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Follistatin induction by nitric oxide through cyclic GMP: a tightly regulated signaling pathway that controls myoblast fusion

¹ Stem Cell Research Institute, Hospital San Raffaele, 20132 Milan, Italy
² Department of Experimental Environmental Medicine and Medical Biotechnology, University of Milano-Bicocca, 20052 Monza, Italy
³ Muscle Gene Expression Group, Laboratory of Muscle Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
⁴ Eugenio Medea Scientific Institute, 23842 Bosisio Parini, Italy
⁵ Institute of Cell Biology and Tissue Engineering, San Raffaele Biomedical Science Park of Roma, 00128 Rome, Italy
⁶ Department of Biology, University of Milano, 20130 Milan, Italy
⁷ Department of Preclinical Sciences, University of Milano, 20157 Milan, Italy

Correspondence to E. Clementi: clementi.emilio{at}hsr.it or; G. Cossu: guilio.cossu{at}hsr.it

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.

Abbreviations used in this paper: BMP, bone morphogenetic protein; CREB, cAMP response element binding protein; cGMP, cyclic guanosine mono- phosphate; DETA-NO, (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate]; E, embryonic day; Fs-luc, luciferase gene; GAPDH, glyceraldehyde3-phosphate dehydrogenase; IGF, insulin-like growth factor; IL-4, interleukin 4; L-NAME, N-nitro-L-arginine methyl ester; MLC1/3F, myosin light chain promoter 1/3 fast; NFAT, nuclear factor of activated T cells; NO, nitric oxide; NOS, nitric oxide synthase; ODQ, 1H-(1,2,4) oxadiazolo [4,3-]quinoxalin-1-one; PCNA, DNA polymerase cofactor; PSM, presomitic mesoderm; (Rp)-8-pCPT-cGMPS, 8-(chlorophenylthio)guanosine-3',5'- cyclic monophosphorothioate; TSA, trichostatin A.

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