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. (Endocrinology 153: 241-253, 2012)

Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins

“…In contrast, the phosphorylation of Akt at Ser 473 increased after only 2 wk, when muscle mass was already increased, and at Thr 308 it remained unchanged. This supports previous results showing that sActRIIB-Fc-induced increase in muscle mass may be Akt independent (18), perhaps in contrast to follistatininduced hypertrophy (27,61). Further studies are requested to investigate upstream regulation of mTOR signaling and muscle protein synthesis after myostatin and activin blocking.…”

“…This supports the evidence that mTORC1 has a role in the muscle growth that is induced by myostatin/activin blocking (27,50,61). However, pathways other than rapamycin-sensitive mTORC1 also regulate muscle protein synthesis (58) and muscle growth (27,50) when myostatin/activins are blocked or inhibited. sActRIIB-Fc also increased the phosphorylation of 4E-BP1, a protein less responsive to rapamycin (12), and eIF2Bε protein.…”

“…In healthy adult muscle, blocking of myostatin and other TGF␤ family members increases protein synthesis (58,61) and muscle size (18,24,27,32,45,50,61,68). This occurs at least partially through the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) pathway (27,50,61).…”

“…This occurs at least partially through the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) pathway (27,50,61). A recent microarray study suggested that decreased oxidative capacity occurs after blocking of myostatin and activins by sActRIIB-Fc (47), but no further signaling analysis was conducted.…”

H19 controls reactivation of the imprinted gene network during muscle regeneration

“…A tight correlation between Mstn and Igf2 expression has been previously established (Kalista et al, 2012;Clark et al, 2015). Taken together, although other genes might also participate in this phenotype, we suggest that the upregulation of the growthpromoting Igf2 and Dlk1 genes at the early postnatal P6 stage coupled with the reduced expression of Mstn in the adult muscle are good candidates for the hypertrophic phenotype observed in the H19 Δ3 mutant muscles.…”