Imatinib attenuates skeletal muscle dystrophy in mdx mice

Ping Huang, Xinyu S. Zhao, Matthew Fields, Richard M. Ransohoff, Lan Zhou

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Duchenne-Meryon muscular dystrophy (DMD) is the most common and lethal genetic muscle disease. Ameliorating muscle necrosis, inflammation, and fibrosis represents an important therapeutic approach for DMD. Imatinib, an antineoplastic agent, demonstrated antiinflammatory and antifibrotic effects in liver, kidney, lung, and skin of various animal models. This study tested antiinflammatory and antifibrotic effects of imatinib in mdx mice, a DMD mouse model. We treated mdx mice with intraperitoneal injections of imatinib at the peak of limb muscle inflammation and the onset of diaphragm fibrosis. Controls received PBS vehicle or were left untreated. Muscle necrosis, inflammation, fibrosis, and function were evaluated by measuring serum CK activity, endomysial CD45 immunoreactive inflammation area, endomysial collagen III deposition, and hind limb grip strength. Phosphorylation of the tyrosine kinase targets of imatinib was assessed by Western blot in diaphragm tissue and in primary cultures of peritoneal macrophages and skeletal muscle fibroblasts. Imatinib markedly reduced muscle necrosis, inflammation, and fibrosis, and significantly improved hind limb grip strength in mdx mice. Reduced clinical disease was accompanied by inhibition of c-abl and PDGFR phosphorylation and suppression of TNF-α and IL-1β expression. Imatinib therapy for DMD may hold promise for ameliorating muscle necrosis, inflammation, and fibrosis by inhibiting c-abl and PDGFR signaling pathways and downstream inflammatory cytokine and fibrotic gene expression.

Original languageEnglish (US)
Pages (from-to)2539-2548
Number of pages10
JournalFASEB Journal
Volume23
Issue number8
DOIs
StatePublished - Aug 1 2009

Keywords

  • Fibrosis
  • Inflammation
  • Necrosis
  • PDGF
  • TGF-β
  • c-abl

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Huang, P., Zhao, X. S., Fields, M., Ransohoff, R. M., & Zhou, L. (2009). Imatinib attenuates skeletal muscle dystrophy in mdx mice. FASEB Journal, 23(8), 2539-2548. https://doi.org/10.1096/fj.09-129833