title: The type 1 insulin-like growth factor receptor (IGF-IR) pathway is mandatory for the follistatin-induced skeletal muscle hypertrophy.
abstract: Myostatin inhibition by follistatin (FS) offers a new approach for muscle mass enhancement. The aim of the present study was to characterize the mediators responsible for the FS hypertrophic action on skeletal muscle in male mice. Because IGF-I and IGF-II, two crucial skeletal muscle growth factors, are induced by myostatin inhibition, we assessed their role in FS action. First, we tested whether type 1 IGF receptor (IGF-IR) is required for FS-induced hypertrophy. By using mice expressing a dominant-negative IGF-IR in skeletal muscle, we showed that IGF-IR inhibition blunted by 63% fiber hypertrophy caused by FS. Second, we showed that FS caused the same degree of fiber hypertrophy in wild-type and IGF-II knockout mice. We then tested the role of the signaling molecules stimulated by IGF-IR, in particular the Akt/mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (S6K) pathway. We investigated whether Akt phosphorylation is required for the FS action. By cotransfecting a dominant-negative form of Akt together with FS, we showed that Akt inhibition reduced by 65% fiber hypertrophy caused by FS. Second, we evaluated the role of mTOR in FS action. Fiber hypertrophy induced by FS was reduced by 36% in rapamycin-treated mice. Finally, because the activity of S6K is increased by FS, we tested its role in FS action. FS caused the same degree of fiber hypertrophy in wild-type and S6K1/2 knockout mice. In conclusion, the IGF-IR/Akt/mTOR pathway plays a critical role in FS-induced muscle hypertrophy. In contrast, induction of IGF-II expression and S6K activity by FS are not required for the hypertrophic action of FS.
authors.affiliation: Pole of Endocrinology, Diabetes, and Nutrition, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Avenue Hippocrate 55 bte B1.55.06, B-1200 Brussels, Belgium. stephanie.kalista@uclouvain.be
authors.forename: S
authors.initials: S
authors.lastname: Kalista
authors.forename: O
authors.initials: O
authors.lastname: Schakman
authors.forename: H
authors.initials: H
authors.lastname: Gilson
authors.forename: P
authors.initials: P
authors.lastname: Lause
authors.forename: B
authors.initials: B
authors.lastname: Demeulder
authors.forename: L
authors.initials: L
authors.lastname: Bertrand
authors.forename: M
authors.initials: M
authors.lastname: Pende
authors.forename: J P
authors.initials: JP
authors.lastname: Thissen
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D038681:Follistatin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006984:Hypertrophy; D007335:Insulin-Like Growth Factor II / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014162:Transfection
chemical_list: D017931:DNA Primers; D038681:Follistatin; C513121:IGF2 protein, mouse; D011994:Recombinant Proteins; C479339:follistatin, 288-amino acid isoform; D007335:Insulin-Like Growth Factor II; C546843:mTOR protein, mouse; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus