Increased caveolin‐3 levels in mdx mouse muscles

Vághy, Pál L.; Jin, Fang; Wu, Wei; Vaghy, Laszlo P.

doi:10.1016/s0014-5793(98)00738-8

Cited by 74 publications

(61 citation statements)

References 24 publications

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“…Several lines of evidence have demonstrated the importance of muscle cell caveolae in the pathogenesis of DMD. 12,13,38 Over two decades ago, freeze-fracture studies have demonstrated that skeletal muscle caveolae undergo particular changes in their size and distribution in patients with DMD. More recent reports have confirmed that skeletal muscle biopsies from DMD patients show an increased number of caveolae, and overexpression of the Cav-3 protein product.…”

Section: Discussionmentioning

confidence: 99%

“…13 In addition, Cav-3 expression was shown to be elevated by ϳ2-fold in skeletal muscle samples from mdx mice. 12 Conversely, transgenic over-expression of Cav-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype, and causes the down-regulation of dystrophin and of dystrophin-associated proteins. 39 Taken together, these results suggest that a particular ratio between Cav-3 and dystrophin may be crucial for the proper functioning of skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that Cav-3 expression levels are increased by ϳ 2-fold in skeletal muscle fibers from mdx mice, 12 as well in skeletal muscle fibers from DMD patients. 13 Figure 7B reveals that Cav-3 expression levels are decreased in skeletal muscle extracts from MG-132-treated mdx mice, as compared with the untreated (PBS only) counterparts.…”

Section: Systemic Treatment With Mg-132mentioning

confidence: 92%

“…11 The only exception is Cav-3, which was shown to be up-regulated by ϳ2-fold in dystrophin-deficient skeletal muscle. 12,13 A lack of dystrophin is thought to cause sarcolemmal instability, which may render the dystrophin-glycoprotein complex more susceptible to proteolytic degradation. 14 Similarly to other tissues, skeletal muscle has at least three different pathways for protein degradation: 1) proteolysis by lysosomal proteases, such as the cathepsins, 2) proteolysis by non-lysosomal Ca2ϩ-dependent proteases, such as calpain, and 3) proteolysis by non-lysosomal ATP-ubiquitin-dependent proteases, eg, the multicatalytic protease complex (or proteasome).…”

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confidence: 99%

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Proteasome Inhibitor (MG-132) Treatment of mdx Mice Rescues the Expression and Membrane Localization of Dystrophin and Dystrophin-Associated Proteins

Bonuccelli

Sotgia

Schubert

et al. 2003

The American Journal of Pathology

116

110

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Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is absent in the skeletal muscle of DMD patients and mdx mice. At the plasma membrane of skeletal muscle fibers, dystrophin associates with a multimeric protein complex, termed the dystrophin-glycoprotein complex (DGC). Protein members of this complex are normally absent or greatly reduced in dystrophin-deficient skeletal muscle fibers, and are thought to undergo degradation through an unknown pathway. As such, we reasoned that inhibition of the proteasomal degradation pathway might rescue the expression and subcellular localization of dystrophin-associated proteins. To test this hypothesis, we treated mdx mice with the wellcharacterized proteasomal inhibitor MG-132. First, we locally injected MG-132 into the gastrocnemius muscle, and observed the outcome after 24 hours. Next, we performed systemic treatment using an osmotic pump that allowed us to deliver different concentrations of the proteasomal inhibitor, over an 8-day period. By immunofluorescence and Western blot analysis, we show that administration of the proteasomal inhibitor MG-132 effectively rescues the expression levels and plasma membrane localization of dystrophin, ␤-dystroglycan, ␣-dystroglycan, and ␣-sarcoglycan in skeletal muscle fibers from mdx mice. Furthermore, we show that systemic treatment with the proteasomal inhibitor 1) reduces muscle membrane damage, as revealed by vital staining (with Evans blue dye) of the diaphragm and gastrocnemius muscle isolated from treated mdx mice, and 2) ameliorates the histopathological signs of muscular dystrophy, as judged by hematoxylin and eosin staining of muscle biopsies taken from treated mdx mice. Duchenne muscular dystrophy (DMD) is one of the most prevalent and severe inherited diseases of childhood, characterized by progressive muscular wasting and weakness. The deficient gene product, dystrophin, 1 is a peripheral membrane protein of ϳ426 kd, which is expressed in muscle tissues and the brain. At the plasma membrane, dystrophin associates with a large multimeric complex, termed the dystrophin-glycoprotein complex (DGC). 2 The DGC is composed of two subcomplexes: the dystroglycan complex (␣ and ␤ subunits) and the sarcoglycan complex (␣, ␤, ␥, and ␦ subunits). The Nterminal region of dystrophin interacts directly with the cytoskeletal protein actin, while the dystrophin C-terminal domain binds to the plasma membrane through interactions with ␤-dystroglycan. As such, dystrophin is thought

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Systemic Treatment With Mg-132mentioning

confidence: 92%

mentioning

confidence: 99%

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Proteasome Inhibitor (MG-132) Treatment of mdx Mice Rescues the Expression and Membrane Localization of Dystrophin and Dystrophin-Associated Proteins

Bonuccelli

Sotgia

Schubert

et al. 2003

The American Journal of Pathology

116

110

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“…Previous studies have shown that interaction of caveolins with NOS enzymes is increased in disease states associated with impaired NOS activity such as Duchenne muscular dystrophy and hypercholesterolaemia [21,40]. Because direct binding of eNOS and nNOS on the scaffolding domains of caveolins inhibits enzymatic activity [30,41], it was of interest to test for possible alterations of eNOS and nNOS binding to skeletal muscle caveolins in diabetes.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of impaired nitric oxide synthase activity in skeletal muscle of streptozotocin-induced diabetic rats

2000

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Type I (insulin-dependent) diabetes mellitus is characterised by pronounced insulin resistance for glucose disposal in skeletal muscle [1,2]. This metabolic impairment is at least in part related to a post-insulin signalling defect in the expression and translocation of GLUT4 glucose transporters to the muscle cell surface [3±5]. The lack of insulin action on glucose metabolism in muscle of people with Type I diabetes could also be explained by an impaired vasodilatory effect of insulin on the muscle vasculature [2], although this impairment has not been confirmed in a more recent study [1]. Several studies have shown that endothelium-dependent relaxation is altered in Abstract Aims/hypothesis. The aims of our study were to investigate whether nitric oxide synthase (NOS) activity is impaired in skeletal muscle of insulin-deficient [Type I (insulin-dependent)] diabetic rats and if the case, to determine the mechanism of NOS dysregulation in this disorder. Methods. Rats were rendered diabetic by streptozotocin injection (65 mg/kg, i. v.) and NOS activity and expression in gastrocnemius muscles were studied 1, 2, 3 or 4 weeks after diabetes induction. Results. The diabetic state was associated with a progressive reduction (down to 42 % of control values after 4 weeks) in muscle NOS activity compared with control rats. Using reverse transcriptase-polymerase chain reaction, we could not detect statistically significant changes in the expression of either neuronal NOS (nNOS) or endothelial NOS (eNOS) mRNAs in diabetic muscle. The contents of nNOS and eNOS protein were, however, progressively reduced in muscle homogenates of diabetic rats and these alterations were prevented by insulin treatment. Subcellular fractionation of skeletal muscle showed that both nNOS and eNOS proteins are mainly localised to the plasma membrane with lower abundance in T-tubules and not detectable in sarcoplasmic reticulum-enriched fractions. After 1 week of diabetes, eNOS protein content was decreased only in the plasma membrane whereas nNOS protein abundance was not affected at this time. Neither the expression nor the interaction of caveolin-1 and caveolin-3 with NOS enzymes was found to be altered in muscle of diabetic rats. Conclusion/interpretation. These results show that skeletal muscle NOS activity is impaired during the progression of insulin-deficient diabetes and reduced NOS activity is associated with a decreased abundance of both nNOS and eNOS proteins, which appears to involve post-transcriptional mechanisms.

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Identification of the increased expression of monocyte chemoattractant protein-1, cathepsin S, UPIX-1, and other genes in dystrophin-deficient mouse muscles by suppression subtractive hybridization

2000

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The lack of dystrophin results in muscular dystrophy characterized by degeneration, inflammation, and partial regeneration of skeletal muscles. The fate of these muscles may be determined by the extent of adaptation to the defect and the efficiency of regeneration that is affected by inflammatory cells. We have used suppression subtractive hybridization and quantitative Northern blot analysis to identify differentially expressed genes. Increased expression of murine monocyte chemoattractant protein-1 (JE/MCP-1), cathepsin S, UPIX-1, nmb, cathepsin B, and lysozyme M mRNAs were identified in 2-month-old mdx mouse leg muscles. UPIX-1 is a novel gene. Although it was not expressed in control muscles, it was expressed in control brain, heart, and spleen. JE/MCP-1 and cathepsin S proteins in mdx muscles, as well as JE/MCP-1 protein in the serum of mdx mice were also detected. JE/MCP-1 may be responsible for attraction of inflammatory cells, and cathepsin S, a potent elastolytic protease, may contribute to the remodeling of the extracellular matrix that is required for the migration of these cells to the injured muscles.

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Increased caveolin‐3 levels in mdx mouse muscles

Cited by 74 publications

References 24 publications

Proteasome Inhibitor (MG-132) Treatment of mdx Mice Rescues the Expression and Membrane Localization of Dystrophin and Dystrophin-Associated Proteins

Proteasome Inhibitor (MG-132) Treatment of mdx Mice Rescues the Expression and Membrane Localization of Dystrophin and Dystrophin-Associated Proteins

Mechanism of impaired nitric oxide synthase activity in skeletal muscle of streptozotocin-induced diabetic rats

Identification of the increased expression of monocyte chemoattractant protein-1, cathepsin S, UPIX-1, and other genes in dystrophin-deficient mouse muscles by suppression subtractive hybridization

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