Trends in Molecular Medicine
Volume 7, Issue 10, 1 October 2001, Pages 435-441
Journal home page for Trends in Molecular Medicine

Review
Caveolae and caveolin-3 in muscular dystrophy

https://doi.org/10.1016/S1471-4914(01)02105-0Get rights and content

Abstract

Caveolae are vesicular invaginations of the plasma membrane, and function as ‘message centers’ for regulating signal transduction events. Caveolin-3, a muscle-specific caveolin-related protein, is the principal structural protein of caveolar membrane domains in skeletal muscle and in the heart. Several mutations within the coding sequence of the human caveolin-3 gene (located at 3p25) have been identified. Mutations that lead to a loss of ∼95% of caveolin-3 protein expression are responsible for a novel autosomal dominant form of limb-girdle muscular dystrophy (LGMD-1C) in humans. By contrast, upregulation of the caveolin-3 protein is associated with Duchenne muscular dystrophy (DMD). Thus, tight regulation of caveolin-3 appears essential for maintaining normal muscle health and homeostasis.

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).

References (52)

  • K.S. Song

    Copurification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains. Detergent free purification of caveolae membranes

    J. Biol. Chem.

    (1996)
  • K.S. Song

    Expression of caveolin-3 in skeletal, cardiac, and smooth muscle cells. Caveolin-3 is a component of the sarcolemma and co-fractionates with dystrophin and dystrophin-associated glycoproteins

    J. Biol. Chem.

    (1996)
  • G. Garcia-Cardena

    Dissecting the interaction between nitric oxide synthase (NOS) and caveolin: functional significance of the NOS caveolin binding domain in vivo

    J. Biol. Chem.

    (1997)
  • V.J. Venema

    Interaction of neuronal nitric-oxide synthase with caveolin-3 in skeletal muscle. Identification of a novel caveolin scaffolding/inhibitory domain

    J. Biol. Chem.

    (1997)
  • M. Yamamoto

    Caveolin is an activator of insulin receptor signaling

    J. Biol. Chem.

    (1998)
  • P.E. Scherer et al.

    Association of phosphofructokinase-M with caveolin-3 in differentiated skeletal myotubes: dynamic regulation by extracellular glucose and intracellular metabolites

    J. Biol. Chem.

    (1997)
  • F. Sotgia

    Caveolin-3 directly interacts with the C-terminal tail of beta-dystroglycan. Identification of a central WW-like domain within caveolin family members

    J. Biol. Chem.

    (2000)
  • R.H. Crosbie

    Caveolin-3 is not an essential component of the dystrophin glycoprotein complex

    FEBS Lett.

    (1998)
  • F. Galbiati

    Targeted down-regulation of caveolin-3 is sufficient to inhibit myotube formation in differentiating C2C12 myoblasts

    J Biol. Chem.

    (1999)
  • P.L. Vaghy

    Increased caveolin-3 levels in mdx mouse muscles

    FEBS Lett.

    (1998)
  • S. Repetto

    Increased number of caveolae and caveolin-3 overexpression in Duchenne muscular dystrophy

    Biochem. Biophys. Res. Commun.

    (1999)
  • J.E. Brenman

    Nitric oxide synthase complexed with dystrophin and absent from skeletal muscle sarcolemma in Duchenne muscular dystrophy

    Cell

    (1995)
  • Z. Tang

    Identification, sequence, and expression of an invertebrate caveolin gene family from the nematode Caenorhabditis elegans: implications for the molecular evolution of mammalian caveolin genes

    J. Biol. Chem.

    (1997)
  • F. Galbiati

    Phenotypic behavior of caveolin-3 mutations that cause autosomal dominant limb girdle muscular dystrophy (LGMD-1C). Retention of LGMD-1C caveolin-3 mutants within the golgi complex

    J. Biol. Chem.

    (1999)
  • F. Galbiati

    Limb-girdle muscular dystrophy (LGMD-1C) mutants of caveolin-3 undergo ubiquitination and proteasomal degradation. Treatment with proteasomal inhibitors blocks the dominant negative effect of LGMD-1C mutants and rescues wild-type caveolin-3

    J. Biol. Chem.

    (2000)
  • F. Galbiati

    Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin-glycoprotein complex, and T-tubule abnormalities

    J. Biol. Chem.

    (2001)
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