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Vol. 18, Issue 3, 986-994, March 2007

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Ghrelin and Des-Acyl Ghrelin Promote Differentiation and Fusion of C2C12 Skeletal Muscle Cells

Nicoletta Filigheddu^*, Viola F. Gnocchi^*, Marco Coscia^*, Miriam Cappelli^*, Paolo E. Porporato^*, Riccardo Taulli, Sara Traini^*, Gianluca Baldanzi^*,, Federica Chianale^*, Santina Cutrupi^*, Elisa Arnoletti, Corrado Ghè, Alberto Fubini^||, Nicola Surico^¶, Fabiola Sinigaglia^*, Carola Ponzetto, Giampiero Muccioli, Tiziana Crepaldi, and Andrea Graziani^*

Departments of *Medical Sciences and ^¶Clinical and Experimental Medicine, University of Piemonte Orientale, 28100 Novara, Italy; Divisions of Anatomy and Pharmacology, Department of Anatomy, Pharmacology, and Forensic Medicine, University of Torino, 10125 Torino, Italy; ^||Department of Traumatology, Orthopaedics and Occupational Medicine, University of Torino, 10126 Torino, Italy; and Centro di Ricerca E. Menni, Fondazione Poliambulanza-Istituto Ospedaliero, 25124 Brescia, Italy

Submitted May 8, 2006; Revised November 9, 2006; Accepted December 21, 2006
Monitoring Editor: Carl-Henrik Heldin

Ghrelin is an acylated peptidyl gastric hormone acting on the pituitary and hypothalamus to stimulate appetite, adiposity, and growth hormone release, through activation of growth hormone secretagogue receptor (GHSR)-1a receptor. Moreover, ghrelin features several activities such as inhibition of apoptosis, regulation of differentiation, and stimulation or inhibition of proliferation of several cell types. Ghrelin acylation is absolutely required for both GHSR-1a binding and its central endocrine activities. However, the unacylated ghrelin form, des-acyl ghrelin, which does not bind GHSR-1a and is devoid of any endocrine activity, is far more abundant than ghrelin in plasma, and it shares with ghrelin some of its cellular activities. Inhere we show that both ghrelin and des-acyl ghrelin stimulate proliferating C2C12 skeletal myoblasts to differentiate and to fuse into multinucleated myotubes in vitro through activation of p38. Consistently, both ghrelin and des-acyl ghrelin inhibit C2C12 proliferation in growth medium. Moreover, the ectopic expression of ghrelin in C2C12 enhances differentiation and fusion of these myoblasts in differentiation medium. Finally, we show that C2C12 cells do not express GHSR-1a, but they do contain a common high-affinity binding site recognized by both acylated and des-acylated ghrelin, suggesting that the described activities on C2C12 are likely mediated by this novel, yet unidentified receptor for both ghrelin forms.

Address correspondence to: Nicoletta Filigheddu (nicoletta.filigheddu{at}med.unipmn.it)

Abbreviations used: D-GHR, des-acyl ghrelin; DM, differentiation medium; EGFP, enhanced green fluorescent protein; GHR, ghrelin; GHSR, growth hormone secretagogue receptor; GM, growth medium; MHC, myosin heavy chain.

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