scholarly journals Myostatin negatively regulates satellite cell activation and self-renewal

2003 ◽  
Vol 162 (6) ◽  
pp. 1135-1147 ◽  
Author(s):  
Seumas McCroskery ◽  
Mark Thomas ◽  
Linda Maxwell ◽  
Mridula Sharma ◽  
Ravi Kambadur
Keyword(s):  
Satellite Cell ◽  
Satellite Cells ◽  
Cell Activation ◽  
Unit Length ◽  
Immunohistochemical Analysis ◽  
Cell Number ◽  
Negative Regulator ◽  
Self Renewal ◽  
Satellite Cell Activation

Satellite cells are quiescent muscle stem cells that promote postnatal muscle growth and repair. Here we show that myostatin, a TGF-β member, signals satellite cell quiescence and also negatively regulates satellite cell self-renewal. BrdU labeling in vivo revealed that, among the Myostatin-deficient satellite cells, higher numbers of satellite cells are activated as compared with wild type. In contrast, addition of Myostatin to myofiber explant cultures inhibits satellite cell activation. Cell cycle analysis confirms that Myostatin up-regulated p21, a Cdk inhibitor, and decreased the levels and activity of Cdk2 protein in satellite cells. Hence, Myostatin negatively regulates the G1 to S progression and thus maintains the quiescent status of satellite cells. Immunohistochemical analysis with CD34 antibodies indicates that there is an increased number of satellite cells per unit length of freshly isolated Mstn−/− muscle fibers. Determination of proliferation rate suggests that this elevation in satellite cell number could be due to increased self-renewal and delayed expression of the differentiation gene (myogenin) in Mstn−/− adult myoblasts. Taken together, these results suggest that Myostatin is a potent negative regulator of satellite cell activation and thus signals the quiescence of satellite cells.

scholarly journals Metformin Delays Satellite Cell Activation and Maintains Quiescence

2019 ◽  
Vol 2019 ◽  
pp. 1-19 ◽  
Author(s):  
Theodora Pavlidou ◽  
Milica Marinkovic ◽  
Marco Rosina ◽  
Claudia Fuoco ◽  
Simone Vumbaca ◽  
...  
Keyword(s):  
Satellite Cell ◽  
Muscle Tissue ◽  
Satellite Cells ◽  
Cell Activation ◽  
Myogenic Differentiation ◽  
Metabolic State ◽  
Cell Pool ◽  
Age Related ◽  
Satellite Cell Activation

The regeneration of the muscle tissue relies on the capacity of the satellite stem cell (SC) population to exit quiescence, divide asymmetrically, proliferate, and differentiate. In age-related muscle atrophy (sarcopenia) and several dystrophies, regeneration cannot compensate for the loss of muscle tissue. These disorders are associated with the depletion of the satellite cell pool or with the loss of satellite cell functionality. Recently, the establishment and maintenance of quiescence in satellite cells have been linked to their metabolic state. In this work, we aimed to modulate metabolism in order to preserve the satellite cell pool. We made use of metformin, a calorie restriction mimicking drug, to ask whether metformin has an effect on quiescence, proliferation, and differentiation of satellite cells. We report that satellite cells, when treated with metformin in vitro, ex vivo, or in vivo, delay activation, Pax7 downregulation, and terminal myogenic differentiation. We correlate the metformin-induced delay in satellite cell activation with the inhibition of the ribosome protein RPS6, one of the downstream effectors of the mTOR pathway. Moreover, in vivo administration of metformin induces a belated regeneration of cardiotoxin- (CTX-) damaged skeletal muscle. Interestingly, satellite cells treated with metformin immediately after isolation are smaller in size and exhibit reduced pyronin Y levels, which suggests that metformin-treated satellite cells are transcriptionally less active. Thus, our study suggests that metformin delays satellite cell activation and differentiation by favoring a quiescent, low metabolic state.

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 A Role for Nitric Oxide in Muscle Repair: Nitric Oxide–mediated Activation of Muscle Satellite Cells

2000 ◽  
Vol 11 (5) ◽  
pp. 1859-1874 ◽  
Author(s):  
Judy E. Anderson
Keyword(s):  
Nitric Oxide ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Knockout Mice ◽  
Cell Activation ◽  
Mdx Mice ◽  
Muscle Repair ◽  
Muscle Satellite Cells ◽  
Satellite Cell Activation

Muscle satellite cells are quiescent precursors interposed between myofibers and a sheath of external lamina. Although their activation and recruitment to cycle enable muscle repair and adaptation, the activation signal is not known. Evidence is presented that nitric oxide (NO) mediates satellite cell activation, including morphological hypertrophy and decreased adhesion in the fiber-lamina complex. Activation in vivo occurred within 1 min after injury. Cell isolation and histology showed that pharmacological inhibition of nitric oxide synthase (NOS) activity prevented the immediate injury-induced myogenic cell release and delayed the hypertrophy of satellite cells in that muscle. Transient activation of satellite cells in contralateral muscles 10 min later suggested that a circulating factor may interact with NO-mediated signaling. Interestingly, satellite cell activation in muscles of mdx dystrophic mice and NOS-I knockout mice quantitatively resembled NOS-inhibited release of normal cells, in agreement with reports of displaced and reduced NOS expression in dystrophin-deficient mdx muscle and the complete loss of NOS-I expression in knockout mice. Brief NOS inhibition in normal and mdx mice during injury produced subtle alterations in subsequent repair, including apoptosis in myotube nuclei and myotube formation inside laminar sheaths. Longer NOS inhibition delayed and restricted the extent of repair and resulted in fiber branching. A model proposes the hypothesis that NO release mediates satellite cell activation, possibly via shear-induced rapid increases in NOS activity that produce “NO transients.”

scholarly journals Rb1 Gene Inactivation Expands Satellite Cell and Postnatal Myoblast Pools

2011 ◽  
Vol 286 (22) ◽  
pp. 19556-19564 ◽  
Author(s):  
Tohru Hosoyama ◽  
Koichi Nishijo ◽  
Suresh I. Prajapati ◽  
Guangheng Li ◽  
Charles Keller
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Satellite Cell ◽  
Muscle Fiber ◽  
Satellite Cells ◽  
Cell Activation ◽  
Cell Lineage ◽  
Cell Number ◽  
Fiber Formation

Satellite cells are well known as a postnatal skeletal muscle stem cell reservoir that under injury conditions participate in repair. However, mechanisms controlling satellite cell quiescence and activation are the topic of ongoing inquiry by many laboratories. In this study, we investigated whether loss of the cell cycle regulatory factor, pRb, is associated with the re-entry of quiescent satellite cells into replication and subsequent stem cell expansion. By ablation of Rb1 using a Pax7CreER,Rb1 conditional mouse line, satellite cell number was increased 5-fold over 6 months. Furthermore, myoblasts originating from satellite cells lacking Rb1 were also increased 3-fold over 6 months, while terminal differentiation was greatly diminished. Similarly, Pax7CreER,Rb1 mice exhibited muscle fiber hypotrophy in vivo under steady state conditions as well as a delay of muscle regeneration following cardiotoxin-mediated injury. These results suggest that cell cycle re-entry of quiescent satellite cells is accelerated by lack of Rb1, resulting in the expansion of both satellite cells and their progeny in adolescent muscle. Conversely, that sustained Rb1 loss in the satellite cell lineage causes a deficit of muscle fiber formation. However, we also show that pharmacological inhibition of protein phosphatase 1 activity, which will result in pRb inactivation accelerates satellite cell activation and/or expansion in a transient manner. Together, our results raise the possibility that reversible pRb inactivation in satellite cells and inhibition of protein phosphorylation may provide a new therapeutic tool for muscle atrophy by short term expansion of the muscle stem cells and myoblast pool.

Estrogen influences satellite cell activation and proliferation following downhill running in rats

2008 ◽  
Vol 104 (2) ◽  
pp. 347-353 ◽  
Author(s):  
Deborah L. Enns ◽  
Peter M. Tiidus
Keyword(s):  
Satellite Cells ◽  
Cell Activation ◽  
Myogenic Differentiation ◽  
Immunohistochemical Analysis ◽  
Treadmill Running ◽  
Female Rats ◽  
Downhill Running ◽  
Glucuronidase Activity ◽  
Estrogen Exposure ◽  
Satellite Cell Activation

To investigate the influence of estrogen on postexercise muscle repair processes, we examined the effects of estrogen supplementation (0.25-mg pellet) on numbers of myofibers positive for markers of total, activated, and proliferating satellite cells in rat skeletal muscles 72 h following downhill running. Ovariectomized female rats ( n = 44) were divided into four groups ( n = 11 per group): sham (no estrogen) controls (SC); sham, exercised (SE); estrogen-supplemented controls (EC); and estrogen-supplemented, exercised (EE). After 8 days of estrogen exposure, animals were exposed to 90 min of treadmill running at 17 m/min (−13.5°). Seventy-two hours later, soleus and white vastus muscles were removed and immunostained for total [paired box homeotic gene 7 (Pax7)], [activated myogenic differentiation factor D (MyoD)], and proliferating [5-bromo-2′-deoxyuridine (BrdU)] satellite cells. β-Glucuronidase activity was increased ( P < 0.05) in both muscles following exercise; however, the postexercise elevations in enzyme activity were attenuated in the EE group compared with the SE group in the soleus ( P < 0.05). Immunohistochemical analysis revealed that exercised groups displayed increased numbers of myofibers containing total, activated, and proliferating satellite cells compared with control groups ( P < 0.05). Furthermore, greater numbers of fibers positive for markers of total, activated, and proliferating satellite cells were observed postexercise in EE animals compared with SE animals for both muscles ( P < 0.05). The results demonstrate that estrogen may potentially influence postdamage repair of skeletal muscle through activation of satellite cells.

scholarly journals Post-transcriptional regulation of satellite cell quiescence by TTP-mediated mRNA decay

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Melissa A Hausburg ◽  
Jason D Doles ◽  
Sandra L Clement ◽  
Adam B Cadwallader ◽  
Monica N Hall ◽  
...  
Keyword(s):  
Satellite Cell ◽  
Satellite Cells ◽  
Muscle Injury ◽  
Mrna Decay ◽  
Cell Activation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cell Quiescence ◽  
Satellite Cell Activation ◽  
Transcriptional Regulatory Mechanisms

Skeletal muscle satellite cells in their niche are quiescent and upon muscle injury, exit quiescence, proliferate to repair muscle tissue, and self-renew to replenish the satellite cell population. To understand the mechanisms involved in maintaining satellite cell quiescence, we identified gene transcripts that were differentially expressed during satellite cell activation following muscle injury. Transcripts encoding RNA binding proteins were among the most significantly changed and included the mRNA decay factor Tristetraprolin. Tristetraprolin promotes the decay of MyoD mRNA, which encodes a transcriptional regulator of myogenic commitment, via binding to the MyoD mRNA 3′ untranslated region. Upon satellite cell activation, p38α/β MAPK phosphorylates MAPKAP2 and inactivates Tristetraprolin, stabilizing MyoD mRNA. Satellite cell specific knockdown of Tristetraprolin precociously activates satellite cells in vivo, enabling MyoD accumulation, differentiation and cell fusion into myofibers. Regulation of mRNAs by Tristetraprolin appears to function as one of several critical post-transcriptional regulatory mechanisms controlling satellite cell homeostasis.

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.

In vivo satellite cell activation via Myf5 and MyoD in regenerating mouse skeletal muscle

1999 ◽  
Vol 112 (17) ◽  
pp. 2895-2901 ◽  
Author(s):  
R.N. Cooper ◽  
S. Tajbakhsh ◽  
V. Mouly ◽  
G. Cossu ◽  
M. Buckingham ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Cell Activation ◽  
Muscle Fibres ◽  
Adult Skeletal Muscle ◽  
Satellite Cell Activation ◽  
Slow Muscle Fibres ◽  
Myogenic Factors ◽  
Beta Galactosidase

Regeneration of adult skeletal muscle is an asynchronous process requiring the activation, proliferation and fusion of satellite cells, to form new muscle fibres. This study was designed to determine the pattern of expression in vivo of the two myogenic regulatory factors, Myf5 and MyoD during this process. Cardiotoxin was used to induce regeneration in the gastrocnemius and soleus muscles of heterozygous Myf5-nlacZ mice, and the muscles were assayed for the presence of (beta)-galactosidase (Myf5) and MyoD. Adult satellite cells identified by M-cadherin labelling, when activated, initially express either MyoD or Myf5 or both myogenic factors. Subsequently all proliferating myoblasts express MyoD and part of the population is (beta)-galactosidase (Myf5) positive. Furthermore, we demonstrate that activated satellite cells, which express either Myf5 or MyoD, do not accumulate selectively on fast or slow muscle fibres.

scholarly journals Heterogeneity of satellite cells implicates DELTA1/NOTCH2 signaling in self-renewal

2019 ◽  
Author(s):  
Valeria Yartseva ◽  
Leonard D. Goldstein ◽  
Julia Rodman ◽  
Lance Kates ◽  
Mark Z. Chen ◽  
...  
Keyword(s):  
Cell Fate ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Receptor Expression ◽  
Self Renewal ◽  
Cell Fate Decisions ◽  
Muscle Homeostasis ◽  
Early Regeneration ◽  
Time Point

SUMMARYHow satellite cells and their progenitors balance differentiation and self-renewal to achieve sustainable tissue regeneration is not well understood. A major roadblock to understanding satellite cell fate decisions has been the difficulty to study this process in vivo. By visualizing expression dynamics of myogenic transcription factors during early regeneration in vivo, we identified the time point at which cells undergo decisions to differentiate or self-renew. Single-cell RNA sequencing revealed heterogeneity of satellite cells during both muscle homeostasis and regeneration, including a subpopulation enriched in Notch2 receptor expression. Furthermore, we reveal that differentiating cells express the Dll1 ligand. Using antagonistic antibodies we demonstrate that the DLL1 and NOTCH2 signaling pair is required for satellite cell self-renewal. Thus, differentiating cells provide the self-renewing signal during regeneration, enabling proportional regeneration in response to injury while maintaining the satellite cell pool. These findings have implications for therapeutic control of muscle regeneration.

Satellite cell activation on fibers: modeling events in vivo — an invited review

2004 ◽  
Vol 82 (5) ◽  
pp. 300-310 ◽  
Author(s):  
Judy E Anderson ◽  
Ashley C Wozniak
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Satellite Cell ◽  
Cell Activation ◽  
Contractile Activity ◽  
Receptor Gene ◽  
Satellite Cell Activation ◽  
Muscle Cultures ◽  
Gene Expression Studies

Knowledge of the events underlying satellite cell activation and the counterpart maintenance of quiescence is essential for planning therapies that will promote the growth and regeneration of skeletal muscle in healthy, disease and aging. By modeling those events of satellite cell activation in studies of single muscle fibers or muscles in culture, the roles of mechanical stretching and nitric oxide are becoming understood. Recent studies demonstrated that stretch-induced activation is very rapid and exhibits some features of satellite cell heterogeneity. As well, gene expression studies showed that expression of the c-met receptor gene rises rapidly after stretching muscles in culture compared to those without stretch. This change in gene expression during activation, and the maintenance of quiescence in both normal and dystrophic muscles are dependent on NO, as they are blocked by inhibition of nitric oxide synthase (NOS). Mechanical, contractile activity is the defining feature of muscle function. Therefore, ongoing studies of stretch effects in satellite cell activation and quiescence in quiescent fiber and muscle cultures provides appropriate models by which to explore the regulatory steps in muscle in vivo under many conditions related to disease, repair, rehabilitation, growth and the prevention or treatment of atrophy.Key words: regeneration, stretch, myofiber culture, muscular dystrophy, quiescence.

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