TY - JOUR
T1 - γ-sarcoglycan deficiency leads to muscle membrane defects and apoptosis independent of dystrophin
AU - Hack, Andrew A.
AU - Ly, Chantal T.
AU - Jiang, Fang
AU - Clendenin, Cynthia J.
AU - Sigrist, Kirsten S.
AU - Wollmann, Robert L.
AU - McNally, Elizabeth M.
PY - 1998/9/7
Y1 - 1998/9/7
N2 - γ-Sarcoglycan is a transmembrane, dystrophin-associated protein expressed in skeletal and cardiac muscle. The murine γ-sarcoglycan gene was disrupted using homologous recombination. Mice lacking γ-sarcoglycan showed pronounced dystrophic muscle changes in early life. By 20 wk of age, these mice developed cardiomyopathy and died prematurely. The loss of γ- sarcoglycan produced secondary reduction of β-and δ-sarcoglycan with partial retention of α- and ε-sarcoglycan, suggesting that β-, γ-, and δ-sarcoglycan function as a unit. Importantly, mice lacking γ-sarcoglycan showed normal dystrophin content and localization, demonstrating that myofiber degeneration occurred independently of dystrophin alteration. Furthermore, β-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 γ- sarcoglycan, suggesting that programmed cell death contributes to myofiber degeneration. Vital staining with Evans blue dye revealed that muscle lacking γ-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.
AB - γ-Sarcoglycan is a transmembrane, dystrophin-associated protein expressed in skeletal and cardiac muscle. The murine γ-sarcoglycan gene was disrupted using homologous recombination. Mice lacking γ-sarcoglycan showed pronounced dystrophic muscle changes in early life. By 20 wk of age, these mice developed cardiomyopathy and died prematurely. The loss of γ- sarcoglycan produced secondary reduction of β-and δ-sarcoglycan with partial retention of α- and ε-sarcoglycan, suggesting that β-, γ-, and δ-sarcoglycan function as a unit. Importantly, mice lacking γ-sarcoglycan showed normal dystrophin content and localization, demonstrating that myofiber degeneration occurred independently of dystrophin alteration. Furthermore, β-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 γ- sarcoglycan, suggesting that programmed cell death contributes to myofiber degeneration. Vital staining with Evans blue dye revealed that muscle lacking γ-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.
KW - Apoptosis
KW - Dystrophin
KW - Extracellular matrix
KW - Muscular dystrophy
KW - Sarcolemma
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U2 - 10.1083/jcb.142.5.1279
DO - 10.1083/jcb.142.5.1279
M3 - Article
C2 - 9732288
AN - SCOPUS:0032494165
VL - 142
SP - 1279
EP - 1287
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 5
ER -