{gamma}-Sarcoglycan Deficiency Leads to Muscle Membrane Defects and Apoptosis Independent of Dystrophin

doi:10.1083/jcb.142.5.1279

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© The Rockefeller University Press, 0021-9525/1998//1279 $5.00
The Journal of Cell Biology, Volume 142, Number 5, , 1998 1279-1287

Articles

${gamma}$ -Sarcoglycan Deficiency Leads to Muscle Membrane Defects and Apoptosis Independent of Dystrophin

Andrew A. Hack^*, Chantal T. Ly, Fang Jiang, Cynthia J. Clendenin, Kirsten S. Sigrist, Robert L. Wollmann, and Elizabeth M. McNally

^* Department of Molecular Genetics and Cell Biology, Department of Medicine, Section of Cardiology, and Department of Pathology, University of Chicago, Chicago, Illinois 60637

${gamma}$ -Sarcoglycan is a transmembrane, dystrophin-associated proteinexpressed in skeletal and cardiac muscle. The murine ${gamma}$ -sarcoglycangene was disrupted using homologous recombination. Mice lacking ${gamma}$ -sarcoglycan showed pronounced dystrophic muscle changes inearly life. By 20 wk of age, these mice developed cardiomyopathyand died prematurely. The loss of ${gamma}$ -sarcoglycan produced secondaryreduction of β- and ${delta}$ -sarcoglycan with partial retentionof ${alpha}$ - and ${varepsilon}$ -sarcoglycan, suggesting that β-, ${gamma}$ -, and ${delta}$ -sarcoglycan function as a unit. Importantly, mice lacking ${gamma}$ -sarco- glycanshowed normal dystrophin content and local- ization, demonstratingthat myofiber degeneration occurred independently of dystrophinalteration. Furthermore, β-dystroglycan and laminin wereleft intact, implying that the dystrophin–dystroglycan–lamininmechanical link was unaffected by sarcoglycan deficiency. Apoptoticmyonuclei were abundant in skeletal muscle lacking ${gamma}$ -sarcoglycan,suggesting that programmed cell death contributes to myofiberdegeneration. Vital staining with Evans blue dye revealed that muscle lacking ${gamma}$ -sarcoglycan developed membrane disruptionslike those seen in dystrophin-deficient muscle. Our data demonstratethat sarcoglycan loss was sufficient, and that dystrophin losswas not necessary to cause membrane defects and apoptosis.As a common molecular feature in a variety of muscular dystrophies, sarcoglycan loss is a likely mediator of pathology.

Key Words: muscular dystrophy • sarcolemma • dystrophin • extracellular matrix • apoptosis

Abbreviations used in this paper: DMD, Duchenne muscular dystrophy; LGMD, limb girdle muscular dystrophy; CK, creatine kinase; EBD, Evans blue dye; DGC, dystrophin-glycoprotein complex; ECM, extracellular matrix.

A.A. Hack is supported by the Medical Scientist Training Programand the Training Program in Development Biology. E.M. McNallyis supported by the National Institues of Health, Muscular DystrophyAssociation, Heart Research Foundation, and a Research Resourcesaward from the Howard Hughes Medical Institute to the Universityof Chicago Biological Sciences Division.

Address all correspondence to Elizabeth M. McNally, M.D., Ph.D.,Department of Medicine, Section of Cardiology, 5841 S. MarylandAve., MC 6088, The University of Chicago, Chicago, IL 60637.Tel.: (773) 702-2672. Fax: (773) 702-2681. E-mail: emcnally{at}medicine.bsd.uchicago.edu

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