Follistatin induction by nitric oxide through cyclic GMP: a tightly regulated signaling pathway that controls myoblast fusion.
The mechanism of skeletal myoblast fusion is not well understood. We show that endogenous nitric oxide (NO) generation is required for myoblast fusion both in embryonic myoblasts and in satellite cells. The effect of NO is concentration and time dependent, being evident only at the onset of differentiation, and direct on the fusion process itself. The action of NO is mediated through a tightly regulated activation of guanylate cyclase and generation of cyclic guanosine monophosphate (cGMP), so much so that deregulation of cGMP signaling leads to a fusion-induced hypertrophy of satellite-derived myotubes and embryonic muscles, and to the acquisition of fusion competence by myogenic precursors in the presomitic mesoderm. NO and cGMP induce expression of follistatin, and this secreted protein mediates their action in myogenesis. These results establish a hitherto unappreciated role of NO and cGMP in regulating myoblast fusion and elucidate their mechanism of action, providing a direct link with follistatin, which is a key player in myogenesis.
Pisconti
Addolorata
A
Stem Cell Research Institute, Hospital San Raffaele, 20132 Milan, Italy.
Brunelli
Silvia
S
Di Padova
Monica
M
De Palma
Clara
C
Deponti
Daniela
D
Baesso
Silvia
S
Sartorelli
Vittorio
V
Cossu
Giulio
G
Clementi
Emilio
E
D000818:Animals; D002459:Cell Fusion; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism*; D005260:Female; D038681:Follistatin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D024510:Muscle Development / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic
D017362:Cyclic AMP Response Element-Binding Protein; D038681:Follistatin; D017570:MyoD Protein; D050778:NFATC Transcription Factors; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP