Role of IGF-I in follistatin-induced skeletal muscle hypertrophy

Abstract

Follistatin, a physiological inhibitor of myostatin, induces a dramatic increase in skeletal muscle mass, requiring the type 1 IGF-I receptor/ Akt/mTOR pathway. The aim of the present study was to investigate the role of IGF-I and insulin, two ligands of the IGF-I receptor, in the follistatin hypertrophic action on skeletal muscle. In a first step, we showed that follistatin increases muscle mass while being associated with a downregulation of muscle IGF-I expression. In addition, follistatin retained its full hypertrophic effect toward muscle in hypophysectomized animals despite very low concentrations of circulating and muscle IGF-I. Furthermore, follistatin did not increase muscle sensitivity to IGF-I in stimulating phosphorylation of Akt but, surprisingly, decreased it once hypertrophy was present. Taken together, these observations indicate that increased muscle IGF-I production or sensitivity does not contribute to the muscle hypertrophy caused by follistatin. Unlike low IGF-I, low insulin, as obtained by streptozotocin injection, attenuated the hypertrophic action of follistatin on skeletal muscle. Moreover, the full anabolic response to follistatin was restored in this condition by insulin but also by IGF-I infusion. Therefore, follistatin-induced muscle hypertrophy requires the activation of the insulin/IGF-I pathway by either insulin or IGF-I. When insulin or IGF-I alone is missing, follistatin retains its full anabolic effect, but when both are deficient, as in streptozotocintreated animals, follistatin fails to stimulate muscle growth.IGF-I; insulin; follistatin; myostatin; skeletal muscle hypertrophy MYOSTATIN (Mstn), a member of the transforming growth factor (TGF)-␤ family expressed primarily in skeletal muscle, is a negative regulator of skeletal muscle mass, as shown by the increase in skeletal muscle mass and strength following Mstn inhibition or gene deletion (28,44). Among Mstn inhibitors, follistatin (FS) and the soluble ligand-binding domain of activin receptor type IIB fused to the Fc domain IgG (sActRIIBFc) have been shown to bind and antagonize Mstn, leading to a dramatic increase in muscle mass (3,30,37). The muscle fiber hypertrophy induced by FS is due to increased protein synthesis and requires the activation of Smad1/5 (63) and the type I IGF-I receptor (IGF-IR)/Akt/mTOR pathway (34, 64).IGF-I is known to be a major positive regulator of skeletal muscle mass. Indeed, IGF-I overexpression specifically in skeletal muscle increases skeletal muscle mass (13, 47), whereas IGF-I knockout mice exhibit significant muscle hypoplasia (42). Increased muscle IGF-I expression has been reported in several models of muscle hypertrophy, such as exercise, overloading, GH, and testosterone treatment (1,20,27,39,40). The role of IGF-I in the muscle hypertrophy caused by Mstn inhibition is suggested by several pieces of evidence. First, muscle mRNA expression and circulating concentrations of IGF-I have been reported to be increased following Mstn inhibition (35,62,64). Moreover, Mstn inhibition causes...

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