Preservation of Muscle Force in Mdx3cv Mice Correlates With Low-Level Expression of a Near Full-Length Dystrophin Protein

Am J Pathol. 2008 May;172(5):1332-41. doi: 10.2353/ajpath.2008.071042. Epub 2008 Apr 1.

Abstract

The complete absence of dystrophin causes Duchenne muscular dystrophy. Its restoration by greater than 20% is needed to reduce muscle pathology and improve muscle force. Dystrophin levels lower than 20% are considered therapeutically irrelevant but are associated with a less severe phenotype in certain Becker muscular dystrophy patients. To understand the role of low-level dystrophin expression, we compared muscle force and pathology in mdx3cv and mdx4cv mice. Dystrophin was eliminated in mdx4cv mouse muscle but was expressed in mdx3cv mice as a near full-length protein at approximately 5% of normal levels. Consistent with previous reports, we found dystrophic muscle pathology in both mouse strains. Surprisingly, mdx3cv extensor digitorium longus muscle showed significantly higher tetanic force and was also more resistant to eccentric contraction-induced injury than mdx4cv extensor digitorium longus muscle. Furthermore, mdx3cv mice had stronger forelimb grip strength than mdx4cv mice. Immunostaining revealed utrophin up-regulation in both mouse strains. The dystrophin-associated glycoprotein complex was also restored in the sarcolemma in both strains although at levels lower than those in normal mice. Our results suggest that subtherapeutic expression levels of near full-length, membrane-bound dystrophin, possibly in conjunction with up-regulated utrophin levels, may help maintain minimal muscle force but not arrest muscle degeneration or necrosis. Our findings provide valuable insight toward understanding delayed clinical onset and/or slow disease progression in certain Becker muscular dystrophy patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dystrophin / biosynthesis*
  • Dystrophin / genetics
  • Forelimb / physiopathology
  • Mice
  • Mice, Inbred mdx
  • Muscle Contraction / physiology*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology*
  • Muscular Dystrophy, Animal / metabolism
  • Muscular Dystrophy, Animal / pathology
  • Muscular Dystrophy, Animal / physiopathology*
  • Necrosis
  • Up-Regulation*
  • Utrophin / physiology

Substances

  • Dystrophin
  • Utrophin