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.

[1]  M. Davisson,et al.  Motor dysfunction in a mouse model for Down syndrome , 1999, Physiology & Behavior.

[2]  J. Engelman,et al.  Caveolins, Liquid-Ordered Domains, and Signal Transduction , 1999, Molecular and Cellular Biology.

[3]  F. Sotgia,et al.  Increased number of caveolae and caveolin-3 overexpression in Duchenne muscular dystrophy. , 1999, Biochemical and biophysical research communications.

[4]  J. Engelman,et al.  Molecular genetics of the caveolin gene family: implications for human cancers, diabetes, Alzheimer disease, and muscular dystrophy. , 1998, American journal of human genetics.

[5]  J. Engelman,et al.  Mutational analysis of caveolin‐induced vesicle formation , 1998, FEBS letters.

[6]  Wenrong Wu,et al.  Increased caveolin‐3 levels in mdx mouse muscles , 1998, FEBS letters.

[7]  J. Engelman,et al.  Chromosomal localization, genomic organization, and developmental expression of the murine caveolin gene family (Cav‐1, ‐2, and ‐3) , 1998, FEBS letters.

[8]  K. Campbell,et al.  Caveolin‐3 is not an integral component of the dystrophin glycoprotein complex , 1998, FEBS letters.

[9]  L. Kunkel,et al.  Caveolin-3 in muscular dystrophy. , 1998, Human molecular genetics.

[10]  F. Zara,et al.  Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy , 1998, Nature Genetics.

[11]  M. Lisanti,et al.  Caveolins, a Family of Scaffolding Proteins for Organizing “Preassembled Signaling Complexes” at the Plasma Membrane* , 1998, The Journal of Biological Chemistry.

[12]  E. V. van Donselaar,et al.  Cell-type and Tissue-specific Expression of Caveolin-2 , 1997, The Journal of Biological Chemistry.

[13]  Charles C. Wykoff,et al.  Recombinant Expression of Caveolin-1 in Oncogenically Transformed Cells Abrogates Anchorage-independent Growth* , 1997, The Journal of Biological Chemistry.

[14]  M. Lisanti,et al.  Molecular and cellular biology of caveolae paradoxes and plasticities. , 1997, Trends in cardiovascular medicine.

[15]  M. Lisanti,et al.  Src tyrosine kinases, Galpha subunits, and H-Ras share a common membrane-anchored scaffolding protein, caveolin. Caveolin binding negatively regulates the auto-activation of Src tyrosine kinases. , 1996, The Journal of biological chemistry.

[16]  R. Parton,et al.  Caveolae and caveolins. , 1996, Current opinion in cell biology.

[17]  Francis Collins,et al.  Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia , 1996, Cell.

[18]  G. Garcı́a-Cardeña,et al.  Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Lisanti,et al.  Expression of Caveolin-3 in Skeletal, Cardiac, and Smooth Muscle Cells , 1996, The Journal of Biological Chemistry.

[20]  M. Lisanti,et al.  Co-purification and Direct Interaction of Ras with Caveolin, an Integral Membrane Protein of Caveolae Microdomains , 1996, The Journal of Biological Chemistry.

[21]  Richard G. W. Anderson,et al.  Acylation Targets Endothelial Nitric-oxide Synthase to Plasmalemmal Caveolae (*) , 1996, The Journal of Biological Chemistry.

[22]  H. Lodish,et al.  Molecular Cloning of Caveolin-3, a Novel Member of the Caveolin Gene Family Expressed Predominantly in Muscle (*) , 1996, The Journal of Biological Chemistry.

[23]  H. Lodish,et al.  Identification, sequence, and expression of caveolin-2 defines a caveolin gene family. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[24]  M. Lisanti,et al.  Expression and Characterization of Recombinant Caveolin , 1996, The Journal of Biological Chemistry.

[25]  M. Masserini,et al.  A photo‐reactive derivative of ganglioside GM1 specifically cross‐links VIP21‐caveolin on the cell surface , 1995, FEBS letters.

[26]  F. Wieland,et al.  VIP21/caveolin is a cholesterol-binding protein. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Lisanti,et al.  Oligomeric structure of caveolin: implications for caveolae membrane organization. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Lisanti,et al.  Evidence for a Regulated Interaction between Heterotrimeric G Proteins and Caveolin , 1995, The Journal of Biological Chemistry.

[29]  D. Baltimore,et al.  Reduction of caveolin and caveolae in oncogenically transformed cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[30]  T. Downie.  Advanced Laboratory Methods in Histology and Pathology , 1995 .

[31]  H. Lodish,et al.  Induction of caveolin during adipogenesis and association of GLUT4 with caveolin-rich vesicles , 1994, The Journal of cell biology.

[32]  M. Lisanti,et al.  Caveolae, caveolin and caveolin-rich membrane domains: a signalling hypothesis. , 1994, Trends in cell biology.

[33]  R. F. Cook,et al.  Characterization of caveolin-rich membrane domains isolated from an endothelial-rich source: implications for human disease , 1994, The Journal of cell biology.

[34]  M. Lisanti,et al.  Signal transducing molecules and glycosyl-phosphatidylinositol-linked proteins form a caveolin-rich insoluble complex in MDCK cells , 1993, The Journal of cell biology.

[35]  J. Small,et al.  Complementary distributions of vinculin and dystrophin define two distinct sarcolemma domains in smooth muscle , 1993, The Journal of cell biology.

[36]  V. Dubowitz,et al.  Experimental regeneration in canine muscular dystrophy—1. Immunocytochemical evaluation of dystrophin and β-spectrin expression , 1992, Neuromuscular Disorders.

[37]  J. Glenney.  The sequence of human caveolin reveals identity with VIP21, a component of transport vesicles , 1992, FEBS letters.

[38]  D. Soppet,et al.  Sequence and expression of caveolin, a protein component of caveolae plasma membrane domains phosphorylated on tyrosine in Rous sarcoma virus-transformed fibroblasts. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[39]  P. Dupree,et al.  VIP21, a 21-kD membrane protein is an integral component of trans-Golgi- network-derived transport vesicles , 1992, The Journal of cell biology.

[40]  Richard G. W. Anderson,et al.  Caveolin, a protein component of caveolae membrane coats , 1992, Cell.

[41]  Yamamura Ken-ichi,et al.  Efficient selection for high-expression transfectants with a novel eukaryotic vector , 1991 .

[42]  H. Niwa,et al.  Efficient selection for high-expression transfectants with a novel eukaryotic vector. , 1991, Gene.

[43]  K. Campbell,et al.  Dystrophin-associated proteins are greatly reduced in skeletal muscle from mdx mice , 1991, The Journal of cell biology.

[44]  E. Bonilla,et al.  Dystrophin in electric organ of Torpedo californica homologous to that in human muscle. , 1989, The Journal of biological chemistry.

[45]  J. Glenney.  Tyrosine phosphorylation of a 22-kDa protein is correlated with transformation by Rous sarcoma virus. , 1989, The Journal of biological chemistry.

[46]  E A Barnard,et al.  The molecular basis of muscular dystrophy in the mdx mouse: a point mutation. , 1989, Science.

[47]  K. Moore,et al.  X chromosome-linked muscular dystrophy (mdx) in the mouse. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[48]  K. Fischbeck,et al.  Freeze-fracture studies of muscle caveolae in human muscular dystrophy. , 1981, The American journal of pathology.