Published online before print December 12, 2008

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(American Journal of Pathology. 2009;174:256-264.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080522

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

Jachinta E. Rooney^*, Praveen B. Gurpur^*, Zipora Yablonka-Reuveni and Dean J. Burkin^*

From the Department of Pharmacology,^* University of Nevada School of Medicine, Reno, Nevada; the Department of Biological Structure, University of Washington School of Medicine, Seattle, Washington; and the Nevada Transgenic Center, University of Nevada School of Medicine, Reno, Nevada

Mutations in the 7 integrin gene cause congenital myopathy characterized by delayed developmental milestones and impaired mobility. Previous studies in dystrophic mice suggest the 7β1 integrin may be critical for muscle repair. To investigate the role that 7β1 integrin plays in muscle regeneration, cardiotoxin was used to induce damage in the tibialis anterior muscle of 7 integrin-null mice. Unlike wild-type muscle, which responded rapidly to repair damaged myofibers, 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 7 integrin-null animals when compared with wild type. We have recently demonstrated that the muscle of 7 integrin-null mice exhibits reduced laminin-2 expression. To test the hypothesis that loss of laminin contributes to the defective muscle regeneration phenotype observed in 7 integrin-null mice, mouse laminin-111 (1, β1, 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 7 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.

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