Stanniocalcin-2 inhibits skeletal muscle growth and is upregulated in functional overload-induced hypertrophy

Aims: Stanniocalcin-2 (STC2) has recently been implicated in human muscle mass variability by genetic analysis. Biochemically, STC2 inhibits the proteolytic activity of the metalloproteinase PAPP-A, which promotes muscle growth by upregulating the insulin-like growth factor (IGF) axis. The aim was to examine if STC2 affects skeletal muscle mass and to assess how the IGF axis mediates muscle hypertrophy induced by functional overload. Methods: We compared muscle mass and muscle fiber morphology between Stc2(-/-) (n = 21) and wild-type (n = 15) mice. We then quantified IGF1, IGF2, IGF binding proteins -4 and -5 (IGFBP-4, IGFBP-5), PAPP-A and STC2 in plantaris muscles of wild-type mice subjected to 4-week unilateral overload (n = 14). Results: Stc2(-/-) mice showed up to 10% larger muscle mass compared with wild-type mice. This increase was mediated by greater cross-sectional area of muscle fibers. Overload increased plantaris mass and components of the IGF axis, including quantities of IGF1 (by 2.41-fold, p = 0.0117), IGF2 (1.70-fold, p = 0.0461), IGFBP-4 (1.48-fold, p = 0.0268), PAPP-A (1.30-fold, p = 0.0154) and STC2 (1.28-fold, p = 0.019). Conclusion: Here we provide evidence that STC2 is an inhibitor of muscle growth upregulated, along with other components of the IGF axis, during overload-induced muscle hypertrophy.

Automated summary

This study suggests that STC2 inhibits muscle growth by inhibiting the activity of PAPP-A, a protease that promotes muscle growth through the IGF axis. Mice lacking STC2 showed increased muscle mass and larger muscle fibers. Functional overload increased muscle mass and the levels of IGF axis components, including IGF1, IGF2, IGFBP-4, PAPP-A, and STC2.