Progressive muscular dystrophy in alpha-sarcoglycan-deficient mice.
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 epsilon-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.
Duclos
F
F
Howard Hughes Medical Institute, Department of Physiology and Biophysics and Department of Neurology, University of Iowa College of Medicine, Iowa City, Iowa 52242-1101, USA.
Straub
V
V
Moore
S A
SA
Venzke
D P
DP
Hrstka
R F
RF
Crosbie
R H
RH
Durbeej
M
M
Lebakken
C S
CS
Ettinger
A J
AJ
van der Meulen
J
J
Holt
K H
KH
Lim
L E
LE
Sanes
J R
JR
Davidson
B L
BL
Faulkner
J A
JA
Williamson
R
R
Campbell
K P
KP
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000235:genetics; D018076:DNA, Complementary; D018450:Disease Progression; D016189:Dystrophin / Q000378:metabolism; D018014:Gene Transfer Techniques; D006023:Glycoproteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009119:Muscle Contraction; D009137:Muscular Dystrophy, Animal / Q000209:etiology* / Q000503:physiopathology; D009363:Neoplasm Proteins; D049031:Sarcoglycans; D012508:Sarcolemma / Q000378:metabolism
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D016189:Dystrophin; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D049031:Sarcoglycans; C491632:Sspn protein, mouse