Myostatin Induces Cyclin D1 Degradation to Cause Cell Cycle Arrest through a Phosphatidylinositol 3-Kinase/AKT/GSK-3β Pathway and Is Antagonized by Insulin-like Growth Factor 1

Wei Yang,Yong Zhang,Yanfeng Li,Zhenguo Wu,Dahai Zhu

doi:10.1074/jbc.m610185200

Abstract

Myostatin is a transforming growth factor beta superfamily member and is known as an inhibitor of skeletal muscle cell proliferation and differentiation. Exposure to myostatin induces G1 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-3beta 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.

Highlights

Myostatin, known as growth differentiation factor 8, or GDF-8, is a transforming growth factor-␤ (TGF-␤)2 superfamily member and is known to be involved in regulation of skeletal muscle mass [1]
We report biochemical and cellular evidence indicating that these effects of myostatin on cyclin D1 expression and cell proliferation can be blocked by treatment with insulin-like growth factor 1 (IGF-1), a survival and proliferation promotion factor
Consistent with the results from the C2C12 myoblasts (Fig. 3c), we found that myostatin-induced cyclin D1 down-regulation was dependent on GSK-3␤, but not Smad3 (Fig. 5c), suggesting that myostatin transduces signaling through an unanticipated ActRIIb/phosphatidylinositol 3-kinase (PI3K)/Akt/GSK-3␤ cascade

Summary

Introduction

Known as growth differentiation factor 8, or GDF-8, is a transforming growth factor-␤ (TGF-␤)2 superfamily member and is known to be involved in regulation of skeletal muscle mass [1]. The PI3K/Akt/GSK-3␤ signaling cascade participates in myostatin-regulated cyclin D1 degradation and cell proliferation inhibition through a proteasome-dependent pathway.

Results

Conclusion