Journal
JOURNAL OF CELL SCIENCE
Volume 124, Issue 13, Pages 2287-2297Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.083311
Keywords
MDC1A; alpha 7 integrin; Transgenic mice; Muscular dystrophy
Categories
Funding
- NIH/NIAMS [R01AR053697]
- NIH-NCRR [5P20RR015581]
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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.
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