Integrins (alpha 7 beta 1) in muscle function and survival - Disrupted expression in merosin-deficient congenital muscular dystrophy

Mutations in genes coding for dystrophin, for alpha, beta, gamma, and delta-sarcoglycans, or for the alpha 2 chain of the basement membrane component merosin (laminin-2/4) cause various forms of muscular dystrophy, Analyses of integrins showed an abnormal expression and localization of alpha 7 beta 1 isoforms in myofibers of merosin-deficient human patients and mice, but not in dystrophin-deficient or sarcoglycan-deficient humans and animals. It was shown previously that skeletal muscle fibers require merosin for survival and function (Vachon, P.H., F. Loechel, H. Xu, U.M. Wewer, and E. Engvall, 1996, J. Cell Biol. 134:1483-1497), Correction of merosin deficiency in vitro through cell transfection with the merosin alpha 2 chain restored the normal localization of alpha 7 beta 1D integrins as well as myotube survival. Overexpression of the apoptosis-suppressing molecule Bcl-2 also promoted the survival of merosin-deficient myotubes, but did not restore a normal expression of alpha 7 beta 1D integrins, Blocking of beta 1 integrins in normal myotubes induced apoptosis and severely reduced their survival. These findings (a) identify alpha 7 beta 1D integrins as the de facto receptors for merosin in skeletal muscle; (6) indicate a merosin dependence for the accurate expression and membrane localization of alpha 7 beta 1D integrins in myofibers; (c) provide a molecular basis for the critical role of merosin in myofiber survival; and (d) add new insights to the pathogenesis of neuromuscular disorders.