more slowly (slope: 0.013 (SD 0.013) CP vs. 0.091 (SD 0.024) TD over 24 h, P < 0.001) and fused less (fusion index: 21.3 (SD 8.6) CP vs. 81.3 (SD 7.7) TD after 48 h, P < 0.001) after exposure to low-serum conditions that stimulated myotube formation. This impairment was associated with downregulation of several markers important for myoblast fusion and myotube formation, including DNA methylation-dependent inhibition of promyogenic integrin-β 1D (ITGB1D) protein expression levels (−50% at 42 h), and ~25% loss of integrin-mediated focal adhesion kinase phosphorylation. The cytidine analog 5-Azacytidine (5-AZA), a demethylating agent, restored ITGB1D levels and promoted myogenesis in CP cultures. Our data demonstrate that muscle contractures in CP are associated with loss of satellite cell myogenic potential that is dependent on DNA methylation patterns affecting expression of genetic programs associated with muscle stem cell differentiation and muscle fiber formation.

scholarly journals POSSIBILITIES OF REGENERATION OF THE MUSCLES OF THE SOFT PALATE DURING ITS NONUNION DEPENDING ON THE MYOGENIC POTENTIAL OF STEM CELLS. Review

2020 ◽  
Vol 16 (3) ◽  
pp. 63-71
Author(s):  
L.V. Kharkov ◽  
R.I. Egorov
Keyword(s):  
Stem Cells ◽  
Cell Therapy ◽  
Satellite Cells ◽  
Soft Palate ◽  
Muscle Regeneration ◽  
Adult Stem Cells ◽  
Future Research ◽  
Congenital Defects ◽  
Muscle Injuries ◽  
Myogenic Potential

Relevance. Today there are more than 150 methods for eliminating congenital defects of the hard and soft palate. However, these techniques do not always lead to high functional results, which leads to repeated surgical interventions and long-term speech therapy rehabilitation. Therefore, there is a problem with the prognosis of such treatment. The search for a marker for assessing the prognosis of surgical intervention is relevant. One of these markers may be the state of the myogenic potential of stem cells. Objective: to analyze the possibility of preliminary assessment of muscle regeneration, depending on the myogenic potential of stem cells, in order to increase the effectiveness of treatment of children with non-union of the soft palate. Method. An analytical review of the literature on keywords from the scientometric databases PubMed, Scopus, Web of Science. Results. Satellite cells represent an adequate system model for studying the biology of adult stem cells. Satellite cells can be considered candidates for cell therapy in muscle regeneration. First, they are one of the most abundant and most accessible cells in our body. Secondly, there is a panel of specific markers that can be used to isolate satellite cells. Third, satellite cells are localized within clear boundaries of the anatomical niche, and signaling mechanisms are currently being studied. Fourth, there is the possibility of recreating muscle injuries in which satellite cells can be studied. Future research aimed at increasing the purification of satellite cells so as to maintain their low differentiation, increase the engraftment potential, as well as new approaches aimed at obtaining satellite cells from iPS cells, will help accelerate the progress and development of drugs for cell therapy in the treatment of muscle degenerative diseases. Conclusions. The data on the myogenic potential of stem cells, in muscle regeneration, obtained on satellite cell models, can be used to increase the effectiveness of the treatment of children with nonunion of the soft palate.

scholarly journals Preservation of satellite cell number and regenerative potential with age reveals locomotory muscle bias

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Robert W. Arpke ◽  
Ahmed S. Shams ◽  
Brittany C. Collins ◽  
Alexie A. Larson ◽  
Nguyen Lu ◽  
...  
Keyword(s):  
Satellite Cell ◽  
Cell Density ◽  
Satellite Cells ◽  
Tibialis Anterior ◽  
Environmental Changes ◽  
Cell Number ◽  
Self Renewal ◽  
Transplantation Assay ◽  
Muscle Groups ◽  
Old Mice

Abstract Background Although muscle regenerative capacity declines with age, the extent to which this is due to satellite cell-intrinsic changes vs. environmental changes has been controversial. The majority of aging studies have investigated hindlimb locomotory muscles, principally the tibialis anterior, in caged sedentary mice, where those muscles are abnormally under-exercised. Methods We analyze satellite cell numbers in 8 muscle groups representing locomotory and non-locomotory muscles in young and 2-year-old mice and perform transplantation assays of low numbers of hind limb satellite cells from young and old mice. Results We find that satellite cell density does not decline significantly by 2 years of age in most muscles, and one muscle, the masseter, shows a modest but statistically significant increase in satellite cell density with age. The tibialis anterior and extensor digitorum longus were clear exceptions, showing significant declines. We quantify self-renewal using a transplantation assay. Dose dilution revealed significant non-linearity in self-renewal above a very low threshold, suggestive of competition between satellite cells for space within the pool. Assaying within the linear range, i.e., transplanting fewer than 1000 cells, revealed no evidence of decline in cell-autonomous self-renewal or regenerative potential of 2-year-old murine satellite cells. Conclusion These data demonstrate the value of comparative muscle analysis as opposed to overreliance on locomotory muscles, which are not used physiologically in aging sedentary mice, and suggest that self-renewal impairment with age is precipitously acquired at the geriatric stage, rather than being gradual over time, as previously thought.

scholarly journals Myogenic progenitor cell transplantation for muscle regeneration following hindlimb ischemia and reperfusion

2021 ◽  
Author(s):  
Franka Messner ◽  
Marco Thurner ◽  
Jule Müller ◽  
Michael Blumer ◽  
Julia Hofmann ◽  
...  
Keyword(s):  
Cell Fate ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Ischemia Reperfusion ◽  
Hindlimb Ischemia ◽  
Reporter Protein ◽  
Differentiation Potential ◽  
Ischemic Time ◽  
Myogenic Progenitor

Abstract Background Muscle is severely affected by ischemia/reperfusion injury (IRI). Quiescent satellite cells differentiating into myogenic progenitor cells (MPC) possess a remarkable regenerative potential. We herein established a model of local application of MPC in murine hindlimb ischemia/reperfusion to study cell engraftment and differentiation required for muscle regeneration.Methods A clamping model of murine (C57b/6J) hindlimb ischemia was established to induce IRI in skeletal muscle. After 2 hours (h) warm ischemic time (WIT) and reperfusion, reporter protein expressing MPC (TdTomato or Luci-GFP, 1x106 cells) obtained from isolated satellite cells were injected intramuscularly. Surface marker expression and differentiation potential of MPC were analyzed in vitro by flow cytometry and differentiation assay. In vivo bioluminescence imaging and histopathologic evaluation of biopsies were performed to quantify cell fate, engraftment and regeneration.Results 2h WIT induced severe IRI on muscle, and muscle fiber regeneration as per histopathology within 14 days after injury. Bioluminescence in vivo imaging demonstrated reporter protein signals of MPC in 2h WIT animals and controls over the study period (75 days). Bioluminescence signals were detected at the injection site and increased over time. TdTomato expressing MPC and myofibers were visible in host tissue on postoperative days 2 and 14, respectively, suggesting that injected MPC differentiated into muscle fibers. Higher reporter protein signals were found after 2h WIT compared to controls without ischemia, indicative for enhanced growth and/or engraftment of MPC injected into IRI-affected muscle antagonizing muscle damage caused by IRI.Conclusion WIT-induced IRI in muscle requests increased numbers of injected MPC to engraft and persist, suggesting a possible rational for cell therapy to antagonize IRI. Further investigations are needed to evaluate the regenerative capacity and therapeutic advantage of MPC in the setting of ischemic limb injury.

scholarly journals Androgen receptor in satellite cells is not essential for muscle regenerations

2020 ◽  
Vol 1 ◽  
Author(s):  
Hiroshi Sakai ◽  
Takahiko Sato ◽  
Motoi Kanagawa ◽  
So-ichiro Fukada ◽  
Yuuki Imai
Keyword(s):  
Androgen Receptor ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Knockout Mice ◽  
Muscle Regeneration ◽  
Skeletal Muscles ◽  
Molecular Mechanisms ◽  
Hindlimb Muscles

AbstractThe anabolic effects of androgen on skeletal muscles are thought to be mediated by androgen receptor (AR). Although multiple studies concerning the effects of AR in males have been performed, the molecular mechanisms of AR in skeletal muscles remain unclear. Here we first confirmed that satellite cells from mouse hindlimb muscles express AR. We then generated satellite cell-specific AR knockout mice using Pax7CreERT2 and ARL2/Y mice to test whether AR in satellite cells is necessary for muscle regeneration. Surprisingly, we found that muscle regeneration was compromised in both Pax7CreERT2(Fan)/+ control mice and Pax7CreERT2(Fan)/+;ARL2/Y mice compared to ARL2/Y mice. However, Pax7CreERT2(Gaka)/+;ARL2/Y;R26tdTomato/+ mice showed no significant differences between control and mutant muscle regeneration. These findings indicate that AR in satellite cells is not essential for muscle regeneration. We propose that Pax7CreERT2(Fan)/+ control mice should be included in all experiments, because these mice negatively affect the muscle regeneration and show the mild regeneration phenotype.

scholarly journals High concentrations of HGF inhibit skeletal muscle satellite cell proliferation in vitro by inducing expression of myostatin: a possible mechanism for reestablishing satellite cell quiescence in vivo

2010 ◽  
Vol 298 (3) ◽  
pp. C465-C476 ◽  
Author(s):  
Michiko Yamada ◽  
Ryuichi Tatsumi ◽  
Keitaro Yamanouchi ◽  
Tohru Hosoyama ◽  
Sei-ichi Shiratsuchi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Time Lag ◽  
Dependent Manner ◽  
Western Blots ◽  
Myogenic Stem Cells ◽  
Cell Quiescence ◽  
High Concentrations

Skeletal muscle regeneration and work-induced hypertrophy rely on molecular events responsible for activation and quiescence of resident myogenic stem cells, satellite cells. Recent studies demonstrated that hepatocyte growth factor (HGF) triggers activation and entry into the cell cycle in response to mechanical perturbation, and that subsequent expression of myostatin may signal a return to cell quiescence. However, mechanisms responsible for coordinating expression of myostatin after an appropriate time lag following activation and proliferation are not clear. Here we address the possible role of HGF in quiescence through its concentration-dependent negative-feedback mechanism following satellite cell activation and proliferation. When activated/proliferating satellite cell cultures were treated for 24 h beginning 48-h postplating with 10–500 ng/ml HGF, the percentage of bromodeoxyuridine-incorporating cells decreased down to a baseline level comparable to 24-h control cultures in a HGF dose-dependent manner. The high level HGF treatment did not impair the cell viability and differentiation levels, and cells could be reactivated by lowering HGF concentrations to 2.5 ng/ml, a concentration that has been shown to optimally stimulate activation of satellite cells in culture. Coaddition of antimyostatin neutralizing antibody could prevent deactivation and abolish upregulation of cyclin-dependent kinase (Cdk) inhibitor p21. Myostatin mRNA expression was upregulated with high concentrations of HGF, as demonstrated by RT-PCR, and enhanced myostatin protein expression and secretion were revealed by Western blots of the cell lysates and conditioned media. These results indicate that HGF could induce satellite cell quiescence by stimulating myostatin expression. The HGF concentration required (over 10–50 ng/ml), however, is much higher than that for activation, which is initiated by rapid release of HGF from its extracellular association. Considering that HGF is produced by satellite cells and spleen and liver cells in response to muscle damage, local concentrations of HGF bathing satellite cells may reach a threshold sufficient to induce myostatin expression. This time lag may delay action of the quiescence signaling program in proliferating satellite cells during initial phases of muscle regeneration followed by induction of quiescence in a subset of cells during later phases.

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