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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Activin Receptors, Type II / biosynthesis
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Activin Receptors, Type II / genetics
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Animals
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Cell Line
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Cell Proliferation
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Collagen / genetics
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Collagen / metabolism
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Fibrosis / genetics
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Fibrosis / metabolism
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Fibrosis / pathology
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Fibrosis / therapy
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Mice
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Mice, Knockout
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Muscle Fibers, Skeletal / metabolism*
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Muscle Fibers, Skeletal / pathology
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Muscle, Skeletal / metabolism*
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Muscle, Skeletal / pathology
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Muscular Diseases / genetics
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Muscular Diseases / metabolism*
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Muscular Diseases / pathology
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Muscular Diseases / therapy
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Myostatin
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Regeneration / genetics
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Signal Transduction / genetics
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Smad Proteins / genetics
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Smad Proteins / metabolism
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Transforming Growth Factor beta / biosynthesis*
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Transforming Growth Factor beta / genetics
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Mstn protein, mouse
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Myostatin
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Smad Proteins
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Transforming Growth Factor beta
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Collagen
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Proto-Oncogene Proteins c-akt
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p38 Mitogen-Activated Protein Kinases
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Activin Receptors, Type II
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activin receptor type II-B