Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin-glycoprotein complex, and t-tubule abnormalities.
Caveolin-3, a muscle-specific caveolin-related protein, is the principal structural protein of caveolae membrane domains in striated muscle cells. Recently, we identified a novel autosomal dominant form of limb-girdle muscular dystrophy (LGMD-1C) in humans that is due to mutations within the coding sequence of the human caveolin-3 gene (3p25). These LGMD-1C mutations lead to an approximately 95% reduction in caveolin-3 protein expression, i.e. a caveolin-3 deficiency. Here, we created a caveolin-3 null (CAV3 -/-) mouse model, using standard homologous recombination techniques, to mimic a caveolin-3 deficiency. We show that these mice lack caveolin-3 protein expression and sarcolemmal caveolae membranes. In addition, analysis of skeletal muscle tissue from these caveolin-3 null mice reveals: (i) mild myopathic changes; (ii) an exclusion of the dystrophin-glycoprotein complex from lipid raft domains; and (iii) abnormalities in the organization of the T-tubule system, with dilated and longitudinally oriented T-tubules. These results have clear mechanistic implications for understanding the pathogenesis of LGMD-1C at a molecular level.
Galbiati
F
F
Department of Molecular Pharmacology, Albert Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Engelman
J A
JA
Volonte
D
D
Zhang
X L
XL
Minetti
C
C
Li
M
M
Hou
H
H
Kneitz
B
B
Edelmann
W
W
Lisanti
M P
MP
D000818:Animals; D020746:Calcium Channels, L-Type / Q000032:analysis / Q000235:genetics; D051244:Caveolin 3; D022461:Caveolins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D016189:Dystrophin / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D021962:Membrane Microdomains / Q000473:pathology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000235:genetics; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000473:pathology; D009154:Mutation; D015183:Restriction Mapping; D019837:Ryanodine Receptor Calcium Release Channel / Q000032:analysis / Q000235:genetics
D020746:Calcium Channels, L-Type; C495548:Cav3 protein, mouse; D051244:Caveolin 3; D022461:Caveolins; D016189:Dystrophin; D006023:Glycoproteins; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel