Sulforaphane mitigates muscle fibrosis in mdx mice via Nrf2-mediated inhibition of TGF-β/Smad signaling

J Appl Physiol (1985). 2016 Feb 15;120(4):377-90. doi: 10.1152/japplphysiol.00721.2015. Epub 2015 Oct 22.

Abstract

Sulforaphane (SFN), an activator of NF-E2-related factor 2 (Nrf2), has been found to have an antifibrotic effect on liver and lung. However, its effects on dystrophic muscle fibrosis remain unknown. This work was undertaken to evaluate the effects of SFN-mediated activation of Nrf2 on dystrophic muscle fibrosis. Male mdx mice (age 3 mo) were treated with SFN by gavage (2 mg/kg body wt per day) for 3 mo. Experimental results demonstrated that SFN remarkably attenuated skeletal and cardiac muscle fibrosis as indicated by reduced Sirius Red staining and immunostaining of the extracellular matrix. Moreover, SFN significantly inhibited the transforming growth factor-β (TGF-β)/Smad signaling pathway and suppressed profibrogenic gene and protein expressions such as those of α-smooth muscle actin (α-SMA), fibronectin, collagen I, plasminogen activator inhibitor-1 (PAI-1), and tissue inhibitor metalloproteinase-1 (TIMP-1) in an Nrf2-dependent manner. Furthermore, SFN significantly decreased the expression of inflammatory cytokines CD45, TNF-α, and IL-6 in mdx mice. In conclusion, these results show that SFN can attenuate dystrophic muscle fibrosis by Nrf2-mediated inhibition of the TGF-β/Smad signaling pathway, which indicates that Nrf2 may represent a new target for dystrophic muscle fibrosis.

Keywords: Duchenne muscular dystrophy; Nrf2; TGF-β/Smad; fibrosis; sulforaphane.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Collagen Type I / metabolism
  • Fibronectins / metabolism
  • Fibrosis / drug therapy*
  • Fibrosis / metabolism
  • Interleukin-6 / metabolism
  • Isothiocyanates / pharmacology*
  • Leukocyte Common Antigens / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Muscular Diseases / drug therapy
  • Muscular Diseases / metabolism
  • NF-E2-Related Factor 2 / metabolism*
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Signal Transduction / drug effects*
  • Smad Proteins / metabolism*
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Actins
  • Collagen Type I
  • Fibronectins
  • Interleukin-6
  • Isothiocyanates
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Plasminogen Activator Inhibitor 1
  • Smad Proteins
  • Tissue Inhibitor of Metalloproteinase-1
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • alpha-smooth muscle actin, mouse
  • Leukocyte Common Antigens
  • sulforafan