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 dystro phy, Analyses of integrins showed an abnormal expression and localizat ion of alpha 7 beta 1 isoforms in myofibers of merosin-deficient human patients and mice, but not in dystrophin-deficient or sarcoglycan-def icient humans and animals. It was shown previously that skeletal muscl e fibers require merosin for survival and function (Vachon, P.H., F. L oechel, H. Xu, U.M. Wewer, and E. Engvall, 1996, J. Cell Biol. 134:148 3-1497), Correction of merosin deficiency in vitro through cell transf ection with the merosin alpha 2 chain restored the normal localization of alpha 7 beta 1D integrins as well as myotube survival. Overexpress ion of the apoptosis-suppressing molecule Bcl-2 also promoted the surv ival of merosin-deficient myotubes, but did not restore a normal expre ssion of alpha 7 beta 1D integrins, Blocking of beta 1 integrins in no rmal myotubes induced apoptosis and severely reduced their survival. T hese findings (a) identify alpha 7 beta 1D integrins as the de facto r eceptors for merosin in skeletal muscle; (6) indicate a merosin depend ence 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 insight s to the pathogenesis of neuromuscular disorders.