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MBC in Press, published online ahead of print August 7, 2003
Mol. Biol. Cell 10.1091/mbc.E03-03-0161

A more recent version of this article appeared on October 1, 2003
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Submitted on March 19, 2003
Revised on May 15, 2003
Accepted on June 10, 2003

Modulation of myoblast fusion by caveolin-3 in dystrophic skeletal muscle cells. Implications for Duchenne muscular dystrophy and Limb-girdle muscular dystrophy-1C

Daniela Volonte1, Aaron J. Peoples1, and Ferruccio Galbiati1*

1 Department of Pharmacology, University of Pittsburgh School of Medicine, Biomedical Science Tower (BST) E1356, Pittsburgh, PA 15261

* Corresponding author. E-mail address: feg5{at}pitt.edu.

Caveolae are vesicular invaginations of the plasma membrane. Caveolin-3 is the principal structural component of caveolae in skeletal muscle cells in vivo. We have recently generated caveolin-3 transgenic mice and demonstrated that overexpression of wild-type caveolin-3 in skeletal muscle fibers is sufficient to induce a Duchenne-like muscular dystrophy phenotype. In addition, we have shown that caveolin-3 null mice display mild muscle fiber degeneration and T-tubule system abnormalities. These data are consistent with the mild phenotype observed in Limb-girdle muscular dystrophy-1C (LGMD-1C) in humans, characterized by a ~95% reduction of caveolin-3 expression. Thus, caveolin-3 transgenic and null mice represent valid mouse models to study Duchenne muscular dystrophy (DMD) and LGMD-1C, respectively, in humans.

Here, we derived conditionally immortalized precursor skeletal muscle cells from caveolin-3 transgenic and null mice. We show that overexpression of caveolin-3 inhibits myoblast fusion to multinucleated myotubes, while lack of caveolin-3 enhances the fusion process. M-cadherin and microtubules have been proposed to mediate the fusion of myoblasts to myotubes. Interestingly, we show that M-cadherin is down-regulated in caveolin-3 transgenic cells and up-regulated in caveolin-3 null cells. For the first time, variations of M-cadherin expression have been linked to a muscular dystrophy phenotype. In addition, we demonstrate that microtubules are disorganized in caveolin-3 null myotubes, indicating the importance of the cytoskeleton network in mediating the phenotype observed in these cells. Taken together, these results propose caveolin-3 as a key player in myoblast fusion and suggest that defects of the fusion process may represent additional molecular mechanisms underlying the pathogenesis of DMD and LGMD-1C in humans.




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