Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy.
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.
Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Jachinta E
JE
Rooney
Praveen B
PB
Gurpur
Dean J
DJ
Burkin
D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D002469:Cell Separation; D003402:Creatine Kinase / Q000097:blood; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics* / Q000378:metabolism; D007797:Laminin / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic
D015703:Antigens, CD; D039001:Integrin alpha Chains; D007797:Laminin; C085725:integrin alpha7; D003402:Creatine Kinase