Skeletal muscle stem cells express anti-apoptotic ErbB receptors during activation from quiescence.
To be effective for tissue repair, satellite cells (the stem cells of adult muscle) must survive the initial activation from quiescence. Using an in vitro model of satellite cell activation, we show that erbB1, erbB2 and erbB3, members of the EGF receptor tyrosine kinase family, appear on satellite cells within 6 h of activation. We show that signalling via erbB2 provides an anti-apoptotic survival mechanism for satellite cells during the first 24 h, as they progress to a proliferative state. Inhibition of erbB2 signalling with AG825 reduced satellite cell numbers, concomitant with elevated caspase-8 activation and TUNEL labelling of apoptotic satellite cells. In serum-free conditions, satellite cell apoptosis could be largely prevented by a mixture of erbB1, erbB3 and erbB4 ligand growth factors, but not by neuregulin alone (erbB3/erbB4 ligand). Furthermore, using inhibitors specific to discrete intracellular signalling pathways, we identify MEK as a pro-apoptotic mediator, and the erbB-regulated factor STAT3 as an anti-apoptotic mediator during satellite cell activation. These results implicate erbB2 signalling in the preservation of a full compliment of satellite cells as they activate in the context of a damaged muscle.
Golding
Jon P
JP
Department of Biological Sciences, Open University, Walton Hall, Milton Keynes, UK. j.p.golding@open.ac.uk
Calderbank
Emma
E
Partridge
Terence A
TA
Beauchamp
Jonathan R
JR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles / Q000494:pharmacology; D002470:Cell Survival; D006801:Humans; D008024:Ligands; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000166:cytology* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology; D020032:Tyrphostins / Q000494:pharmacology
D052160:Benzothiazoles; D008024:Ligands; D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; C098214:tyrphostin AG825; C101044:RTKI cpd