Truncated dystrophins reduce muscle stiffness in the extensor digitorum longus muscle of mdx mice

J Appl Physiol (1985). 2013 Feb 15;114(4):482-9. doi: 10.1152/japplphysiol.00866.2012. Epub 2012 Dec 6.

Abstract

Muscle stiffness is a major clinical feature in Duchenne muscular dystrophy (DMD). DMD is the most common lethal inherited muscle-wasting disease in boys, and it is caused by the lack of the dystrophin protein. We recently showed that the extensor digitorum longus (EDL) muscle of mdx mice (a DMD mouse model) exhibits disease-associated muscle stiffness. Truncated micro- and mini-dystrophins are the leading candidates for DMD gene therapy. Unfortunately, it has never been clear whether these truncated genes can mitigate muscle stiffness. To address this question, we examined the passive properties of the EDL muscle in transgenic mdx mice that expressed a representative mini- or micro-gene (ΔH2-R15, ΔR2-15/ΔR18-23/ΔC, or ΔR4-23/ΔC). The passive properties were measured at the ages of 6 and 20 mo and compared with those of age-matched wild-type and mdx mice. Despite significant truncation of the gene, surprisingly, the elastic and viscous properties were completely restored to the wild-type level in every transgenic strain we examined. Our results demonstrated for the first time that truncated dystrophin genes may effectively treat muscle stiffness in DMD.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Animals
  • Biomechanical Phenomena
  • Body Weight
  • Disease Models, Animal
  • Dystrophin / genetics
  • Dystrophin / metabolism*
  • Elasticity
  • Fibrosis
  • Hydroxyproline / metabolism
  • Isometric Contraction*
  • Kinetics
  • Male
  • Mice
  • Mice, Inbred mdx
  • Mice, Transgenic
  • Muscle Strength*
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Muscular Dystrophy, Duchenne / genetics
  • Muscular Dystrophy, Duchenne / metabolism*
  • Muscular Dystrophy, Duchenne / pathology
  • Muscular Dystrophy, Duchenne / physiopathology
  • Viscosity

Substances

  • Dystrophin
  • Hydroxyproline