Transgenic overexpression of caveolin-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype.
It recently was reported that Duchenne muscular dystrophy (DMD) patients and mdx mice have elevated levels of caveolin-3 expression in their skeletal muscle. However, it remains unknown whether increased caveolin-3 levels in DMD patients contribute to the pathogenesis of DMD. Here, using a genetic approach, we test this hypothesis directly by overexpressing wild-type caveolin-3 as a transgene in mice. Analysis of skeletal muscle tissue from caveolin-3- overexpressing transgenic mice reveals: (i) a dramatic increase in the number of sarcolemmal muscle cell caveolae; (ii) a preponderance of hypertrophic, necrotic, and immature/regenerating skeletal muscle fibers with characteristic central nuclei; and (iii) down-regulation of dystrophin and beta-dystroglycan protein expression. In addition, these mice show elevated serum creatine kinase levels, consistent with the myo-necrosis observed morphologically. The Duchenne-like phenotype of caveolin-3 transgenic mice will provide an important mouse model for understanding the pathogenesis of DMD in humans.
Galbiati
F
F
Departments of Molecular Pharmacology, Pathology, Developmental and Molecular Biology, and Neuropathology and Pathology, and The Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Volonte
D
D
Chu
J B
JB
Li
M
M
Fine
S W
SW
Fu
M
M
Bermudez
J
J
Pedemonte
M
M
Weidenheim
K M
KM
Pestell
R G
RG
Minetti
C
C
Lisanti
M P
MP
D000818:Animals; D051244:Caveolin 3; D022461:Caveolins; D002467:Cell Nucleus / Q000473:pathology; D003402:Creatine Kinase / Q000097:blood; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D049030:Dystroglycans; D016189:Dystrophin / Q000378:metabolism; D005260:Female; D006614:Hindlimb / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009336:Necrosis; D010641:Phenotype; D012399:Rotation; D012508:Sarcolemma / Q000473:pathology; D019076:Transgenes / Q000235:genetics
C495548:Cav3 protein, mouse; D051244:Caveolin 3; D022461:Caveolins; D003598:Cytoskeletal Proteins; D016189:Dystrophin; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D049030:Dystroglycans; D003402:Creatine Kinase