Myostatin Induces Cyclin D1 Degradation to Cause Cell Cycle Arrest through a Phosphatidylinositol 3-Kinase/AKT/GSK-3beta Pathway and Is Antagonized by Insulin-like Growth Factor 1
Journal of Biological Chemistry
Myostatin is a transforming growth factor ␤ superfamily member and is known as an inhibitor of skeletal muscle cell proliferation and differentiation. Exposure to myostatin induces G 1 phase cell cycle arrest. In this study, we demonstrated that myostatin down-regulates Cdk4 activity via promotion of cyclin D1 degradation. Overexpression of cyclin D1 significantly blocked myostatin-induced proliferation inhibition. We further showed that phosphorylation at threonine 286 by GSK-3␤ was required
... K-3␤ was required for myostatin-stimulated cyclin D1 nuclear export and degradation. This process is dependent upon the activin receptor IIB and the phosphatidylinositol 3-kinase/ Akt pathway but not Smad3. Insulin-like growth factor 1 (IGF-1) treatment or Akt activation attenuated the myostatin-stimulated cyclin D1 degradation as well as the associated cell proliferation repression. In contrast, attenuation of IGF-1 signaling caused C2C12 cells to undergo apoptosis in response to myostatin treatment. The observation that IGF-1 treatment increases myostatin expression through a phosphatidylinositol 3-kinase pathway suggests a possible feedback regulation between IGF-1 and myostatin. These findings uncover a novel role for myostatin in the regulation of cell growth and cell death in concert with IGF-1.