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Unformatted text preview: Transgenic overexpression of caveolin-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype Ferruccio Galbiati* , Daniela Volonte * , Jeffrey B. Chu* , Maomi Li , Samson W. Fine , Maofu Fu , Jorge Bermudez , Marina Pedemonte i , Karen M. Weidenheim , Richard G. Pestell , Carlo Minetti i , and Michael P. Lisanti* ** Departments of *Molecular Pharmacology, Pathology, Developmental and Molecular Biology, and Neuropathology and Pathology, and The Albert Einstein Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461; and i Servizio Malattie Neuro-Muscolari, Universita ` di Genova, Istituto Gaslini, Largo Gaslini 5, 16147 Genova, Italy Communicated by Dominick P. Purpura, Albert Einstein College of Medicine, Bronx, New York, May 30, 2000 (received for review December 9, 1999) It recently was reported that Duchenne muscular dystrophy (DMD) patients and mdx mice have elevated levels of caveolin-3 expres- sion 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 caveo- lin-3- overexpressing transgenic mice reveals: ( i ) a dramatic in- crease in the number of sarcolemmal muscle cell caveolae; ( ii ) a preponderance of hypertrophic, necrotic, and immature y regener- ating skeletal muscle fibers with characteristic central nuclei; and ( iii ) down-regulation of dystrophin and b-dystroglycan protein expression. In addition, these mice show elevated serum creatine kinase levels, consistent with the myo-necrosis observed morpho- logically. The Duchenne-like phenotype of caveolin-3 transgenic mice will provide an important mouse model for understanding the pathogenesis of DMD in humans. C aveolae are 50- to 100-nm vesicular invaginations of the plasma membrane that participate in vesicular trafficking events and signal transduction processes (15). Caveolin, a 21- to 24-kDa integral membrane protein, is a principal component of caveolae membranes in vivo (610). Caveolin is only the first member of a new gene family; as a consequence, caveolin has been retermed caveolin-1 (11). The mammalian caveolin gene family consists of caveolins 1, 2, and 3 (3, 1113). Caveolins 1 and 2 are coexpressed and form a hetero-oligomeric complex (14) in many cell types, with particularly high levels in adipocytes, whereas expression of caveolin-3 is muscle-specific and found in both cardiac and skeletal muscle, as well as smooth muscle cells (15). It has been proposed that caveolin family members function as scaffolding proteins (16) to organize and concentrate specific lipids (cho- lesterol and glyco-sphingolipids; refs. 1719) and lipid-modified signaling molecules (Src-like kinases, H-Ras, eNOS, and G...
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This note was uploaded on 10/12/2010 for the course BC BC367 taught by Professor Millard during the Spring '10 term at Colby.
- Spring '10