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J. Cell Biol.,
Volume 142, Number 5, September 7, 1998 1279-1287
-Sarcoglycan Deficiency Leads to Muscle Membrane
Defects and Apoptosis Independent of Dystrophin
* Department of Molecular Genetics and Cell Biology, Department of Medicine, Section of Cardiology, and § Department of
Pathology, University of Chicago, Chicago, Illinois 60637
-Sarcoglycan is a transmembrane, dystrophin-associated protein expressed in skeletal and cardiac muscle. The murine -sarcoglycan gene was disrupted using homologous recombination. Mice lacking -sarcoglycan showed pronounced dystrophic muscle
changes in early life. By 20 wk of age, these mice developed cardiomyopathy and died prematurely. The loss
of -sarcoglycan produced secondary reduction of 
-
and 
-sarcoglycan with partial retention of 
- and
-sarcoglycan, suggesting that -, -, and -sarcoglycan
function as a unit. Importantly, mice lacking -sarco-
glycan showed normal dystrophin content and local-
ization, demonstrating that myofiber degeneration
occurred independently of dystrophin alteration. Furthermore, -dystroglycan and laminin were left intact,
implying that the dystrophin-dystroglycan-laminin
mechanical link was unaffected by sarcoglycan deficiency. Apoptotic myonuclei were abundant in skeletal
muscle lacking -sarcoglycan, suggesting that programmed cell death contributes to myofiber degeneration. Vital staining with Evans blue dye revealed that
muscle lacking -sarcoglycan developed membrane disruptions like those seen in dystrophin-deficient muscle.
Our data demonstrate that sarcoglycan loss was sufficient, and that dystrophin loss was 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.
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