Severe muscular dystrophy in mice that lack dystrophin and alpha7 integrin.
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 alpha7beta1 integrin is a second transmembrane laminin receptor expressed in skeletal muscle. Mutations in the alpha7 integrin gene cause congenital myopathy in humans and mice. The alpha7beta1 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 alpha7beta1 integrin have complementary functional and structural roles. To test this hypothesis, we generated mice lacking both dystrophin and alpha7 integrin (mdx/alpha7(-/-)). The mdx/alpha7(-/-) mice developed early-onset muscular dystrophy and died at 2-4 weeks of age. Muscle fibers from mdx/alpha7(-/-) 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 alpha7-integrin null animals. In addition, loss of dystrophin and/or alpha7 integrin resulted in altered expression of laminin-alpha2 chain. These results point to complementary roles for dystrophin and alpha7beta1 integrin in maintaining the functional integrity of skeletal muscle.
Rooney
Jachinta E
JE
Department of Pharmacology, University of Nevada, Reno, 89557, USA. dburkin@med.unr.edu
Welser
Jennifer V
JV
Dechert
Melissa A
MA
Flintoff-Dye
Nichole L
NL
Kaufman
Stephen J
SJ
Burkin
Dean J
DJ