Altered expression of the α7β1 integrin in human and murine muscular dystrophies

Abstract

The α7β1 integrin is the primary laminin receptor on skeletal myoblasts and adult myofibers. It has distinct functions during muscle development and contributes to muscle structural integrity. We have studied this integrin in cases where expression of dystrophin or laminin are compromised. Immunofluorescence demonstrates an increase in α7β1 in patients with Duchenne muscular dystrophy and in mdx mice that lack dystrophin. Analysis of RNA from mdx mice and from patients with Duchenne and Becker muscular dystrophies indicates that the increase in the α7β1 integrin is regulated at the level of α7 gene transcription. In contrast, the levels of α7β1 integrin are severely diminished in patients with laminin α2 chain congenital dystrophy muscular dystrophy and in dy/dy mice that also do not make the α2 laminin chain. Analysis of RNA from the hindlimbs of dy/dy mice demonstrated that in the absence of laminin α7 gene transcription is inhibited and limited to specific alternatively spliced isoforms. We suggest that the increased expression of α7β1 integrin in the absence of dystrophin compensates for the reduced dystrophin-mediated linkage of fibers with the basal lamina and modulates the development of pathology associated with these diseases. The decrease in α7β1 integrin and its transcripts in the absence of laminin likely contributes to the severe myopathy that results from laminin α2 chain deficiency and suggests that laminin-2 regulates expression of the α7 integrin gene. The role of the α7β1 integrin in muscle integrity also suggests that compromised expression of this receptor may underlie as yet undefined myopathies.