Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Caveolins are a crucial component of plasma membrane (PM) caveolae but have also been localized to intracellular compartments, including the Golgi complex and lipid bodies. Mutant caveolins associated with human disease show aberrant trafficking to the PM and Golgi accumulation. We now show that the Golgi pool of mainly newly synthesized protein is detergent-soluble and predominantly in a monomeric state, in contrast to the surface pool. Caveolin at the PM is not recognized by specific caveolin antibodies unless PM cholesterol is depleted. Exit from the Golgi complex of wild-type caveolin-1 or -3, but not vesicular stomatitis virus-G protein, is modulated by changing cellular cholesterol levels. In contrast, a muscular dystrophy-associated mutant of caveolin-3, Cav3P104L, showed increased accumulation in the Golgi complex upon cholesterol treatment. In addition, we demonstrate that in response to fatty acid treatment caveolin can follow a previously undescribed pathway from the PM to lipid bodies and can move from lipid bodies to the PM in response to removal of fatty acids. The results suggest that cholesterol is a rate-limiting component for caveolin trafficking. Changes in caveolin flux through the exocytic pathway can therefore be an indicator of cellular cholesterol and fatty acid levels.
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PMID:Cholesterol and fatty acids regulate dynamic caveolin trafficking through the Golgi complex and between the cell surface and lipid bodies. 1568 93

Caveolae are vesicular organelles (50-100-nm in diameter) that are particularly abundant in cells of the cardiovascular system, including endothelial cells, smooth muscle cells, macrophages, cardiac myocytes and fibroblasts. In these cell types, caveolae function both in protein trafficking and signal transduction, as well as in cholesterol homeostasis. Caveolins are the structural proteins that are both necessary and sufficient for the formation of caveolae membrane domains. Caveolins 1 and 2 are co-expressed in most cell types, while the expression of caveolin-3 is muscle-specific. Thus, endothelial cells and fibroblasts are rich in caveolins 1 and 2, while cardiac myocytes and skeletal muscle fibers express caveolin-3. In contrast, smooth muscle cells express all three caveolins (Cav-1, -2, and -3). Mechanistically, caveolins interact with a variety of downstream signaling molecules, including Src-family tyrosine kinases, p42/44 mitogen activated protein (MAP) kinase, and endothelial nitric oxide synthase (eNOS), and hold these signal transducers in the inactive conformation until activation by an appropriate stimulus. In many ways, caveolins serve both to compartmentalize and regulate signaling. Recent studies using caveolin-deficient mouse models dramatically show that caveolae and caveolins play a prominent role in various human patho-biological conditions, especially those related to the cardiovascular system. These disease phenotypes include: atherosclerosis, cardiac hypertrophy, cardiomyopathy, pulmonary hypertension, and neointimal hyperplasia (smooth muscle cell proliferation). In addition, caveolins play a significant role in other disease phenotypes, such as cancer, diabetes, bladder dysfunction, and muscular dystrophy, as we discuss in this review. Thus, caveolin-deficient mice will serve as important new animal models to dissect the intricate role of caveolae and caveolins in the pathogenesis of human diseases.
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PMID:The Caveolin genes: from cell biology to medicine. 1576 30

Dysferlin and Caveolin-3 are plasma membrane proteins associated with muscular dystrophy. Patients with mutations in the CAV3 gene show dysferlin mislocalization in muscle cells. By utilizing caveolin-null cells, expression of caveolin mutants, and different mutants of dysferlin, we have dissected the site of action of caveolin with respect to dysferlin trafficking pathways. We now show that Caveolin-1 or -3 can facilitate exit of a dysferlin mutant that accumulates in the Golgi complex of Cav1(-/-) cells. In contrast, wild type dysferlin reaches the plasma membrane but is rapidly endocytosed in Cav1(-/-) cells. We demonstrate that the primary effect of caveolin is to cause surface retention of dysferlin. Caveolin-1 or Caveolin-3, but not specific caveolin mutants, inhibit endocytosis of dysferlin through a clathrin-independent pathway colocalizing with internalized glycosylphosphatidylinositol-anchored proteins. Our results provide new insights into the role of this endocytic pathway in surface remodeling of specific surface components. In addition, they highlight a novel mechanism of action of caveolins relevant to the pathogenic mechanisms underlying caveolin-associated disease.
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PMID:Caveolin regulates endocytosis of the muscle repair protein, dysferlin. 1809 99

Caveolae are formed by the caveolin (CAV) family of proteins, CAV-1, -2, and -3. CAV-1 and -2 are co expressed in many cell types, whereas CAV-3 is muscle-specific and mutation of the CAV-3 gene causes muscular dystrophy. CAV-3 has also been detected in brain astroglial cells and in peripheral nerves along with CAV-1. Therefore, we sought to determine whether CAV-3 protein is expressed in developing peripheral nerves by using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). We found that CAV-3 immunoreactivities (IRs) were Localized in the myelin sheath during peripheral nerve development. CAV-3 IRs were intense during the early postnatal stage, but decreased as the peripheral nerves matured at postnatal weeks 3-5. CAV-3 mRNA expression was also markedly decreased during postnatal development. Because the expression pattern of CAV-3 IRs was opposite that of CAV-1 IRs. CAV-1 and -3 might be involved in different phases of peripheral nerve myelination and play complementary roles in myelin maturation and peripheral nerve development.
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PMID:Expression of caveolin-3 immunoreactivities in the developing sciatic nerve of the rat. 1872 May 74

Mutations in or ablation of the gene encoding caveolin-3, a protein of muscle cell caveolae, result in forms of muscular dystrophy and cardiomyopathy. Another member of the caveolin gene family, caveolin-1, is widely considered not to be expressed in myocytes, yet ablation of the gene encoding this protein in mice also results in cardiomyopathy. By applying the high-resolution electron-microscopical imaging technique of freeze-fracture replica immunolabelling, we report here evidence that caveolin-1 is expressed in human cardiac myocytes, localized to both caveolae and non-caveolar domains in the plasma membrane. Disorders of the myocyte resulting from defects in caveolin-1 may thus arise directly, at the level of the myocyte, rather than via other cell types as previously proposed.
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PMID:Freeze-fracture replica immunolabelling reveals caveolin-1 in the human cardiomyocyte plasma membrane. 1879 48

Here we review the clinical and translational implications of the caveolin gene family for understanding the pathogenesis of human diseases, including breast and prostate cancers, pulmonary hypertension, cardiomyopathy, diabetes, and muscular dystrophy. Detailed phenotypic analysis of caveolin knockout mice has served to highlight the crucial role of a caveolin deficiency in the pathogenesis of many human disease processes. Mutations in the human caveolin genes are associated with a number of established genetic disorders (such as breast cancer, lipodystrophy, muscular dystrophy, and cardiomyopathy), making the caveolins important and novel targets for drug development. The implementation of new strategies for caveolin replacement therapy-including caveolin mimetic peptides-is ongoing.
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PMID:Clinical and translational implications of the caveolin gene family: lessons from mouse models and human genetic disorders. 1933 35

Caveolae are invaginations of the plasma membrane involved in many cellular processes, including clathrin-independent endocytosis, cholesterol transport, and signal transduction. They are characterized by the presence of caveolin proteins. Mutations that cause deficiency in caveolin-3, which is expressed exclusively in skeletal and cardiac muscle, have been linked to muscular dystrophy. Polymerase I and transcript release factor (PTRF; also known as cavin) is a caveolar-associated protein suggested to play an essential role in the formation of caveolae and the stabilization of caveolins. Here, we identified PTRF mutations in 5 nonconsanguineous patients who presented with both generalized lipodystrophy and muscular dystrophy. Muscle hypertrophy, muscle mounding, mild metabolic complications, and elevated serum creatine kinase levels were observed in these patients. Skeletal muscle biopsies revealed chronic dystrophic changes, deficiency and mislocalization of all 3 caveolin family members, and reduction of caveolae structure. We generated expression constructs recapitulating the human mutations; upon overexpression in myoblasts, these mutations resulted in PTRF mislocalization and disrupted physical interaction with caveolins. Our data confirm that PTRF is essential for formation of caveolae and proper localization of caveolins in human cells and suggest that clinical features observed in the patients with PTRF mutations are associated with a secondary deficiency of caveolins.
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PMID:Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. 2044 52

Caveolae are specialized lipid rafts that form flask-shaped invaginations of the plasma membrane. They are involved in cell signalling and transport and have been shown critically regulate vascular reactivity and blood pressure. The organization and functions of caveolae are mediated by coat proteins (caveolins) and support or adapter proteins (cavins). The caveolins, caveolin-1, -2, and -3, form the structural backbone of caveolae. These proteins are also highly integrated into caveolae function and have their own activity independent of caveolae. The cavins, cavins 1-4, are involved in regulation of caveolae and modulate the function of caveolins by promoting the membrane remodelling and trafficking of caveolin-derived structures. The relationships between these different proteins are complex and intersect with many aspects of cell function. Caveolae have also been implicated in chronic inflammatory conditions and other pathologies including atherosclerosis, inflammatory bowel disease, muscular dystrophy, and generalized dyslipidaemia. The pathogenic role of the caveolins is an emerging area, however, the roles of cavins in disease is just beginning to be explored. This review will examine the relationship between caveolins and cavins and explore the role of caveolae in inflammatory signalling mechanisms.
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PMID:Caveolae, caveolins, and cavins: complex control of cellular signalling and inflammation. 2020 78

Members of the caveolin family are the main component of caveolae, and caveolin-3 is a muscle-specific protein. Caveolin-3 deficiency induces a muscular dystrophic phenotype, while its overexpression is also harmful to muscle cells. Increased caveolae were observed in chicken muscular dystrophy; however, the underlying mechanism causing the onset remains unclear. Therefore, the current study analyzes the expression of caveolin-3 and other caveola-related proteins in dystrophic chickens. Western blotting and semi-quantitative RT-PCR analysis revealed that (1) caveolin-3 is highly expressed in the damaged muscle of dystrophic chickens (7.12-fold); (2) the amount of caveolin-3 protein is regulated in posttranslational modification, since no significant increase is observed at the mRNA level (1.09-fold); and (3) the expression pattern of other caveola-related proteins is similar to that of caveolin-3. These results suggest that the accumulation of caveolin-3 protein may be associated with the causative process of chicken muscular dystrophy.
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PMID:Accumulation of caveolin-3 protein is limited in damaged muscle in chicken muscular dystrophy. 2045 48

Rapid repair of plasma membrane wounds is critical for cellular survival. Muscle fibers are particularly susceptible to injury, and defective sarcolemma resealing causes muscular dystrophy. Caveolae accumulate in dystrophic muscle fibers and caveolin and cavin mutations cause muscle pathology, but the underlying mechanism is unknown. Here we show that muscle fibers and other cell types repair membrane wounds by a mechanism involving Ca(2+)-triggered exocytosis of lysosomes, release of acid sphingomyelinase, and rapid lesion removal by caveolar endocytosis. Wounding or exposure to sphingomyelinase triggered endocytosis and intracellular accumulation of caveolar vesicles, which gradually merged into larger compartments. The pore-forming toxin SLO was directly visualized entering cells within caveolar vesicles, and depletion of caveolin inhibited plasma membrane resealing. Our findings directly link lesion removal by caveolar endocytosis to the maintenance of plasma membrane and muscle fiber integrity, providing a mechanistic explanation for the muscle pathology associated with mutations in caveolae proteins. DOI:http://dx.doi.org/10.7554/eLife.00926.001.
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PMID:Caveolae internalization repairs wounded cells and muscle fibers. 2405 12


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