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Michael P. Lisanti - One of the best experts on this subject based on the ideXlab platform.

  • Caveolinopathies: from the biology of Caveolin-3 to human diseases
    European Journal of Human Genetics, 2010
    Co-Authors: Elisabetta Gazzerro, Michael P. Lisanti, Federica Sotgia, Claudio Bruno, Carlo Minetti
    Abstract:

    In muscle tissue the protein Caveolin-3 forms caveolae – flask-shaped invaginations localized on the cytoplasmic surface of the sarcolemmal membrane. Caveolae have a key role in the maintenance of plasma membrane integrity and in the processes of vesicular trafficking and signal transduction. Mutations in the Caveolin-3 gene lead to skeletal muscle pathology through multiple pathogenetic mechanisms. Indeed, Caveolin-3 deficiency is associated to sarcolemmal membrane alterations, disorganization of skeletal muscle T-tubule network and disruption of distinct cell-signaling pathways. To date, there have been 30 Caveolin-3 mutations identified in the human population. Caveolin-3 defects lead to four distinct skeletal muscle disease phenotypes: limb girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. In addition, one Caveolin-3 mutant has been described in a case of hypertrophic cardiomyopathy. Many patients show an overlap of these symptoms and the same mutation can be linked to different clinical phenotypes. This variability can be related to additional genetic or environmental factors. This review will address Caveolin-3 biological functions in muscle cells and will describe the muscle and heart disease phenotypes associated with Caveolin-3 mutations.

  • Caveolinopathies: mutations in Caveolin-3 cause four distinct autosomal dominant muscle diseases.
    Neurology, 2004
    Co-Authors: Scott Eric Woodman, Ferruccio Galbiati, Federica Sotgia, Carlo Minetti, Michael P. Lisanti
    Abstract:

    The Caveolin-3 protein is expressed exclusively in muscle cells. Caveolin-3 expression is sufficient to form caveolae-sarcolemmal invaginations that are 50 to 100 nm in diameter. Monomers of Caveolin-3 oligomerize to form high molecular mass scaffolding on the cytoplasmic surface of the sarcolemmal membrane. A mutation in one Caveolin-3 allele produces an aberrant protein product capable of sequestering the normal Caveolin-3 protein in the Golgi apparatus of skeletal muscle cells. Improper Caveolin-3 oligomerization and membrane localization result in skeletal muscle T-tubule system derangement, sarcolemmal membrane alterations, and large subsarcolemmal vesicle formation. To date, there have been eight autosomal dominant Caveolin-3 mutations identified in the human population. Caveolin-3 mutations can result in four distinct, sometimes overlapping, muscle disease phenotypes: limb girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. Thus, the Caveolin-3 mutant genotype-to-phenotype relation represents a clear example of how genetic background can influence phenotypic outcome. This review examines in detail the reported cases of patients with Caveolin-3 mutations and their corresponding muscle disease phenotypes.

  • Transgenic overexpression of Caveolin-3 in the heart induces a cardiomyopathic phenotype
    Human molecular genetics, 2003
    Co-Authors: Bharathi Aravamudan, Daniela Volonte, Michael P. Lisanti, Ravi Ramani, Erdal Gursoy, Barry London, Ferruccio Galbiati
    Abstract:

    Caveolins are structural protein components of caveolar membrane domains. Caveolin-3, a muscle-specific member of the Caveolin family, is expressed in skeletal muscle tissue and in the heart. The multiple roles that Caveolin-3 plays in cellular physiology are becoming more apparent. We have shown that lack of Caveolin-3 expression in skeletal muscle resembles limb-girdle muscular dystrophy-1C. In contrast, we have demonstrated that overexpression of Caveolin-3 in skeletal muscle tissue promotes defects similar to those seen in Duchenne muscular dystrophy (DMD). Thus, a tight regulation of Caveolin-3 expression is fundamental for normal muscle functions. Since Caveolin-3 is also endogenously expressed in cardiac myocytes, and cardiomyopathies are observed in DMD patients, we looked at the effects of overexpression of Caveolin-3 on cardiac structure and function by characterizing Caveolin-3 transgenic mice. Our results indicate that overexpression of Caveolin-3 causes severe cardiac tissue degeneration, fibrosis and a reduction in cardiac functions. We also show that dystrophin and its associated glycoproteins are down-regulated in Caveolin-3 transgenic heart. In addition, we demonstrate that the activity of nitric oxide synthase (NOS) is down-regulated by high levels of Caveolin-3 in the heart. Taken together, these results indicate that overexpression of Caveolin-3 is sufficient to induce severe cardiomyopathy. In addition, these findings suggest that Caveolin-3 transgenic mice may represent a valid mouse model for studying the molecular mechanisms underlying cardiomyopathies associated with Duchenne muscular dystrophy.

  • Familial isolated hyperCKaemia associated with a new mutation in the Caveolin-3 (CAV-3) gene
    Journal of neurology neurosurgery and psychiatry, 2002
    Co-Authors: Luciano Merlini, Michael P. Lisanti, Federica Sotgia, Claudio Bruno, I. Carbone, Cristina Capanni, Patrizia Sabatelli, Silvia Tortorelli, Carlo Minetti
    Abstract:

    An 18 year old man and his mother both presented with persistent, isolated raised serum creatine kinase (hyperCKaemia) without muscle symptoms. Analysis of Caveolin-3 protein expression in muscle biopsy of the propositus showed a reduction in the protein. Genetic analysis revealed a new heterozygous mutation in the Caveolin-3 (CAV-3) gene: a C→T transition at nucleotide position 83 in exon 1 leading to a substitution of a proline for a leucine at amino acid position 28 (P28L). This is the first pathogenic mutation in the CAV-3 gene associated with isolated familial hyperCKaemia. It expands the genetic heterogeneity in patients with Caveolin-3 deficiency and confirms that Caveolin-3 deficiency should be considered in the differential diagnosis of isolated hyperCKaemia.

  • Caveolin-3 Null Mice Show a Loss of Caveolae, Changes in the Microdomain Distribution of the Dystrophin-Glycoprotein Complex, and T-tubule Abnormalities
    The Journal of biological chemistry, 2001
    Co-Authors: Ferruccio Galbiati, Daniela Volonte, Jeffrey A Engelman, Carlo Minetti, Xiao Lan Zhang, Harry Hou, Burkhard Kneitz, Winfried Edelmann, Michael P. Lisanti
    Abstract:

    Caveolin-3, a muscle-specific Caveolin-related protein, is the principal structural protein of caveolae membrane domains in striated muscle cells. Recently, we identified a novel autosomal dominant form of limb-girdle muscular dystrophy (LGMD-1C) in humans that is due to mutations within the coding sequence of the human Caveolin-3 gene (3p25). These LGMD-1C mutations lead to an approximately 95% reduction in Caveolin-3 protein expression, i.e. a Caveolin-3 deficiency. Here, we created a Caveolin-3 null (CAV3 -/-) mouse model, using standard homologous recombination techniques, to mimic a Caveolin-3 deficiency. We show that these mice lack Caveolin-3 protein expression and sarcolemmal caveolae membranes. In addition, analysis of skeletal muscle tissue from these Caveolin-3 null mice reveals: (i) mild myopathic changes; (ii) an exclusion of the dystrophin-glycoprotein complex from lipid raft domains; and (iii) abnormalities in the organization of the T-tubule system, with dilated and longitudinally oriented T-tubules. These results have clear mechanistic implications for understanding the pathogenesis of LGMD-1C at a molecular level.

Ferruccio Galbiati - One of the best experts on this subject based on the ideXlab platform.

  • Caveolin-3 promotes nicotinic acetylcholine receptor clustering and regulates neuromuscular junction activity.
    Molecular biology of the cell, 2009
    Co-Authors: Michael P. Hezel, William C. De Groat, Ferruccio Galbiati
    Abstract:

    The molecular mechanisms that regulate the organization and activity of the neuromuscular junction remain to be fully identified. Caveolae are invaginations of the plasma membrane. Caveolin-3 is the structural protein component of caveolae in muscle cells. We show that Caveolin-3 is expressed at the neuromuscular junction, that it associates with the nicotinic acetylcholine receptor (nAChR), and that a lack of Caveolin-3 inhibits clustering of the nAChR in myotubes. At the molecular level, we demonstrate that Caveolin-3 is a novel muscle-specific kinase (MuSK) binding protein and that altered nAChR clustering in Caveolin-3–lacking myotubes results from inhibition of agrin-induced phosphorylation/activation of MuSK and activation of Rac-1. Functional studies in Caveolin-3 null mice show abnormal neuromuscular junction activity that is consistent with altered nAChR localization at the sarcolemma. Together, these data identify Caveolin-3 as a critical component of the signaling machinery that drives nicotinic acetylcholine receptor clustering and controls neuromuscular junction function.

  • Caveolin-1 and Caveolin-3 form heterooligomeric complexes in atrial cardiac myocytes that are required for doxorubicin-induced apoptosis.
    American journal of physiology. Heart and circulatory physiology, 2007
    Co-Authors: Daniela Volonte, Charles F. Mctiernan, Marek Drab, Michael Kasper, Ferruccio Galbiati
    Abstract:

    Caveolae are 50- to 100-nm invaginations of the plasma membrane. Caveolins are the structural protein components of caveolar membranes. The Caveolin gene family is composed of three members: Caveolin-1, Caveolin-2, and Caveolin-3. Caveolin-1 and Caveolin-2 are coexpressed in many cell types, including adipocytes, endothelial cells, epithelial cells, and fibroblasts. In contrast, Caveolin-3 expression is essentially restricted to skeletal and smooth muscle cells as well as cardiac myocytes. While the interaction between Caveolin-1 and Caveolin-2 has been documented previously, the reciprocal interaction between endogenous Caveolin-1 and Caveolin-3 and their functional role in cell types expressing both isoforms have yet to be identified. Here we demonstrate for the first time that Caveolin-1 and Caveolin-3 are coexpressed in mouse and rat cardiac myocytes of the atria but not ventricles. We also found that Caveolin-1 and Caveolin-3 can interact and form heterooligomeric complexes in this cell type. Doxorubicin is an effective anticancer agent, but its use is limited by the possible development of cardiotoxicity. Using Caveolin-1- and Caveolin-3-null mice, we show that both Caveolin-1 and Caveolin-3 expression are required for doxorubicin-induced apoptosis in the atria through activation of caspase 3. Together, these results bring new insight into the functional role of caveolae and suggest that Caveolin-1/Caveolin-3 heterooligomeric complexes may play a key role in chemotherapy-induced cardiotoxicity in the atria.

  • Caveolinopathies: mutations in Caveolin-3 cause four distinct autosomal dominant muscle diseases.
    Neurology, 2004
    Co-Authors: Scott Eric Woodman, Ferruccio Galbiati, Federica Sotgia, Carlo Minetti, Michael P. Lisanti
    Abstract:

    The Caveolin-3 protein is expressed exclusively in muscle cells. Caveolin-3 expression is sufficient to form caveolae-sarcolemmal invaginations that are 50 to 100 nm in diameter. Monomers of Caveolin-3 oligomerize to form high molecular mass scaffolding on the cytoplasmic surface of the sarcolemmal membrane. A mutation in one Caveolin-3 allele produces an aberrant protein product capable of sequestering the normal Caveolin-3 protein in the Golgi apparatus of skeletal muscle cells. Improper Caveolin-3 oligomerization and membrane localization result in skeletal muscle T-tubule system derangement, sarcolemmal membrane alterations, and large subsarcolemmal vesicle formation. To date, there have been eight autosomal dominant Caveolin-3 mutations identified in the human population. Caveolin-3 mutations can result in four distinct, sometimes overlapping, muscle disease phenotypes: limb girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. Thus, the Caveolin-3 mutant genotype-to-phenotype relation represents a clear example of how genetic background can influence phenotypic outcome. This review examines in detail the reported cases of patients with Caveolin-3 mutations and their corresponding muscle disease phenotypes.

  • Transgenic overexpression of Caveolin-3 in the heart induces a cardiomyopathic phenotype
    Human molecular genetics, 2003
    Co-Authors: Bharathi Aravamudan, Daniela Volonte, Michael P. Lisanti, Ravi Ramani, Erdal Gursoy, Barry London, Ferruccio Galbiati
    Abstract:

    Caveolins are structural protein components of caveolar membrane domains. Caveolin-3, a muscle-specific member of the Caveolin family, is expressed in skeletal muscle tissue and in the heart. The multiple roles that Caveolin-3 plays in cellular physiology are becoming more apparent. We have shown that lack of Caveolin-3 expression in skeletal muscle resembles limb-girdle muscular dystrophy-1C. In contrast, we have demonstrated that overexpression of Caveolin-3 in skeletal muscle tissue promotes defects similar to those seen in Duchenne muscular dystrophy (DMD). Thus, a tight regulation of Caveolin-3 expression is fundamental for normal muscle functions. Since Caveolin-3 is also endogenously expressed in cardiac myocytes, and cardiomyopathies are observed in DMD patients, we looked at the effects of overexpression of Caveolin-3 on cardiac structure and function by characterizing Caveolin-3 transgenic mice. Our results indicate that overexpression of Caveolin-3 causes severe cardiac tissue degeneration, fibrosis and a reduction in cardiac functions. We also show that dystrophin and its associated glycoproteins are down-regulated in Caveolin-3 transgenic heart. In addition, we demonstrate that the activity of nitric oxide synthase (NOS) is down-regulated by high levels of Caveolin-3 in the heart. Taken together, these results indicate that overexpression of Caveolin-3 is sufficient to induce severe cardiomyopathy. In addition, these findings suggest that Caveolin-3 transgenic mice may represent a valid mouse model for studying the molecular mechanisms underlying cardiomyopathies associated with Duchenne muscular dystrophy.

  • Modulation of myoblast fusion by Caveolin-3 in dystrophic skeletal muscle cells: implications for Duchenne muscular dystrophy and limb-girdle muscular dystrophy-1C.
    Molecular biology of the cell, 2003
    Co-Authors: Daniela Volonte, Aaron J. Peoples, Ferruccio Galbiati
    Abstract:

    Caveolae are vesicular invaginations of the plasma membrane. Caveolin-3 is the principal structural component of caveolae in skeletal muscle cells in vivo. We have recently generated Caveolin-3 transgenic mice and demonstrated that overexpression of wild-type Caveolin-3 in skeletal muscle fibers is sufficient to induce a Duchenne-like muscular dystrophy phenotype. In addition, we have shown that Caveolin-3 null mice display mild muscle fiber degeneration and T-tubule system abnormalities. These data are consistent with the mild phenotype observed in Limb-girdle muscular dystrophy-1C (LGMD-1C) in humans, characterized by a ∼95% reduction of Caveolin-3 expression. Thus, Caveolin-3 transgenic and null mice represent valid mouse models to study Duchenne muscular dystrophy (DMD) and LGMD-1C, respectively, in humans. Here, we derived conditionally immortalized precursor skeletal muscle cells from Caveolin-3 transgenic and null mice. We show that overexpression of Caveolin-3 inhibits myoblast fusion to multinucleated myotubes and lack of Caveolin-3 enhances the fusion process. M-cadherin and microtubules have been proposed to mediate the fusion of myoblasts to myotubes. Interestingly, we show that M-cadherin is downregulated in Caveolin-3 transgenic cells and upregulated in Caveolin-3 null cells. For the first time, variations of M-cadherin expression have been linked to a muscular dystrophy phenotype. In addition, we demonstrate that microtubules are disorganized in Caveolin-3 null myotubes, indicating the importance of the cytoskeleton network in mediating the phenotype observed in these cells. Taken together, these results propose Caveolin-3 as a key player in myoblast fusion and suggest that defects of the fusion process may represent additional molecular mechanisms underlying the pathogenesis of DMD and LGMD-1C in humans.

Daniela Volonte - One of the best experts on this subject based on the ideXlab platform.

  • Caveolin-1 and Caveolin-3 form heterooligomeric complexes in atrial cardiac myocytes that are required for doxorubicin-induced apoptosis.
    American journal of physiology. Heart and circulatory physiology, 2007
    Co-Authors: Daniela Volonte, Charles F. Mctiernan, Marek Drab, Michael Kasper, Ferruccio Galbiati
    Abstract:

    Caveolae are 50- to 100-nm invaginations of the plasma membrane. Caveolins are the structural protein components of caveolar membranes. The Caveolin gene family is composed of three members: Caveolin-1, Caveolin-2, and Caveolin-3. Caveolin-1 and Caveolin-2 are coexpressed in many cell types, including adipocytes, endothelial cells, epithelial cells, and fibroblasts. In contrast, Caveolin-3 expression is essentially restricted to skeletal and smooth muscle cells as well as cardiac myocytes. While the interaction between Caveolin-1 and Caveolin-2 has been documented previously, the reciprocal interaction between endogenous Caveolin-1 and Caveolin-3 and their functional role in cell types expressing both isoforms have yet to be identified. Here we demonstrate for the first time that Caveolin-1 and Caveolin-3 are coexpressed in mouse and rat cardiac myocytes of the atria but not ventricles. We also found that Caveolin-1 and Caveolin-3 can interact and form heterooligomeric complexes in this cell type. Doxorubicin is an effective anticancer agent, but its use is limited by the possible development of cardiotoxicity. Using Caveolin-1- and Caveolin-3-null mice, we show that both Caveolin-1 and Caveolin-3 expression are required for doxorubicin-induced apoptosis in the atria through activation of caspase 3. Together, these results bring new insight into the functional role of caveolae and suggest that Caveolin-1/Caveolin-3 heterooligomeric complexes may play a key role in chemotherapy-induced cardiotoxicity in the atria.

  • Transgenic overexpression of Caveolin-3 in the heart induces a cardiomyopathic phenotype
    Human molecular genetics, 2003
    Co-Authors: Bharathi Aravamudan, Daniela Volonte, Michael P. Lisanti, Ravi Ramani, Erdal Gursoy, Barry London, Ferruccio Galbiati
    Abstract:

    Caveolins are structural protein components of caveolar membrane domains. Caveolin-3, a muscle-specific member of the Caveolin family, is expressed in skeletal muscle tissue and in the heart. The multiple roles that Caveolin-3 plays in cellular physiology are becoming more apparent. We have shown that lack of Caveolin-3 expression in skeletal muscle resembles limb-girdle muscular dystrophy-1C. In contrast, we have demonstrated that overexpression of Caveolin-3 in skeletal muscle tissue promotes defects similar to those seen in Duchenne muscular dystrophy (DMD). Thus, a tight regulation of Caveolin-3 expression is fundamental for normal muscle functions. Since Caveolin-3 is also endogenously expressed in cardiac myocytes, and cardiomyopathies are observed in DMD patients, we looked at the effects of overexpression of Caveolin-3 on cardiac structure and function by characterizing Caveolin-3 transgenic mice. Our results indicate that overexpression of Caveolin-3 causes severe cardiac tissue degeneration, fibrosis and a reduction in cardiac functions. We also show that dystrophin and its associated glycoproteins are down-regulated in Caveolin-3 transgenic heart. In addition, we demonstrate that the activity of nitric oxide synthase (NOS) is down-regulated by high levels of Caveolin-3 in the heart. Taken together, these results indicate that overexpression of Caveolin-3 is sufficient to induce severe cardiomyopathy. In addition, these findings suggest that Caveolin-3 transgenic mice may represent a valid mouse model for studying the molecular mechanisms underlying cardiomyopathies associated with Duchenne muscular dystrophy.

  • Modulation of myoblast fusion by Caveolin-3 in dystrophic skeletal muscle cells: implications for Duchenne muscular dystrophy and limb-girdle muscular dystrophy-1C.
    Molecular biology of the cell, 2003
    Co-Authors: Daniela Volonte, Aaron J. Peoples, Ferruccio Galbiati
    Abstract:

    Caveolae are vesicular invaginations of the plasma membrane. Caveolin-3 is the principal structural component of caveolae in skeletal muscle cells in vivo. We have recently generated Caveolin-3 transgenic mice and demonstrated that overexpression of wild-type Caveolin-3 in skeletal muscle fibers is sufficient to induce a Duchenne-like muscular dystrophy phenotype. In addition, we have shown that Caveolin-3 null mice display mild muscle fiber degeneration and T-tubule system abnormalities. These data are consistent with the mild phenotype observed in Limb-girdle muscular dystrophy-1C (LGMD-1C) in humans, characterized by a ∼95% reduction of Caveolin-3 expression. Thus, Caveolin-3 transgenic and null mice represent valid mouse models to study Duchenne muscular dystrophy (DMD) and LGMD-1C, respectively, in humans. Here, we derived conditionally immortalized precursor skeletal muscle cells from Caveolin-3 transgenic and null mice. We show that overexpression of Caveolin-3 inhibits myoblast fusion to multinucleated myotubes and lack of Caveolin-3 enhances the fusion process. M-cadherin and microtubules have been proposed to mediate the fusion of myoblasts to myotubes. Interestingly, we show that M-cadherin is downregulated in Caveolin-3 transgenic cells and upregulated in Caveolin-3 null cells. For the first time, variations of M-cadherin expression have been linked to a muscular dystrophy phenotype. In addition, we demonstrate that microtubules are disorganized in Caveolin-3 null myotubes, indicating the importance of the cytoskeleton network in mediating the phenotype observed in these cells. Taken together, these results propose Caveolin-3 as a key player in myoblast fusion and suggest that defects of the fusion process may represent additional molecular mechanisms underlying the pathogenesis of DMD and LGMD-1C in humans.

  • Impairment of Caveolae Formation and T-System Disorganization in Human Muscular Dystrophy with Caveolin-3 Deficiency
    The American journal of pathology, 2002
    Co-Authors: Carlo Minetti, Ferruccio Galbiati, Daniela Volonte, Federica Sotgia, Claudio Bruno, M. Bado, Paolo Broda, Giuseppe Lucania, Antonio Pavan, Eduardo Bonilla
    Abstract:

    Caveolin-3, a muscle specific Caveolin-related protein, is the principal structural protein of caveolar membranes. We have recently identified an autosomal dominant form of limb girdle muscular dystrophy (LGMD-1C) that is due to Caveolin-3 deficiency and Caveolin-3 gene mutations. Here, we studied by electron microscopy, including freeze-fracture and lanthanum staining, the distribution of caveolae and the organization of the T-tubule system in Caveolin-3 deficient human muscle fibers. We found a severe impairment of caveolae formation at the muscle cell surface, demonstrating that Caveolin-3 is essential for the formation and organization of caveolae in muscle fibers. In addition, we also detected a striking disorganization of the T-system openings at the sub-sarcolemmal level in LGMD-1C muscle fibers. These observations provide new perspectives in our understanding of the role of Caveolin-3 in muscle and of the pathogenesis of muscle weakness in Caveolin-3 deficient muscle.

  • Caveolin-3 Null Mice Show a Loss of Caveolae, Changes in the Microdomain Distribution of the Dystrophin-Glycoprotein Complex, and T-tubule Abnormalities
    The Journal of biological chemistry, 2001
    Co-Authors: Ferruccio Galbiati, Daniela Volonte, Jeffrey A Engelman, Carlo Minetti, Xiao Lan Zhang, Harry Hou, Burkhard Kneitz, Winfried Edelmann, Michael P. Lisanti
    Abstract:

    Caveolin-3, a muscle-specific Caveolin-related protein, is the principal structural protein of caveolae membrane domains in striated muscle cells. Recently, we identified a novel autosomal dominant form of limb-girdle muscular dystrophy (LGMD-1C) in humans that is due to mutations within the coding sequence of the human Caveolin-3 gene (3p25). These LGMD-1C mutations lead to an approximately 95% reduction in Caveolin-3 protein expression, i.e. a Caveolin-3 deficiency. Here, we created a Caveolin-3 null (CAV3 -/-) mouse model, using standard homologous recombination techniques, to mimic a Caveolin-3 deficiency. We show that these mice lack Caveolin-3 protein expression and sarcolemmal caveolae membranes. In addition, analysis of skeletal muscle tissue from these Caveolin-3 null mice reveals: (i) mild myopathic changes; (ii) an exclusion of the dystrophin-glycoprotein complex from lipid raft domains; and (iii) abnormalities in the organization of the T-tubule system, with dilated and longitudinally oriented T-tubules. These results have clear mechanistic implications for understanding the pathogenesis of LGMD-1C at a molecular level.

Carlo Minetti - One of the best experts on this subject based on the ideXlab platform.

  • Caveolinopathies: translational implications of Caveolin-3 in skeletal and cardiac muscle disorders.
    Handbook of clinical neurology, 2011
    Co-Authors: Elisabetta Gazzerro, Andrea Bonetto, Carlo Minetti
    Abstract:

    Abstract Caveolae are specialized lipid rafts localized on the cytoplasmic surface of the sarcolemmal membrane. Caveolae contribute to the maintenance of plasma membrane integrity, constitute specific macromolecular complexes that provide highly localized regulation of ion channels, and regulate vesicular trafficking and signal transduction. In skeletal muscle, the main structural assembly of caveolae is mediated by Caveolin-3. Another family of adapter proteins, the cavins, is involved in the regulation of caveolae function and in the trafficking of Caveolin-derived structures. Caveolin-3 defects lead to four distinct skeletal muscle disease phenotypes: limb-girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. Many patients show an overlap of these symptoms, and the same mutation can be linked to different clinical phenotypes. An ever-growing interest is also focused on the association between Caveolin-3 mutations and heart disorders. Indeed, Caveolin-3 mutants have been described in a patient with hypertrophic cardiomyopathy and two patients with dilated cardiomyopathy, and mutations in the Caveolin-3 gene ( CAV3 ) have been identified in patients affected by congenital long QT syndrome. Although Caveolin-3 deficiency represents the primary event, multiple secondary molecular mechanisms lead to muscle tissue damage. Among these, sarcolemmal membrane alterations, disorganization of skeletal muscle T-tubule network, and disruption of distinct cell signaling pathways have been determined.

  • Caveolinopathies: from the biology of Caveolin-3 to human diseases
    European Journal of Human Genetics, 2010
    Co-Authors: Elisabetta Gazzerro, Michael P. Lisanti, Federica Sotgia, Claudio Bruno, Carlo Minetti
    Abstract:

    In muscle tissue the protein Caveolin-3 forms caveolae – flask-shaped invaginations localized on the cytoplasmic surface of the sarcolemmal membrane. Caveolae have a key role in the maintenance of plasma membrane integrity and in the processes of vesicular trafficking and signal transduction. Mutations in the Caveolin-3 gene lead to skeletal muscle pathology through multiple pathogenetic mechanisms. Indeed, Caveolin-3 deficiency is associated to sarcolemmal membrane alterations, disorganization of skeletal muscle T-tubule network and disruption of distinct cell-signaling pathways. To date, there have been 30 Caveolin-3 mutations identified in the human population. Caveolin-3 defects lead to four distinct skeletal muscle disease phenotypes: limb girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. In addition, one Caveolin-3 mutant has been described in a case of hypertrophic cardiomyopathy. Many patients show an overlap of these symptoms and the same mutation can be linked to different clinical phenotypes. This variability can be related to additional genetic or environmental factors. This review will address Caveolin-3 biological functions in muscle cells and will describe the muscle and heart disease phenotypes associated with Caveolin-3 mutations.

  • Caveolinopathies: mutations in Caveolin-3 cause four distinct autosomal dominant muscle diseases.
    Neurology, 2004
    Co-Authors: Scott Eric Woodman, Ferruccio Galbiati, Federica Sotgia, Carlo Minetti, Michael P. Lisanti
    Abstract:

    The Caveolin-3 protein is expressed exclusively in muscle cells. Caveolin-3 expression is sufficient to form caveolae-sarcolemmal invaginations that are 50 to 100 nm in diameter. Monomers of Caveolin-3 oligomerize to form high molecular mass scaffolding on the cytoplasmic surface of the sarcolemmal membrane. A mutation in one Caveolin-3 allele produces an aberrant protein product capable of sequestering the normal Caveolin-3 protein in the Golgi apparatus of skeletal muscle cells. Improper Caveolin-3 oligomerization and membrane localization result in skeletal muscle T-tubule system derangement, sarcolemmal membrane alterations, and large subsarcolemmal vesicle formation. To date, there have been eight autosomal dominant Caveolin-3 mutations identified in the human population. Caveolin-3 mutations can result in four distinct, sometimes overlapping, muscle disease phenotypes: limb girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. Thus, the Caveolin-3 mutant genotype-to-phenotype relation represents a clear example of how genetic background can influence phenotypic outcome. This review examines in detail the reported cases of patients with Caveolin-3 mutations and their corresponding muscle disease phenotypes.

  • Dysferlin in a hyperCKaemic patient with Caveolin 3 mutation and in C2C12 cells after p38 MAP kinase inhibition
    Experimental & Molecular Medicine, 2003
    Co-Authors: Cristina Capanni, Carlo Minetti, Patrizia Sabatelli, Elisabetta Mattioli, Andrea Ognibene, Marta Columbaro, Giovanna Lattanzi, Luciano Merlini, Nadir M Maraldi, Stefano Squarzoni
    Abstract:

    Dysferlin is a plasma membrane protein of skeletal muscle whose deficiency causes Miyoshi myopathy, limb girdle muscular dystrophy 2B and distal anterior compartment myopathy. Recent studies have reported that dysferlin is implicated in membrane repair mechanism and coimmunoprecipitates with Caveolin 3 in human skeletal muscle. Caveolin 3 is a principal structural protein of caveolae membrane domains in striated muscle cells and cardiac myocytes. Mutations of Caveolin 3 gene (CAV3) cause different diseases and where Caveolin 3 expression is defective, dysferlin localization is abnormal. We describe the alteration of dysferlin expression and localization in skeletal muscle from a patient with raised serum creatine kinase (hyperCKaemia), whose reduction of Caveolin 3 is caused by a CAV3 P28L mutation. Moreover, we performed a study on dysferlin interaction with Caveolin 3 in C2C12 cells. We show the association of dysferlin to cellular membrane of C2C12 myotubes and the low affinity link between dysferlin and Caveolin 3 by immunoprecipitation techniques. We also reproduced Caveolinopathy conditions in C2C12 cells by a selective p38 MAP kinase inhibition with SB203580, which blocks the expression of Caveolin 3. In this model, myoblasts do not fuse into myotubes and we found that dysferlin expression is reduced. These results underline the importance of dysferlin-Caveolin 3 relationship for skeletal muscle integrity and propose a cellular model to clarify the dysferlin alteration mechanisms in Caveolinopathies.

  • Familial isolated hyperCKaemia associated with a new mutation in the Caveolin-3 (CAV-3) gene
    Journal of neurology neurosurgery and psychiatry, 2002
    Co-Authors: Luciano Merlini, Michael P. Lisanti, Federica Sotgia, Claudio Bruno, I. Carbone, Cristina Capanni, Patrizia Sabatelli, Silvia Tortorelli, Carlo Minetti
    Abstract:

    An 18 year old man and his mother both presented with persistent, isolated raised serum creatine kinase (hyperCKaemia) without muscle symptoms. Analysis of Caveolin-3 protein expression in muscle biopsy of the propositus showed a reduction in the protein. Genetic analysis revealed a new heterozygous mutation in the Caveolin-3 (CAV-3) gene: a C→T transition at nucleotide position 83 in exon 1 leading to a substitution of a proline for a leucine at amino acid position 28 (P28L). This is the first pathogenic mutation in the CAV-3 gene associated with isolated familial hyperCKaemia. It expands the genetic heterogeneity in patients with Caveolin-3 deficiency and confirms that Caveolin-3 deficiency should be considered in the differential diagnosis of isolated hyperCKaemia.

Federica Sotgia - One of the best experts on this subject based on the ideXlab platform.

  • Caveolinopathies: from the biology of Caveolin-3 to human diseases
    European Journal of Human Genetics, 2010
    Co-Authors: Elisabetta Gazzerro, Michael P. Lisanti, Federica Sotgia, Claudio Bruno, Carlo Minetti
    Abstract:

    In muscle tissue the protein Caveolin-3 forms caveolae – flask-shaped invaginations localized on the cytoplasmic surface of the sarcolemmal membrane. Caveolae have a key role in the maintenance of plasma membrane integrity and in the processes of vesicular trafficking and signal transduction. Mutations in the Caveolin-3 gene lead to skeletal muscle pathology through multiple pathogenetic mechanisms. Indeed, Caveolin-3 deficiency is associated to sarcolemmal membrane alterations, disorganization of skeletal muscle T-tubule network and disruption of distinct cell-signaling pathways. To date, there have been 30 Caveolin-3 mutations identified in the human population. Caveolin-3 defects lead to four distinct skeletal muscle disease phenotypes: limb girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. In addition, one Caveolin-3 mutant has been described in a case of hypertrophic cardiomyopathy. Many patients show an overlap of these symptoms and the same mutation can be linked to different clinical phenotypes. This variability can be related to additional genetic or environmental factors. This review will address Caveolin-3 biological functions in muscle cells and will describe the muscle and heart disease phenotypes associated with Caveolin-3 mutations.

  • Caveolinopathies: mutations in Caveolin-3 cause four distinct autosomal dominant muscle diseases.
    Neurology, 2004
    Co-Authors: Scott Eric Woodman, Ferruccio Galbiati, Federica Sotgia, Carlo Minetti, Michael P. Lisanti
    Abstract:

    The Caveolin-3 protein is expressed exclusively in muscle cells. Caveolin-3 expression is sufficient to form caveolae-sarcolemmal invaginations that are 50 to 100 nm in diameter. Monomers of Caveolin-3 oligomerize to form high molecular mass scaffolding on the cytoplasmic surface of the sarcolemmal membrane. A mutation in one Caveolin-3 allele produces an aberrant protein product capable of sequestering the normal Caveolin-3 protein in the Golgi apparatus of skeletal muscle cells. Improper Caveolin-3 oligomerization and membrane localization result in skeletal muscle T-tubule system derangement, sarcolemmal membrane alterations, and large subsarcolemmal vesicle formation. To date, there have been eight autosomal dominant Caveolin-3 mutations identified in the human population. Caveolin-3 mutations can result in four distinct, sometimes overlapping, muscle disease phenotypes: limb girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. Thus, the Caveolin-3 mutant genotype-to-phenotype relation represents a clear example of how genetic background can influence phenotypic outcome. This review examines in detail the reported cases of patients with Caveolin-3 mutations and their corresponding muscle disease phenotypes.

  • Familial isolated hyperCKaemia associated with a new mutation in the Caveolin-3 (CAV-3) gene
    Journal of neurology neurosurgery and psychiatry, 2002
    Co-Authors: Luciano Merlini, Michael P. Lisanti, Federica Sotgia, Claudio Bruno, I. Carbone, Cristina Capanni, Patrizia Sabatelli, Silvia Tortorelli, Carlo Minetti
    Abstract:

    An 18 year old man and his mother both presented with persistent, isolated raised serum creatine kinase (hyperCKaemia) without muscle symptoms. Analysis of Caveolin-3 protein expression in muscle biopsy of the propositus showed a reduction in the protein. Genetic analysis revealed a new heterozygous mutation in the Caveolin-3 (CAV-3) gene: a C→T transition at nucleotide position 83 in exon 1 leading to a substitution of a proline for a leucine at amino acid position 28 (P28L). This is the first pathogenic mutation in the CAV-3 gene associated with isolated familial hyperCKaemia. It expands the genetic heterogeneity in patients with Caveolin-3 deficiency and confirms that Caveolin-3 deficiency should be considered in the differential diagnosis of isolated hyperCKaemia.

  • Impairment of Caveolae Formation and T-System Disorganization in Human Muscular Dystrophy with Caveolin-3 Deficiency
    The American journal of pathology, 2002
    Co-Authors: Carlo Minetti, Ferruccio Galbiati, Daniela Volonte, Federica Sotgia, Claudio Bruno, M. Bado, Paolo Broda, Giuseppe Lucania, Antonio Pavan, Eduardo Bonilla
    Abstract:

    Caveolin-3, a muscle specific Caveolin-related protein, is the principal structural protein of caveolar membranes. We have recently identified an autosomal dominant form of limb girdle muscular dystrophy (LGMD-1C) that is due to Caveolin-3 deficiency and Caveolin-3 gene mutations. Here, we studied by electron microscopy, including freeze-fracture and lanthanum staining, the distribution of caveolae and the organization of the T-tubule system in Caveolin-3 deficient human muscle fibers. We found a severe impairment of caveolae formation at the muscle cell surface, demonstrating that Caveolin-3 is essential for the formation and organization of caveolae in muscle fibers. In addition, we also detected a striking disorganization of the T-system openings at the sub-sarcolemmal level in LGMD-1C muscle fibers. These observations provide new perspectives in our understanding of the role of Caveolin-3 in muscle and of the pathogenesis of muscle weakness in Caveolin-3 deficient muscle.

  • Caveolin 3 directly interacts with the c terminal tail of β dystroglycan identification of a central ww like domain within Caveolin family members
    Journal of Biological Chemistry, 2000
    Co-Authors: Federica Sotgia, Carlo Minetti, Franca Dagna Bricarelli, Mark T Bedford, Tamara C Petrucci, Pompeo Macioce, Massimo Sargiacomo, Marius Sudol, Michael P. Lisanti
    Abstract:

    Abstract Caveolin-3, the most recently recognized member of the Caveolin gene family, is muscle-specific and is found in both cardiac and skeletal muscle, as well as smooth muscle cells. Several independent lines of evidence indicate that Caveolin-3 is localized to the sarcolemma, where it associates with the dystrophin-glycoprotein complex. However, it remains unknown which component of the dystrophin complex interacts with Caveolin-3. Here, we demonstrate that Caveolin-3 directly interacts with β-dystroglycan, an integral membrane component of the dystrophin complex. Our results indicate that Caveolin-3 co-localizes, co-fractionates, and co-immunoprecipitates with a fusion protein containing the cytoplasmic tail of β-dystroglycan. In addition, we show that a novel WW-like domain within Caveolin-3 directly recognizes the extreme C terminus of β-dystroglycan that contains a PPXY motif. As the WW domain of dystrophin recognizes the same site within β-dystroglycan, we also demonstrate that Caveolin-3 can effectively block the interaction of dystrophin with β-dystroglycan. In this regard, interaction of Caveolin-3 with β-dystroglycan may competitively regulate the recruitment of dystrophin to the sarcolemma. We discuss the possible implications of our findings in the context of Duchenne muscular dystrophy.