Endocrine Actions of Myostatin: Systemic Regulation of the IGF and IGF Binding Protein Axis

Abstract

Myostatin’s inhibitory actions on striated muscle growth are believed to be directly mediated by locally produced myostatin and possibly by IGF binding proteins (IGFBPs). We therefore measured skeletal muscle, heart, and liver expression, in neonates and adults, and circulating levels of various IGF axis components (IGF-I, IGFBP-1 to IGFBP-3, and acid labile subunit) in wild-type and mstn−/− mice. Compared with wild type, differences in muscle expression were tissue specific, although IGF-I receptor expression was higher in all mstn−/− neonatal tissues and in adult gastrocnemius. Liver expression of several components also differed between genotype as IGF-I receptor, IGFBP-3 and IGFBP-5 expression was higher in mstn−/− neonates and IGF-I and IGFBP-3 in adults. Circulating IGF-I levels were also higher in mstn−/− adults, whereas IGFBP-1 and IGFBP-2 levels were lower. Comparing IGF-I:IGFBP molar ratios suggested that the relative IGF-binding capacity was potentially lower in mstn−/− mice, and thus, total and “free” IGF-I levels may be elevated. This in turn may increase negative feedback control on GH, because mstn−/− liver weights were lower. Bone growth was similar in both genotypes, suggesting that changes in circulating IGF-I may be more important to muscle, whose mass is enhanced in mstn−/− mice, than to bone. Myostatin receptors, but not myostatin itself, are expressed in the liver. Changes in hepatic production of circulating IGF axis components could therefore result from the loss of endocrine myostatin. Thus, myostatin may inhibit striated muscle growth directly at the cellular level and indirectly through systemic effects on the IGF axis.