Laminin-111 restores regenerative capacity in a mouse model for alpha7 integrin congenital myopathy.
Mutations in the alpha7 integrin gene cause congenital myopathy characterized by delayed developmental milestones and impaired mobility. Previous studies in dystrophic mice suggest the alpha7beta1 integrin may be critical for muscle repair. To investigate the role that alpha7beta1 integrin plays in muscle regeneration, cardiotoxin was used to induce damage in the tibialis anterior muscle of alpha7 integrin-null mice. Unlike wild-type muscle, which responded rapidly to repair damaged myofibers, alpha7 integrin-deficient muscle exhibited defective regeneration. Analysis of Pax7 and MyoD expression revealed a profound delay in satellite cell activation after cardiotoxin treatment in alpha7 integrin-null animals when compared with wild type. We have recently demonstrated that the muscle of alpha7 integrin-null mice exhibits reduced laminin-alpha2 expression. To test the hypothesis that loss of laminin contributes to the defective muscle regeneration phenotype observed in alpha7 integrin-null mice, mouse laminin-111 (alpha1, beta1, gamma1) 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 alpha7 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.
Rooney
Jachinta E
JE
Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada 89557, USA.
Gurpur
Praveen B
PB
Yablonka-Reuveni
Zipora
Z
Burkin
Dean J
DJ
D000818:Animals; D054715:Cardiotoxins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D039001:Integrin alpha Chains / Q000172:deficiency*; D007797:Laminin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D020914:Myopathies, Structural, Congenital / Q000378:metabolism* / Q000473:pathology; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D054715:Cardiotoxins; D039001:Integrin alpha Chains; D007797:Laminin; C121346:laminin 1