Role of integrins and extracellular matrix proteins in skeletal muscle development, formation of the neuromuscular junction, and muscular dystrophy

General: The α7β1 integrin is a laminin receptor on the surface of skeletal myoblasts and muscle fibers. For a review, see Burkin and Kaufman (1999), Cell and Tissue Research 296:183-190. Our research focuses on the roles of this integrin in

• skeletal muscle development 
• the integrity of normal and dystrophic muscle
• the formation of neuromuscular junctions – molecular mechanisms and signal transduction

Role of the α7β1 integrin in the integrity of normal and dystrophic muscle in humans and mice: The α7β1 integrin appears to be both directly and indirectly causally related to several neuromuscular diseases (J. Cell Science 110:2873-2881, 1997; Cell and Tissue Research 296:183-190, 1999). Increased expression of α7β1-mediated linkage of fibers and the extracellular matrix is seen in Duchenne muscular dystrophy and this may compensate for the absence of the dystrophin-mediated linkage. In contrast, down-regulation of expression of the integrin contributes to the development of pathology in congenital laminin-deficiencies. Furthermore, mutations in the α7 integrin gene underlie additional congenital neuromuscular diseases (Nature Genetics 19:94-97, 1998). The functional roles of this integrin in the formation and stability of neuromuscular and myotendinous junctions and its localization between fibers suggest that altered expression or function of this integrin may have a widespread involvement in other neuromyopathies. Studies of additional muscle diseases that appear to be caused by altered expression of the integrin are in progress.

Enhanced expression of the α7β1 integrin inhibits development of muscular dystrophy and restores longevity: The defective association of skeletal and cardiac muscle with their surrounding basal lamina underlies the pathologies associated with a variety of congenital and acquired muscular dystrophies and cardiomyopathies. Two major mechanisms by which fibers attach to laminin in the basal lamina are the dystrophin glycoprotein complex and the α7β1 integrin. Duchenne muscular dystrophy, α2 laminin congenital muscular dystrophy, sarcoglycan related muscular dystrophy, and α7 integrin congenital muscular dystrophy result when one of those linkage systems is defective. Expression of the α7β1 integrin linkage system is enhanced in Duchenne patients and in mdx mice and both have mutations in their dystrophin gene. This led us to suggest that the integrin may compensate for the absence of the dystrophin glycoprotein complex.

To test this hypothesis we over-expressed the α7 integrin gene in mdx/utrophin (-/-) mice. We recently reported that the transgenic expression of the integrin extended the longevity of these animals threefold and largely reduced the development of muscular dystrophy (J. Cell Biology 152:1202-1218, 2001). We believe that the enhanced expression of the α7β1 integrin provides a novel approach to treat Duchenne muscular dystrophy as well as other diseases that arise due to additional defects in the dystrophin glycoprotein complex. Studies to explore this are currently a major focus of our research. A video that contrasts the untreated and transgenic animals can be viewed at http://www.jcb.org/cgi/content/full/152/6/1207.

The α7β1 integrin in the formation of neuromuscular junctions—molecular mechanisms and signal transduction: We recently discovered that specific isoforms of the α7β1 integrin play a functional role in the formation of neuromuscular junctions (J. Cell Biology 143:1067-1076, 1998; J. Cell Science 113:2877-2886, 2000). We are currently studying the physiologic and signal transduction mechanism mediated by this integrin during formation of neuromuscular junctions in cell culture and in transgenic mice.

This research was funded by the NIH and Muscular Dystrophy Association of America.