Severe muscular dystrophy in mice that lack dystrophin and α7 integrin

Jachinta E Rooney,Stephen J Kaufman,Jennifer V Welser,Melissa A Dechert,Dean J Burkin,Nichole L Flintoff-Dye

doi:10.1242/jcs.02952

Jachinta E Rooney, Stephen J Kaufman + Show 4 more

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https://doi.org/10.1242/jcs.02952

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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 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.

Highlights

Duchenne muscular dystrophy (DMD) is the most common Xchromosome-linked human disease that affects approximately 1 in 3,500 males
DMD patients and mdx mice have dystrophin gene mutations that result in an absence of the dystrophin protein (Bulfield et al, 1984; Campbell, 1995; Matsumura et al, 1992; Monaco et al, 1986; Sicinski et al, 1989)
Dystrophin is localized to the cytoplasmic face of the plasma membrane and mediates the interaction between the cell cytoskeleton and the extracellular matrix (ECM) through a complex of associated glycoproteins called the dystrophin-glycoprotein complex (DGC)

Summary

Introduction

Duchenne muscular dystrophy (DMD) is the most common Xchromosome-linked human disease that affects approximately 1 in 3,500 males. Dystrophin is localized to the cytoplasmic face of the plasma membrane and mediates the interaction between the cell cytoskeleton and the extracellular matrix (ECM) through a complex of associated glycoproteins called the dystrophin-glycoprotein complex (DGC). The DGC is localized along muscle fibers and at myotendinous and neuromuscular junctions (MTJs and NMJs, respectively). This complex includes dystroglycans, sarcoglycans and syntrophins (Suzuki et al, 1994). The C-terminus interacts with syntrophins and with the cytoplasmic tail of ␤-dystroglycan (Henry and Campbell, 1996). The DGC links the muscle cell cytoskeleton to the extracellular matrix and maintains sarcolemmal integrity

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