Sulforaphane Alleviates Muscular Dystrophy in MDX Mice by Activation of Nrf2

J Appl Physiol (1985). 2015 Jan 15;118(2):224-37. doi: 10.1152/japplphysiol.00744.2014. Epub 2014 Nov 13.

Abstract

Sulforaphane (SFN), one of the most important isothiocyanates in the human diet, is known to have chemo-preventive and antioxidant activities in different tissues via activation of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated induction of antioxidant/phase II enzymes, such as heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. However, its effects on muscular dystrophy remain unknown. This work was undertaken to evaluate the effects of SFN on Duchenne muscular dystrophy. Four-week-old mdx mice were treated with SFN by gavage (2 mg·kg body wt(-1)·day(-1) for 8 wk), and our results demonstrated that SFN treatment increased the expression and activity of muscle phase II enzymes NAD(P)H quinone oxidoreductase 1 and heme oxygenase-1 with a Nrf2-dependent manner. SFN significantly increased skeletal muscle mass, muscle force (∼30%), running distance (∼20%), and GSH-to-GSSG ratio (∼3.2-fold) of mdx mice and decreased the activities of plasma creatine phosphokinase (∼45%) and lactate dehydrogenase (∼40%), gastrocnemius hypertrophy (∼25%), myocardial hypertrophy (∼20%), and malondialdehyde levels (∼60%). Furthermore, SFN treatment also reduced the central nucleation (∼40%), fiber size variability, and inflammation and improved the sarcolemmal integrity of mdx mice. Collectively, these results show that SFN can improve muscle function and pathology and protect dystrophic muscle from oxidative damage in mdx mice associated with Nrf2 signaling pathway, which indicate Nrf2 may have clinical implications for the treatment of patients with muscular dystrophy.

Keywords: Duchenne muscular dystrophy; Nrf2; oxidative stress; sulforaphane.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticarcinogenic Agents / pharmacology
  • Anticarcinogenic Agents / therapeutic use*
  • Antioxidant Response Elements / drug effects
  • Drug Evaluation, Preclinical
  • Gene Expression Regulation / drug effects
  • Heart / drug effects
  • Heme Oxygenase-1 / metabolism
  • Inflammation / drug therapy
  • Isothiocyanates / pharmacology
  • Isothiocyanates / therapeutic use*
  • Male
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Muscle, Skeletal / drug effects
  • Muscular Dystrophy, Animal / drug therapy*
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / drug effects
  • Random Allocation
  • Sarcolemma / drug effects
  • Signal Transduction / drug effects

Substances

  • Anticarcinogenic Agents
  • Isothiocyanates
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • NAD(P)H Dehydrogenase (Quinone)
  • Nqo1 protein, mouse
  • sulforafan