Inhibition of myostatin reverses muscle fibrosis through apoptosis

Zhao Bo Li, Jiangyang Zhang, Kathryn R. Wagner

Research output: Contribution to journalArticlepeer-review

Abstract

Skeletal muscle fibrosis is a defining feature of the muscular dystrophies in which contractile myofibers are replaced by fibroblasts, adipocytes and extracellular matrix. This maladaptive response of muscle to repetitive injury is progressive, self-perpetuating and thus far, has been considered irreversible. We have previously shown that myostatin, a known endogenous modulator of muscle growth, stimulates normal muscle fibroblasts to proliferate. Here, we demonstrate that myostatin also regulates the proliferation of dystrophic muscle fibroblasts, and increases resistance of fibroblasts to apoptosis through Smad and MAPK signaling. Inhibition of myostatin signaling pathways with a soluble activin IIB receptor (ActRIIB.Fc) reduces resistance of muscle fibroblasts to apoptosis in vitro. Systemic administration of ActRIIB.Fc in senescent mdx mice, a model of muscular dystrophy, significantly increases the number of muscle fibroblasts undergoing apoptosis. This leads to the reversal of pre-existing muscle fibrosis as determined by histological, biochemical and radiographical criteria. These results demonstrate that skeletal muscle fibrosis can be pharmacologically reversed through induction of fibroblast apoptosis.

Original languageEnglish (US)
Pages (from-to)3957-3965
Number of pages9
JournalJournal of cell science
Volume125
Issue number17
DOIs
StatePublished - Sep 1 2012

Keywords

  • Fibrosis
  • Muscle
  • Muscular dystrophy
  • Myostatin
  • Regeneration

ASJC Scopus subject areas

  • Cell Biology

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