Transgenic overexpression of the α7 integrin reduces muscle pathology and improves viability in the dyW mouse model of merosin-deficient congenital muscular dystrophy type 1A

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 alpha 7 beta 1 integrin; however, it is unclear how the secondary loss of alpha 7 beta 1 integrin contributes to MDC1A disease progression. To investigate whether restoring alpha 7 integrin expression can alleviate the myopathic phenotype observed in MDC1A, we produced transgenic mice that overexpressed the alpha 7 integrin in the skeletal muscle of the dy(W-/-) mouse model of MDC1A. Enhanced expression of the alpha 7 integrin restored sarcolemmal localization of the alpha 7 beta 1 integrin to laminin. alpha 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 alpha 7 integrin prevents muscle disease progression through augmentation and/or stabilization of the existing extracellular matrix in laminin-alpha 2-deficient mice, and strategies that increase alpha 7 integrin in muscle might provide an innovative approach for the treatment of MDC1A.