Severe muscular dystrophy in mice that lack dystrophin and α7 integrin

Abstract

The dystrophin glycoprotein complex links laminin in the extracellular matrix to the cell cytoskeleton. Loss of dystrophin causes Duchenne muscular dystrophy, the most common human X-chromosome-linked genetic disease. The α7β1 integrin is a second transmembrane laminin receptor expressed in skeletal muscle. Mutations in the α7 integrin gene cause congenital myopathy in humans and mice. The α7β1 integrin is increased in the skeletal muscle of Duchenne muscular dystrophy patients and mdx mice. This observation has led to the suggestion that dystrophin and α7β1 integrin have complementary functional and structural roles. To test this hypothesis, we generated mice lacking both dystrophin and α7 integrin (mdx/α7-/-). The mdx/α7-/- mice developed early-onset muscular dystrophy and died at 2-4 weeks of age. Muscle fibers from mdx/ α7-/- mice exhibited extensive loss of membrane integrity, increased centrally located nuclei and inflammatory cell infiltrate, greater necrosis and increased muscle degeneration compared to mdx or α7-integrin null animals. In addition, loss of dystrophin and/or α7 integrin resulted in altered expression of laminin-α2 chain. These results point to complementary roles for dystrophin and α7β1 integrin in maintaining the functional integrity of skeletal muscle.