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.
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.
F
F
Galbiati
D
D
Volonte
J B
JB
Chu
M
M
Li
S W
SW
Fine
M
M
Fu
J
J
Bermudez
M
M
Pedemonte
K M
KM
Weidenheim
R G
RG
Pestell
C
C
Minetti
M P
MP
Lisanti
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