Laminin-111 Restores Regenerative Capacity in a Mouse Model for alpha 7 Integrin Congenital Myopathy

Mutations in the alpha 7 integrin gene cause congenital myopathy characterized by delayed developmental milestones and impaired mobility. Previous studies in dystrophic mice suggest the alpha 7 beta 1 integrin may be critical for muscle repair. To investigate the role that alpha 7 beta 1 integrin plays in muscle regeneration, cardiotoxin was used to induce damage in the tibialis anterior muscle of alpha 7 integrin-null mice. Unlike wild-type muscle, which responded rapidly to repair damaged myofibers, alpha 7 integrin-deficient muscle exhibited defective regeneration. Analysis of Pax7 and MyoD expression revealed a profound delay in satellite cell activation after cardiotoxin treatment in alpha 7 integrin-null animals when compared with wild type. We have recently demonstrated that the muscle of alpha 7 integrin-null mice exhibits reduced laminin-alpha 2 expression. To test the hypothesis that loss of laminin contributes to the defective muscle regeneration phenotype observed in alpha 7 integrin-null mice, mouse laminin-111 (alpha 1, beta 1, gamma 1) protein was injected into the tibialis anterior muscle 3 days before cardiotoxin-induced injury. The injected laminin-111 protein infiltrated the entire muscle and restored myogenic repair and muscle regeneration in alpha 7 integrin-mill muscle to wild-type levels. Our data demonstrate a critical role for a laminin-rich micro-environment in muscle repair and suggest laminin-111 protein may serve as an unexpected and novel therapeutic agent for patients with congenital myopathies. (Am J Pathol 2009, 174:256-264; DOI: 10.2353/ajpath.2009.080522)