Myostatin Directly Regulates Skeletal Muscle Fibrosis

Zhao Bo Li,Helen D Kollias,Kathryn R Wagner

doi:10.1074/jbc.m802585200

Zhao Bo Li, Helen D Kollias + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m802585200

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Abstract

Skeletal muscle fibrosis is a major pathological hallmark of chronic myopathies in which myofibers are replaced by progressive deposition of collagen and other extracellular matrix proteins produced by muscle fibroblasts. Recent studies have shown that in the absence of the endogenous muscle growth regulator myostatin, regeneration of muscle is enhanced, and muscle fibrosis is correspondingly reduced. We now demonstrate that myostatin not only regulates the growth of myocytes but also directly regulates muscle fibroblasts. Our results show that myostatin stimulates the proliferation of muscle fibroblasts and the production of extracellular matrix proteins both in vitro and in vivo. Further, muscle fibroblasts express myostatin and its putative receptor activin receptor IIB. Proliferation of muscle fibroblasts, induced by myostatin, involves the activation of Smad, p38 MAPK and Akt pathways. These results expand our understanding of the function of myostatin in muscle tissue and provide a potential target for anti-fibrotic therapies.

Highlights

Myostatin is a highly conserved transforming growth factor-␤ (TGF-␤)2 family member that is expressed in skeletal muscle, which is the primary target tissue [4]
Cultured muscle fibroblasts were treated with recombinant myostatin at concentrations of 12–300 ng/ml for 24 h, and proliferation was assayed by various measures
Most studies of myostatin have focused on its role as an inhibitor of muscle growth that occurs via its effects on the activation, proliferation, and differentiation of myoblasts (6 – 8)

Summary

Introduction

Myostatin is a highly conserved transforming growth factor-␤ (TGF-␤)2 family member that is expressed in skeletal muscle, which is the primary target tissue [4]. Myostatin-induced expression of PCNA and cyclin D1, as well as fibroblast-associated proteins ␣-SMA, HSP47, fibronectin, and vimentin, were blocked or reduced by co-treatment of myostatin and equimolar concentrations of follistatin (Fig. 1d).

Results

Conclusion