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© The Rockefeller University Press, 0021-9525/1998//1461 $5.00
The Journal of Cell Biology, Volume 142, Number 6, , 1998 1461-1471

Regular Articles

Progressive Muscular Dystrophy in {alpha}-Sarcoglycan–deficient Mice



Franck Duclos*, Volker Straub*, Steven A. Moore{ddagger}, David P. Venzke*, Ron F. Hrstka§, Rachelle H. Crosbie*, Madeleine Durbeej*, Connie S. Lebakken*, Audrey J. Ettinger||, Jack van der Meulen**, Kathleen H. Holt*, Leland E. Lim*, Joshua R. Sanes||, Beverly L. Davidson, John A. Faulkner**, Roger Williamson§, and Kevin P. Campbell*

* Howard Hughes Medical Institute, Department of Physiology and Biophysics and Department of Neurology, University of Iowa College of Medicine, Iowa City, Iowa 52242-1101; {ddagger} Department of Pathology and § Department of Obstetrics and Gynecology, University of Iowa College of Medicine, Iowa City, Iowa 52242; || Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110; Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242; and ** Institute of Gerontology, University of Michigan, Ann Arbor, Michigan 48109

Limb-girdle muscular dystrophy type 2D (LGMD 2D) is an autosomal recessive disorder caused by mutations in the {alpha}-sarcoglycan gene. To determine how {alpha}-sarcoglycan deficiency leads to muscle fiber degeneration, we generated and analyzed {alpha}-sarcoglycan– deficient mice. Sgca-null mice developed progressive muscular dystrophy and, in contrast to other animal models for muscular dystrophy, showed ongoing muscle necrosis with age, a hallmark of the human disease. Sgca-null mice also revealed loss of sarcolemmal integrity, elevated serum levels of muscle enzymes, increased muscle masses, and changes in the generation of absolute force. Molecular analysis of Sgca-null mice demonstrated that the absence of {alpha}-sarcoglycan resulted in the complete loss of the sarcoglycan complex, sarcospan, and a disruption of {alpha}-dystroglycan association with membranes. In contrast, no change in the expression of {varepsilon}-sarcoglycan ({alpha}-sarcoglycan homologue) was observed. Recombinant {alpha}-sarcoglycan adenovirus injection into Sgca-deficient muscles restored the sarcoglycan complex and sarcospan to the membrane. We propose that the sarcoglycan–sarcospan complex is requisite for stable association of {alpha}-dystroglycan with the sarcolemma. The Sgca-deficient mice will be a valuable model for elucidating the pathogenesis of sarcoglycan deficient limb-girdle muscular dystrophies and for the development of therapeutic strategies for this disease.

Key Words: gene targeting • muscular dystrophy • sarcoglycan • dystroglycan • sarcospan

Abbreviations used in this paper: CK, creatine kinase; DGC, dystrophin-glycoprotein complex; EBD, Evans blue dye; EDL, extensor digitorum longus; H & E, haematoxilin and eosin; LGMD, limb-girdle muscular dystrophy; Po, maximum isometric tetanic force; PK, pyruvate kinase; SG, sarcoglycan.

V. Straub was supported by the Deutsche Forschungsgemeinschaft (Str 498/1-1). R.H. Crosbie is supported by the Robert G. Sampson postdoctoral research fellowship from the Muscular Dystrophy Association. M. Durbeej was supported by The Swedish Foundation for International Cooperation in Research and Higher Education (STINT). C.S. Lebakken was supported by the Iowa Cardiovascular Interdisciplinary Research Fellowship (HL07121). K.H. Holt was supported by the University of Iowa Diabetes and Endocrinology Research Center (DK07018). A.J. Ettinger and J.R. Sanes were supported by the National Institutes of Health (R01NS19195). This work was also supported by the Muscular Dystrophy Association. K.P. Campbell is an investigator of the Howard Hughes Medical Institute.

Address all correspondence to Kevin P. Campbell, Howard Hughes Medical Institute, University of Iowa College of Medicine, 400 EMRB, Iowa City, IA 52242. Tel.: (319) 335-7867. Fax: (319) 335-6957. E-mail: kevin-campbell{at}uiowa.edu WWW site: http://www-camlab.physiology. uiowa.edu/


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