Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 174, Issue 1, Pages 256-264Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2009.080522
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Funding
- National Institutes of Health (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [R01AR053697-01]
- National Institutes of Health (National Institute of Neurological Disorders and Stroke) [R21NS058429-01]
- National Institute on Aging [R01AG021566-06]
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR053697] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R21NS058429] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG021566] Funding Source: NIH RePORTER
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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)
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