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Results for “Caveolin 3”

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PubMed2005

Rippling muscle disease may be caused by "silent" action potentials in the tubular system of skeletal muscle fibers.

Rippling muscle disease (RMD) is a generally benign, myotonic-like myopathy associated with rapid rolling contractions and percussion-induced contractions. These contractions are electrically silent in electromyographic recordings, which is taken as evidence that action potentials are not involved in the phenomena. The pathophysiological mechanisms underlying the symptoms have not been elucidated. Many cases of RMD are caused by mutations in caveolin-3, and aberrations in the tubular system are commonly observed. Here, recent data are discussed showing that action potentials can travel over substantial distances entirely within the transverse and longitudinal tubular systems of a muscle fiber and that stretch can induce such action potentials. Action potentials travelling in the tubular system in most circumstances probably cannot excite the sarcolemma and hence would not be detected. It is suggested that the distinctive contractions in RMD may be due to stretch-induced generation of action potentials within the tubular system.

Action Potentials↗

PubMed2005

Late-onset distal myopathy with rimmed vacuoles without mutation in the GNE or dysferlin genes.

We report two brothers from a Japanese family with a late-onset distal myopathy characterized by rimmed vacuoles and dysferlin deficiency with no inflammatory infiltration and dystrophic changes in muscle biopsy. Mutations in the GNE, dysferlin, caveolin 3, emerin, and lamin A/C genes were excluded. We speculate that dysferlin is involved in the pathogenesis of the myopathy in these patients, which may represent a new disease entity presenting as a distal myopathy.

Adult↗

PubMed1997

Mouse adhalin: primary structure and expression during late stages of muscle differentiation in vitro.

Adhalin, or alpha-sarcoglycan, is a 50-kDa glycoprotein that was originally characterized as a muscle membrane protein. The importance of adhalin is suggested by the diseases associated with its absence, notably the limb-girdle muscular dystrophies. However, the function of adhalin is unknown. To analyze the biological roles of adhalin, we cloned the mouse adhalin cDNA, raised peptide-specific antibodies to its cytoplasmic domain, and examined its expression and localization in vivo and in vitro. The mouse adhalin sequence was 80% identical to that of human, rabbit, and hamster. Adhalin was specifically expressed in striated muscle cells and their immediate precursors, and absent in many other cell types. Adhalin expression in embryonic mouse muscle was coincident with primary myogenesis. Its expression was found to be up-regulated at mRNA and protein levels during myogenic differentiation in vitro. The proper localization of adhalin to the muscle cell membrane was observed only in late stages of myotube maturation, coincident with the re-distribution of caveolin-3 and dystrophin. These data suggest that adhalin is highly specific for striated muscle and that it is linked with the formation of a fully functional muscle fiber.

Amino Acid Sequence↗

PubMed1999

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

Caveolae are small pockets or invaginations localized at the plasma membrane. Caveolins are the principal protein components of caveolae and play an important structural role in the formation of caveolae membranes. Here, we studied by freeze fracture and immunological techniques the spatial organization of caveolae at the muscle cell plasma membrane and the expression of caveolin-3 in Duchenne muscular dystrophy (DMD) muscle fibers. In DMD muscle, we found an increased number of caveolae at the sarcolemma that corresponds to an overexpression of caveolin-3 by immunohistochemistry and by Western blot analysis. These findings suggest a possible role for caveolae and caveolin-3 in the pathogenesis of DMD.

Adolescent↗

PubMed1999

Caveolin-3 is associated with the T-tubules of mature skeletal muscle fibers.

Caveolae are abundant in skeletal muscle and their coat contains a specific isoform of caveolin, caveolin-3. It has been suggested that during muscle development, caveolin-3 is associated with the T-tubules, but that in adult muscle it is found on the plasma membrane only. We have studied the distribution of caveolin-3 in single skeletal muscle fibers from adult rat soleus by confocal immunofluorescence and by immunogold electron microscopy. We found that caveolin-3 occurs at the highest density on the plasma membrane but is also present in the core of the fibers, at the I-band/A-band interface where it is associated with the T-tubules. In neither domain of the muscle surface does caveolin-3 colocalize with the glucose transporter GLUT4 and there is no evidence for internalization of the caveolae in muscle.

Animals↗

PubMed2001

Protein targeting to the plasma membrane of adult skeletal muscle fiber: an organized mosaic of functional domains.

The plasma membrane of differentiated skeletal muscle fibers comprises the sarcolemma, the transverse (T) tubule network, and the neuromuscular and muscle-tendon junctions. We analyzed the organization of these domains in relation to defined surface markers, beta-dystroglycan, dystrophin, and caveolin-3. These markers were shown to exhibit highly organized arrays along the length of the fiber. Caveolin-3 and beta-dystroglycan/dystrophin showed distinct, but to some extent overlapping, labeling patterns and both markers left transverse tubule openings clear. This labeling pattern revealed microdomains over the entire plasma membrane with the exception of the neuromuscular and muscle-tendon junctions which formed distinct demarcated macrodomains. Our results suggest that the entire plasma membrane of mature muscle comprises a mosaic of T tubule domains together with sareolemmal caveolae and beta-dystroglycan domains. The domains identified with these markers were examined with respect to targeting of viral proteins and other expresseddomain-specific markers. We found that each marker protein was targeted to distinct microdomains. The macrodomains were intensely labeled with all our markers. Replacing the cytoplasmic tail of the vesicular stomatitis virus glycoprotein with that of CD4 resulted in retargeting from one domain to another. The domain-specific protein distribution at the muscle cell surface may be generated by targeting pathways requiring specific sorting information but this trafficking is different from the conventional apical-basolateral division.

Animals↗

PubMed2003

Variable reduction of caveolin-3 in patients with LGMD2B/MM.

Mutations in the human dysferlin gene ( DYSF) cause autosomal recessive muscular dystrophies characterized by degeneration and weakness of proximal and/or distal muscles: limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). Recently, an interaction between caveolin-3 and dysferlin in normal and dystrophic muscle (primary caveolin-3 deficiency; LGMD1C) was shown. In this study, clinical,morphological and genetic analysis was carried out in four independent LGMD2B/MM patients. All patients presented with an adult-onset, slowly progressive muscular dystrophy with variable involvement of proximal and distal muscles. We found complete lack of dysferlin in the four LGMD2B/MM patients. Secondary reduction of caveolin-3 was detected in three out of the four patients. Regular caveolae were detected along the basal lamina in two patients by electron microscopy. We provide further evidence that dysferlin and caveolin-3 interact in human skeletal muscle. It remains to be elucidated whether the loss of this interaction contributes to pathogenic events in muscular dystrophy.

Adult↗

PubMed2005

Colocalization between caveolin isoforms in the intestinal smooth muscle and interstitial cells of Cajal of the Cav1(+/+) and Cav1 (-/-) mouse.

Confocal microscopic images were obtained from the immunohistochemical sections of jejeunum to determine the localization/colocalization between caveolin-1, caveolin-2 and caveolin-3 in intestinal smooth muscle cells (SMCs) and interstitial cells of Cajal (ICC) of Cav1(+/+) and Cav1(-/-) mouse. Intestinal regions were segmented [inner circular muscle (icm), outer circular muscle (ocm), myenteric plexus region (mp), and longitudinal muscle (lm)] by LSM 5 and analyzed by ImageJ to show Pearson's correlation (r (p)) and overlap coefficient (r) of colocalization. In the intestine of Cav1(+/+), caveolin-1 (cav1) was colocalized with caveolin-2 (cav2) and caveolin-3 (cav3). Cav2 also was well colocalized with cav3. In the intestine of Cav1(-/-), cav1 and cav2 were absent in all images, but reduced cav3 was expressed in ocm. Caveolae were present in cell types with cav1 in Cav1(+/+), and present with cav3 in ocm of Cav1(-/-). C-kit occurred in deep muscular plexus (ICC-DMP) and myenteric plexus (ICC-MP), in both Cav1(+/+) and Cav1(-/-), and colocalized with cav1 and cav2 in the intestine of Cav1(+/+). Cav3 was absent/present at low immunoreactivity in ICC-DMP and ICC-MP of the intestines of Cav1(+/+) and Cav1(-/-). To conclude, cav1 is necessary for the expression of cav2 in SMC and ICC of intestine and facilitates, but is not necessary for the expression of cav3.

Animals↗

PubMed2000

Characterization of caveolins from human knee joint catilage: expression of caveolin-1, -2, and -3 in chondrocytes and association with integrin beta1.

Interactions between the extracellular matrix (ECM) and chondrocytes are of great importance for structure and function of cartilage. The present study was undertaken to answer the question whether caveolins take part in integrin-mediated cell-ECM interactions in the human cartilage. In samples of human knee joint cartilage, we detected the caveolin subtypes -1, -2, and -3 by immunohistochemical methods. Double-label experiments revealed a colocalization of caveolin with beta1-integrin. Results of immunoprecipitation and immunoblotting assays show that beta1-integrins associate with all three caveolin subtypes in human chondrocytes and indicate that they are part of the same complexes. Furthermore, immunoelectron microscopy shows the localization of beta1-integrin in caveolae-like structures of the cell membrane. The data stimulate further investigations on the role of the caveolin-integrin complex for integrin-mediated signaling pathways in chondrocytes.

Cartilage↗

PubMed1995

M-caveolin, a muscle-specific caveolin-related protein.

Caveolae, small invaginations of the plasma membrane, are a characteristic feature of many mammalian cells. The best-characterised caveolar protein is the integral membrane protein, VIP21-caveolin. We now describe a novel homologue of VIP21-caveolin, M-caveolin, which is expressed exclusively in muscle. M-caveolin was shown to be expressed in differentiated myotubes but not myoblasts. Epitope-tagged M-caveolin expressed in non-muscle cells was targetted to surface caveolae where it colocalized with endogenous VIP21-caveolin. M-caveolin may play a specialised role in the caveolae of muscle cells.

Amino Acid Sequence↗

PubMed1996

M-caveolin, a muscle-specific caveolin-related protein.

Amino Acid Sequence↗

PubMed2004

Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are caused by mutations in 14 and 15 different disease genes, respectively, in a part of the patients and the disease genes for cardiomyopathy overlap in part with that for limb-girdle muscular dystrophy (LGMD). In this study, we examined an LGMD gene encoding caveolin-3 (CAV3) for mutation in the patients with HCM or DCM. A Thr63Ser mutation was identified in a sibling case of HCM. Because the mutation was found at the residue that is involved in the LGMD-causing mutations, we investigate the functional change due to the Thr63Ser mutation as compared with the LGMD mutations by examining the distribution of GFP-tagged CAV3 proteins. It was observed that the Thr63Ser mutation reduced the cell surface expression of caveolin-3, albeit the change was mild as compared with the LGMD mutations. These observations suggest that HCM is a clinical spectrum of CAV3 mutations.

Amino Acid Sequence↗

PubMed2004

Junctophilin type 2 is associated with caveolin-3 and is down-regulated in the hypertrophic and dilated cardiomyopathies.

Functional coupling between the sarcolemmal membrane and the sarcoplasmic reticulum is based on distinct structures called junctional membrane complexes (JMCs). Recently, junctophilins are found to be responsible for normal formation of JMCs. In the present study, we found that junctophilin type 2 (JP-2), a unique isoform in the heart, was localized in caveolin-rich membranes, and that the expression of JP-2 was up-regulated during normal development and down-regulated in a hypertrophic or a dilated cardiomyopathic mouse model. The expression levels of JP-2 may be associated with the development of T-tubules and impaired Ca(2+)-induced Ca(2+) release in the heart.

Animals↗

PubMed2004

Effects of alpha1-adrenergic stimulation on normal and hypertrophied mouse hearts. Relation to caveolin-3 expression.

BACKGROUND: Modulation of the transduction efficiency through G-protein coupled receptors, caused by external stimulation, is essential in designing antihypertrophic treatment strategies in the dysfunctional heart. We compared protein-kinase C (PKC)-dependent regulation of positive inotropic effect via alpha1-adrenoreceptor (ADR)/Gq protein in hyperdynamic versus hypertrophied myocardium. METHODS: Inotropic (work performing isolated heart) and cellular effects of alpha1-adrenoreceptor stimulation were studied in nontransgenic (Ntg) and transgenic (Tg) mice with cardiac specific overexpression of L-type voltage-dependent calcium channels (L-type VDCC). RESULTS: Transgenic hyperdynamic and hypertrophic myocardium (due to overexpression of the L-type VDCC alpha1 subunit) were characterized by a lack of positive inotropic effect (PIE) to alpha1-ADR stimulation with phenylephrine (PE), as compared to a positive response in Ntg hearts. This was partially restored by PKC inhibition with chelerythrine and staurosporine only at the hyperdynamic stage. The inability of PKC inhibition to increase positive inotropy was associated with markedly decreased cardiac-specific caveolin-3 expression, and no changes in Galphaq, PLC-beta1, caveolin-1 and alpha1-adrenoreceptor expression. CONCLUSION: In the hyperdynamic myocardium, PKC activation may be one of the switches responsible for an impaired alpha1-adrenergic positive inotropic response. In the hypertrophied myocardium, the interruption of the transduction from Galphaq-protein coupled receptors to downstream effectors may be due to the down-regulation of caveolin-3 expression.

Action Potentials↗

PubMed2004

Lung remodeling and pulmonary hypertension after myocardial infarction: pathogenic role of reduced caveolin expression.

OBJECTIVES: Pulmonary hypertension (PH) and lung structural remodeling are frequent complications of congestive heart failure (CHF). Yet, the molecular mechanisms involved in CHF-induced PH and lung remodeling remain unknown. Caveolins (Cav-1, -2 and -3) are the principal structural proteins of the vesicular invaginations of the plasma membrane, termed caveolae. Mice with homozygous deletion of the caveolin-1 gene (Cav-1(-/-)) have been shown to develop dilated cardiomyopathy, PH and lung structural remodeling, characterized by hypercellularity and thickening of the alveolar septa. However, the physiological relevance of these observations for the pathogenesis of PH and lung remodeling remains to be determined. METHODS AND RESULTS: Here, we investigate the natural behavior of the endogenous caveolin proteins during the development of PH and lung structural remodeling, using a rat model of myocardial infarction (MI). MI was induced in male Wistar rats by ligating the left anterior coronary artery. Two weeks post-MI, rats were anesthetized and hemodynamic and morphometric measurements were obtained. Rats subjected to MI developed marked PH, lung structural remodeling and right ventricular hypertrophy (RVH). Both immunoblot analysis and immunohistochemistry dramatically show that Cav-1 and Cav-2 expression is downregulated to almost undetectable levels in the lungs of post-MI rats. Mechanistically, the reduced expression of caveolins was associated with the increased tyrosine-phosphorylation of the signal transducer and activator of transcription-3 (STAT3) and the upregulation of cyclin D1 and D3 expression. We also show that STAT3 is hyperphosphorylated, and cyclin D1 and D3 levels are dramatically upregulated, in lung tissue samples derived from Cav-1 (-/-)- and Cav-2 (-/-)-deficient mice. CONCLUSIONS: Thus, down-modulation of pulmonary Cav-1 and Cav-2 expression in rats subjected to MI may represent an initiating mechanism leading to the activation of the STAT3/Cyclins pathway and, ultimately, to the development of PH and lung structural remodeling.

Animals↗

PubMed2005

Expression of caveolin-1, -2, and -3 in the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis.

The expression of caveolin-1, -2, and -3 in the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis (EAE) was analyzed. Western blot analysis showed that three isotypes of caveolins including caveolin-1, -2 and -3 increased significantly in the spinal cords of rats during the early stage of EAE, as compared with the levels in control animals (p<0.05); the elevated level of each caveolin persisted during the peak and recovery stage of EAE. Immunohistochemistry demonstrated that caveolin-1 and -2 were expressed constitutively in the vascular endothelial cells and ependymal cells of the normal rat spinal cord, whereas caveolin-3 was almost exclusively localized in astrocytes. In EAE lesions, the immunoreactivity of caveolin-1 was increased in the ependymal cells, some astrocytes, and some inflammatory cells of the spinal cord, while that of caveolin-2 showed an intense immunoreactivity. Caveolin-3 was expressed constitutively in some astrocytes, but not in endothelial cells; its immunoreactivity was increased in reactive astrocytes in EAE lesions. The results of the Western blot analysis largely confirmed the observations obtained with immunohistochemistry. Taking all the findings into consideration, we postulate that the expression levels of each caveolin begin to increase when EAE is initiated, possibly contributing to the modulation of signal transduction pathways in the affected cells.

Animals↗

PubMed2004

A novel mutation in the caveolin-3 gene causing familial isolated hyperCKaemia.

Three members of a family were known to have persistent elevated serum CK levels without muscle weakness. A muscle biopsy showed a partial reduction of caveolin-3 at the sarcolemma of muscle fibres, which was confirmed by Western blot analysis. Mutational analysis identified a novel heterozygous mutation: G-->A transition at nucleotide position 169 in exon 2 in the CAV-3 gene, generating a Val-->Met change at codon 57 of the aminoacid chain. This is the second mutation in the CAV-3 gene associated with familial isolated hyperCKaemia.

Adolescent↗

PubMed2004

Two novel CAV3 gene mutations in Japanese families.

Caveolin-3 deficiency is a rare, autosomal dominant, muscle disorder caused by caveolin-3 gene (CAV3) mutations and consists of four clinical phenotypes: limb-girdle muscular dystrophy type 1C (LGMD-1C), rippling muscle disease, distal myopathy, and familial hyperCKemia. So far, only 13 mutations have been reported. We here report two novel heterozygous mutations, 96C>G (N32K) and 128T>A (V43E), in the CAV3 gene in two unrelated Japanese families with LGMD-1C. Both probands presented with elevated serum CK level with calf muscle hypertrophy in their childhood but without apparent muscle weakness. However, their mothers showed mild limb-girdle weakness in addition to high CK level. Caveolin-3 was deficient and caveolae were lacking in muscles from both patients. Our data confirm that caveolin-3 deficiency causes LGMD-1C and expand the variability in CAV3 gene mutations.

Adult↗