Gamma-sarcoglycan deficiency leads to muscle membrane defects and apoptosis independent of dystrophin.
gamma-Sarcoglycan is a transmembrane, dystrophin-associated protein expressed in skeletal and cardiac muscle. The murine gamma-sarcoglycan gene was disrupted using homologous recombination. Mice lacking gamma-sarcoglycan showed pronounced dystrophic muscle changes in early life. By 20 wk of age, these mice developed cardiomyopathy and died prematurely. The loss of gamma-sarcoglycan produced secondary reduction of beta- and delta-sarcoglycan with partial retention of alpha- and epsilon-sarcoglycan, suggesting that beta-, gamma-, and delta-sarcoglycan function as a unit. Importantly, mice lacking gamma-sarco- glycan showed normal dystrophin content and local- ization, demonstrating that myofiber degeneration occurred independently of dystrophin alteration. Furthermore, beta-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 gamma-sarcoglycan, suggesting that programmed cell death contributes to myofiber degeneration. Vital staining with Evans blue dye revealed that muscle lacking gamma-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.
Hack
A A
AA
Department of Molecular Genetics and Cell Biology, Section of Cardiology, University of Chicago, Chicago, Illinois 60637, USA.
Ly
C T
CT
Jiang
F
F
Clendenin
C J
CJ
Sigrist
K S
KS
Wollmann
R L
RL
McNally
E M
EM
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D049030:Dystroglycans; D016189:Dystrophin / Q000378:metabolism*; D006651:Histocytochemistry; D007150:Immunohistochemistry; D007797:Laminin / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009124:Muscle Proteins / Q000502:physiology*; D018482:Muscle, Skeletal / Q000473:pathology; D009136:Muscular Dystrophies / Q000235:genetics; D009206:Myocardium / Q000473:pathology
D003598:Cytoskeletal Proteins; D016189:Dystrophin; D007797:Laminin; D008562:Membrane Glycoproteins; D009124:Muscle Proteins; D049030:Dystroglycans