Inhibition of Notch signaling induces myotube hypertrophy by recruiting a subpopulation of reserve cells.
During muscle differentiation, a population of quiescent undifferentiated myoblasts (reserve cells) emerges among mature muscle cells. However, the molecular mechanisms underlying such cell segregation and the characterization of this subpopulation of myoblasts remain to be determined. Notch is known to control the behavior and fate of murine muscle stem cells. In this study, we examined the role of Notch in myoblast segregation. We showed that inhibition of Notch activity by either overexpressing Numb or by using a pharmacological gamma-secretase inhibitor (DAPT) enhanced differentiation of murine and human myoblasts. This effect was not restricted to in vitro culture systems since DAPT-treated zebrafish embryos also showed increased differentiation. Using C2.7 myoblasts as a model, we showed that inhibition of Notch induced myotube hypertrophy by recruiting reserve cells that do not normally fuse. We further showed that endogenous Notch-signaling components were differentially expressed and activated in reserve cells with respect to Notch 1 and CD34 expression. We identified CD34 negative reserve cells as the subpopulation of myoblasts recruited to fuse into myotubes during differentiation in response to Notch inhibition. Therefore, we showed here that the activation of Notch 1 is important to maintain a subpopulation of CD34 negative reserve cells in an undifferentiated state.
Kitzmann
Magali
M
Adult stem cells and facioscapulohumeral dystrophy," CNRS FRE2593, 1919 route de Mende, 34293 Montpellier 5, France.
Bonnieu
Anne
A
Duret
Cédric
C
Vernus
Barbara
B
Barro
Marietta
M
Laoudj-Chenivesse
Dalila
D
Verdi
Joseph M
JM
Carnac
Gilles
G
D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D002459:Cell Fusion; D002460:Cell Line; D006801:Humans; D006984:Hypertrophy; D007700:Kinetics; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D018482:Muscle, Skeletal / Q000166:cytology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014162:Transfection; D014280:Triglycerides / Q000494:pharmacology; D015027:Zebrafish; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
D018952:Antigens, CD34; D051880:Receptors, Notch; D014280:Triglycerides; D005680:gamma-Aminobutyric Acid; C057077:1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol; D008156:Luciferases