Follistatin induces muscle hypertrophy through satellite cell proliferation and inhibition of both myostatin and activin.
Follistatin (FS) inhibits several members of the TGF-beta superfamily, including myostatin (Mstn), a negative regulator of muscle growth. Mstn inhibition by FS represents a potential therapeutic approach of muscle atrophy. The aim of our study was to investigate the mechanisms of the FS-induced muscle hypertrophy. To test the role of satellite cells in the FS effect, we used irradiation to destroy their proliferative capacity. FS overexpression increased the muscle weight by about 37% in control animals, but the increase reached only 20% in irradiated muscle, supporting the role of cell proliferation in the FS-induced hypertrophy. Surprisingly, the muscle hypertrophy caused by FS reached the same magnitude in Mstn-KO as in WT mice, suggesting that Mstn might not be the only ligand of FS involved in the regulation of muscle mass. To assess the role of activin (Act), another FS ligand, in the FS-induced hypertrophy, we electroporated FSI-I, a FS mutant that does not bind Act with high affinity. Whereas FS electroporation increased muscle weight by 32%, the muscle weight gain induced by FSI-I reached only 14%. Furthermore, in Mstn-KO mice, FSI-I overexpression failed to induce hypertrophy, in contrast to FS. Therefore, these results suggest that Act inhibition may contribute to FS-induced hypertrophy. Finally, the role of Act as a regulator of muscle mass was supported by the observation that ActA overexpression induced muscle weight loss (-15%). In conclusion, our results show that satellite cell proliferation and both Mstn and Act inhibition are involved in the FS-induced muscle hypertrophy.
Gilson
Hélène
H
Unité de Diabétologie et Nutrition, Université Catholique de Louvain, 54 Ave. Hippocrate, B-1200, Brussels, Belgium. helene.gilson@uclouvain.be
Schakman
Olivier
O
Kalista
Stéphanie
S
Lause
Pascale
P
Tsuchida
Kunihiro
K
Thissen
Jean-Paul
JP
D028341:Activins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D038681:Follistatin / Q000235:genetics / Q000502:physiology*; D006984:Hypertrophy / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009133:Muscular Atrophy / Q000235:genetics* / Q000378:metabolism; D055435:Myostatin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D032496:Satellite Cells, Skeletal Muscle / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
D038681:Follistatin; D055435:Myostatin; D028341:Activins