Laminin-111 Restores Regenerative Capacity in a Mouse Model for α7 Integrin Congenital Myopathy

Mutations in the α7 integrin gene cause congenital myopathy characterized by delayed developmental milestones and impaired mobility. Previous studies in dystrophic mice suggest the α7β1 integrin may be critical for muscle repair. To investigate the role that α7β1 integrin plays in muscle regeneration, cardiotoxin was used to induce damage in the tibialis anterior muscle of α7 integrin-null mice. Unlike wild-type muscle, which responded rapidly to repair damaged myofibers, α7 integrin-deficient muscle exhibited defective regeneration. Analysis of Pax7 and MyoD expression revealed a profound delay in satellite cell activation after cardiotoxin treatment in α7 integrin-null animals when compared with wild type. We have recently demonstrated that the muscle of α7 integrin-null mice exhibits reduced laminin-α2 expression. To test the hypothesis that loss of laminin contributes to the defective muscle regeneration phenotype observed in α7 integrin-null mice, mouse laminin-111 (α1, β1, γ1) 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 α7 integrin-null muscle to wild-type levels. Our data demonstrate a critical role for a laminin-rich microenvironment in muscle repair and suggest laminin- 111 protein may serve as an unexpected and novel therapeutic agent for patients with congenital myopathies.