Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

Proc Natl Acad Sci U S A. 2009 May 12;106(19):7991-6. doi: 10.1073/pnas.0811599106. Epub 2009 Apr 28.

Abstract

Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The alpha(7)beta(1)-integrin is a laminin-binding protein up-regulated in the skeletal muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the alpha(7)-integrin alleviates muscle disease in dystrophic mice, making this gene a target for pharmacological intervention. Studies suggest laminin may regulate alpha(7)-integrin expression. To test this hypothesis, mouse and human myoblasts were treated with laminin and assayed for alpha(7)-integrin expression. We show that laminin-111 (alpha(1), beta(1), gamma(1)), which is expressed during embryonic development but absent in normal or dystrophic skeletal muscle, increased alpha(7)-integrin expression in mouse and DMD patient myoblasts. Injection of laminin-111 protein into the mdx mouse model of DMD increased expression of alpha(7)-integrin, stabilized the sarcolemma, restored serum creatine kinase to wild-type levels, and protected muscle from exercised-induced damage. These findings demonstrate that laminin-111 is a highly potent therapeutic agent for the mdx mouse model of DMD and represents a paradigm for the systemic delivery of extracellular matrix proteins as therapies for genetic diseases.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / genetics*
  • Antigens, CD / metabolism
  • Cell Separation
  • Creatine Kinase / blood
  • Extracellular Matrix / metabolism
  • Humans
  • Integrin alpha Chains / genetics*
  • Integrin alpha Chains / metabolism
  • Laminin / genetics*
  • Laminin / metabolism
  • Laminin / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Mice, Transgenic
  • Models, Biological
  • Muscles / metabolism
  • Muscular Dystrophy, Duchenne / genetics*
  • Muscular Dystrophy, Duchenne / metabolism
  • Promoter Regions, Genetic

Substances

  • Antigens, CD
  • Integrin alpha Chains
  • Laminin
  • integrin alpha7
  • Creatine Kinase