Alpha7beta1 integrin does not alleviate disease in a mouse model of limb girdle muscular dystrophy type 2F.
Transgenic expression of the alpha7beta1 integrin in the dystrophic mdx/utr-/- mouse decreases development of muscular dystrophy and enhances longevity. To explore the possibility that elevating alpha7beta1 integrin expression could also ameliorate different forms of muscular dystrophy, we used transgenic technology to enhance integrin expression in mice lacking delta-sarcoglycan (delta sgc), a mouse model for human limb girdle muscular dystrophy type 2F. Unlike alpha7 transgenic mdx/utr-/- mice, enhanced alpha7beta1 integrin expression in the delta sgc-null mouse did not alleviate muscular dystrophy in these animals. Expression of the transgene in the delta sgc-null did not alleviate dystrophic histopathology, nor did it decrease cardiomyopathy or restore exercise tolerance. One hallmark of integrin-mediated alleviation of muscular dystrophy in the mdx/utr-/- background is the restoration of myotendinous junction integrity. As assessed by atomic force microscopy, myotendinous junctions from normal and delta sgc-null mice were indistinguishable, thus suggesting the important influence of myotendinous junction integrity on the severity of muscular dystrophy and providing a possible explanation for the inability of enhanced integrin expression to alleviate dystrophy in the delta sgc-null mouse. These results suggest that distinct mechanisms underlie the development of the diseases that arise from deficiencies in dystrophin and sarcoglycan.
Milner
Derek J
DJ
Department of Cell and Developmental Biology, University of Illinois, B107 Chemical and Life Sciences Laboratory, 601 South Goodwin Ave., Urbana, IL 61801, USA.
Kaufman
Stephen J
SJ
D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D016189:Dystrophin / Q000172:deficiency; D017079:Exercise Tolerance / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D016023:Integrins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018625:Microscopy, Atomic Force; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049031:Sarcoglycans / Q000172:deficiency; D013710:Tendons / Q000378:metabolism / Q000648:ultrastructure*; D019076:Transgenes; D049411:Utrophin / Q000172:deficiency
D016189:Dystrophin; D016023:Integrins; D049031:Sarcoglycans; D049411:Utrophin; C082908:integrin alpha7beta1