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PMID: 11257121 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Enhanced expression of the alpha 7 beta 1 integrin reduces muscular dystrophy and restores viability in dystrophic mice.

The Journal of cell biology ·Vol. 152 ·No. 6 ·2001-03-19 ·Pages 1207-18

Burkin DJ, Wallace GQ, Nicol KJ, Kaufman DJ, Kaufman SJ

Abstract

Muscle fibers attach to laminin in the basal lamina using two distinct mechanisms: the dystrophin glycoprotein complex and the alpha 7 beta 1 integrin. Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), alpha 2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and alpha 7 integrin congenital muscular dystrophy. Therefore, the molecular continuity between the extracellular matrix and cell cytoskeleton is essential for the structural and functional integrity of skeletal muscle. To test whether the alpha 7 beta 1 integrin can compensate for the absence of dystrophin, we expressed the rat alpha 7 chain in mdx/utr(-/-) mice that lack both dystrophin and utrophin. These mice develop a severe muscular dystrophy highly akin to that in DMD, and they also die prematurely. Using the muscle creatine kinase promoter, expression of the alpha 7BX2 integrin chain was increased 2.0-2.3-fold in mdx/utr(-/-) mice. Concomitant with the increase in the alpha 7 chain, its heterodimeric partner, beta 1D, was also increased in the transgenic animals. Transgenic expression of the alpha 7BX2 chain in the mdx/utr(-/-) mice extended their longevity by threefold, reduced kyphosis and the development of muscle disease, and maintained mobility and the structure of the neuromuscular junction. Thus, bolstering alpha 7 beta 1 integrin-mediated association of muscle cells with the extracellular matrix alleviates many of the symptoms of disease observed in mdx/utr(-/-) mice and compensates for the absence of the dystrophin- and utrophin-mediated linkage systems. This suggests that enhanced expression of the alpha 7 beta 1 integrin may provide a novel approach to treat DMD and other muscle diseases that arise due to defects in the dystrophin glycoprotein complex. A video that contrasts kyphosis, gait, joint contractures, and mobility in mdx/utr(-/-) and alpha 7BX2-mdx/utr(-/-) mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207.

MeSH Terms
Animals Blotting, Western Body Weight Contracture/physiopathology Creatine Kinase/genetics Creatine Kinase, MM Form Cytoskeletal Proteins/genetics,metabolism Dystrophin/genetics,metabolism Female Hindlimb Humans Integrins/genetics,metabolism Isoenzymes/genetics Joints Kyphosis Magnetic Resonance Imaging Male Membrane Proteins/genetics,metabolism Mice Mice, Inbred mdx Mice, Transgenic Microscopy, Fluorescence Muscle, Skeletal/pathology,physiopathology Muscular Dystrophy, Animal/genetics,pathology,physiopathology Muscular Dystrophy, Duchenne/genetics,pathology,physiopathology Neuromuscular Junction/ultrastructure Promoter Regions, Genetic Rats Receptors, Cholinergic/metabolism,ultrastructure Survival Rate Transgenes Utrophin
Chemicals
Cytoskeletal Proteins Dystrophin Integrins Isoenzymes Membrane Proteins Receptors, Cholinergic Utrn protein, mouse Utrophin Creatine Kinase Creatine Kinase, MM Form integrin alpha7beta1
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Burkin D J
Department of Cell and Structural Biology, University of Illinois, Urbana, Illinois 61801, USA.
Wallace G Q
Nicol K J
Kaufman D J
Kaufman S J
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.152.6.1207
Published
2001-03-19
Pages
1207-18
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2199213
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.152.6.1207 PMC Full Text View journal details
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