Trends in Molecular Medicine
ReviewCaveolae and caveolin-3 in muscular dystrophy
Section snippets
Caveolin-3: a muscle-specific form of caveolin
Caveolin-3 is most closely related to caveolin-1. Based on protein sequence homology, caveolin-3 and caveolin-1 are ∼65% identical and 85% similar 5. Identification of a muscle-specific member of the caveolin gene family has implications for understanding the role of caveolins in different muscle cell types (smooth, cardiac and skeletal), because morphological studies have already demonstrated that caveolae are abundant in these cells.
Caveolin-1 and -3 form ∼350 kDa homo-oligomers containing
Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is one of the most severe muscle disorders, caused by a deficiency of dystrophin, the protein product of the DMD gene. Several morphological and biochemical observations seemingly implicate caveolae and caveolin-3 in the pathogenesis of DMD. Studies using electron microscopy and freeze-fracture techniques have shown that there is an increased number of caveolae in the skeletal muscle of DMD patients, but not in the other forms of muscular dystrophy examined 32.
Transgenic overexpression of wild-type caveolin-3
As discussed above, increased levels of caveolin-3 protein expression have been reported in DMD patients and in mdx mice, suggesting a possible involvement of caveolin-3 in the pathogenesis of Duchenne muscular dystrophy. To examine if caveolin-3 upregulation might represent an important step in the pathogenesis of DMD, Galbiati et al. 47 generated a transgenic mouse model that overexpresses the wild-type caveolin-3. Overproduction of wild-type caveolin-3 in skeletal muscle fibers was
Implications for human cancers
Several laboratories have previously suggested that the caveolin-1 gene functions as a novel tumor suppressor 51. In support of this observation, Hayashiet al. 52 have recently identified a common sporadic mutation in caveolin-1 in human breast cancers. Interestingly, this mutation is analogous to one of the inherited mutations previously identified in human caveolin-3 (Pro104Leu) in LGMD-1C patients 38. More specifically, the same invariant proline residue in caveolin-1 is mutated to leucine
Conclusion and perspectives
In the past three to five years, it has become clear how caveolae and caveolin-3 act as key elements in skeletal muscle functioning, and how alterations in caveolin-3 protein expression are responsible for muscle damage. Although caveolin-3 has been associated with different forms of muscular dystrophy, further studies are necessary to elucidate the signaling pathways and the signaling molecules that are affected by abnormal levels of caveolin-3 protein expression. Generation of primary
Acknowledgements
This work was supported by grants from the NIH, the Muscular Dystrophy Association (MDA), the American Heart Association (AHA), and the Susan B. Komen Breast Cancer Foundation (to M.P.L.). B.R. is supported by a National Institutes of Health Medical Scientist Training Grant (T32-GM07288). M.P.L. is the recipient of a Hirschl/Weil-Caulier Career Scientist Award. F.G. is the recipient of a Scientist Development Grant (SDG) from the American Heart Association (AHA).
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