Transgenic overexpression of the ?7 integrin reduces muscle pathology and improves viability in the dy(W) mouse model of merosin-deficient congenital muscular dystrophy type 1A.

ABSTRACT: Merosin-deficient congenital muscular dystrophy 1A (MDC1A) is a devastating neuromuscular disease that results in children being confined to a wheelchair, requiring ventilator assistance to breathe and premature death. MDC1A is caused by mutations in the LAMA2 gene, which results in the partial or complete loss of laminin-211 and laminin-221, the major laminin isoforms found in the basal lamina of skeletal muscle. MDC1A patients exhibit reduced ?7?1 integrin; however, it is unclear how the secondary loss of ?7?1 integrin contributes to MDC1A disease progression. To investigate whether restoring ?7 integrin expression can alleviate the myopathic phenotype observed in MDC1A, we produced transgenic mice that overexpressed the ?7 integrin in the skeletal muscle of the dy(W?/?) mouse model of MDC1A. Enhanced expression of the ?7 integrin restored sarcolemmal localization of the ?7?1 integrin to laminin-?2-deficient myofibers, changed the composition of the muscle extracellular matrix, reduced muscle pathology, maintained muscle strength and function and improved the life expectancy of dy(W?/?) mice. Taken together, these results indicate that enhanced expression of ?7 integrin prevents muscle disease progression through augmentation and/or stabilization of the existing extracellular matrix in laminin-?2-deficient mice, and strategies that increase ?7 integrin in muscle might provide an innovative approach for the treatment of MDC1A.

SUBMITTER: Doe JA 

PROVIDER: S-EPMC3113674 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature