uPA deficiency exacerbates muscular dystrophy in MDX mice

Duchenne muscular dystrophy (DMD) is a fatal and incurable muscle degenerative disorder. We identify a function of the protease urokinase plasminogen activator (uPA) in mdx mice, a mouse model of DMD. The expression of uPA is induced in mdx dystrophic muscle, and the genetic loss of uPA in mdx mice...

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Bibliographic Details
Published in:	The Journal of cell biology Vol. 178; no. 6; pp. 1039 - 1051
Main Authors:	Suelves, Mònica, Vidal, Berta, Serrano, Antonio L, Tjwa, Marc, Roma, Josep, López-Alemany, Roser, Luttun, Aernout, de Lagrán, María Martínez, Díaz, Maria Àngels, Jardí, Mercè, Roig, Manuel, Dierssen, Mara, Dewerchin, Mieke, Carmeliet, Peter, Muñoz-Cánoves, Pura
Format:	Journal Article
Language:	English
Published:	United States The Rockefeller University Press 10-09-2007 Rockefeller University Press
Subjects:	Animal migration behavior Animals Bone Marrow Transplantation Cell Movement Cells Cells, Cultured Duchenne muscular dystrophy Fibrin - metabolism Gene expression Kinases Macrophages Macrophages - physiology Mice Mice, Inbred mdx Muscle, Skeletal - metabolism Muscle, Skeletal - pathology Muscles Muscular diseases Muscular dystrophies Muscular dystrophy Muscular Dystrophy, Duchenne - genetics Muscular Dystrophy, Duchenne - metabolism Muscular Dystrophy, Duchenne - pathology Myoblasts - metabolism Myoblasts - pathology Proteases Receptors, Cell Surface - metabolism Receptors, Urokinase Plasminogen Activator Regeneration Rodents Skeletal muscle Transplantation Urokinase-Type Plasminogen Activator - deficiency
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Summary:	Duchenne muscular dystrophy (DMD) is a fatal and incurable muscle degenerative disorder. We identify a function of the protease urokinase plasminogen activator (uPA) in mdx mice, a mouse model of DMD. The expression of uPA is induced in mdx dystrophic muscle, and the genetic loss of uPA in mdx mice exacerbated muscle dystrophy and reduced muscular function. Bone marrow (BM) transplantation experiments revealed a critical function for BM-derived uPA in mdx muscle repair via three mechanisms: (1) by promoting the infiltration of BM-derived inflammatory cells; (2) by preventing the excessive deposition of fibrin; and (3) by promoting myoblast migration. Interestingly, genetic loss of the uPA receptor in mdx mice did not exacerbate muscular dystrophy in mdx mice, suggesting that uPA exerts its effects independently of its receptor. These findings underscore the importance of uPA in muscular dystrophy.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Correspondence to Pura Muñoz-Cánoves: pura.munoz@crg.es Abbreviations used in this paper: BM, bone marrow; CK, creatine kinase; CTX, cardiotoxin; DMD, Duchenne muscular dystrophy; HE, hematoxylin/eosin; HGF, hepatocyte growth factor; SC, satellite cell; SF, scatter factor; uPA, urokinase plasminogen activator; uPAR, uPA receptor; WT, wild type.
ISSN:	0021-9525 1540-8140
DOI:	10.1083/jcb.200705127