Increasing alpha 7 beta 1-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression.
The dystrophin-glycoprotein complex maintains the integrity of skeletal muscle by associating laminin in the extracellular matrix with the actin cytoskeleton. Several human muscular dystrophies arise from defects in the components of this complex. The alpha(7)beta(1)-integrin also binds laminin and links the extracellular matrix with the cytoskeleton. Enhancement of alpha(7)-integrin levels alleviates pathology in mdx/utrn(-/-) mice, a model of Duchenne muscular dystrophy, and thus the integrin may functionally compensate for the absence of dystrophin. To test whether increasing alpha(7)-integrin levels affects transcription and cellular functions, we generated alpha(7)-integrin-inducible C2C12 cells and transgenic mice that overexpress the integrin in skeletal muscle. C2C12 myoblasts with elevated levels of integrin exhibited increased adhesion to laminin, faster proliferation when serum was limited, resistance to staurosporine-induced apoptosis, and normal differentiation. Transgenic expression of eightfold more integrin in skeletal muscle did not result in notable toxic effects in vivo. Moreover, high levels of alpha(7)-integrin in both myoblasts and in skeletal muscle did not disrupt global gene expression profiles. Thus increasing integrin levels can compensate for defects in the extracellular matrix and cytoskeleton linkage caused by compromises in the dystrophin-glycoprotein complex without triggering apparent overt negative side effects. These results support the use of integrin enhancement as a therapy for muscular dystrophy.
Liu
Jianming
J
Department of Cell and Developmental Biology, University of Illinois, 601 S. Goodwin Ave., B107 Chemical and Life Sciences Laboratory, Urbana, IL 61801, USA.
Burkin
Dean J
DJ
Kaufman
Stephen J
SJ
D008841:Actin Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D016189:Dystrophin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D016023:Integrins / Q000235:genetics* / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D032446:Myoblasts / Q000378:metabolism / Q000648:ultrastructure; D012038:Regeneration / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
D016189:Dystrophin; D016023:Integrins; D007797:Laminin; C082908:integrin alpha7beta1