30 results on '"Lattanzi, G."'
Search Results
2. Nuclear envelope proteins and chromatin arrangement: a pathogenic mechanism for laminopathies
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Maraldi, N. M., Lattanzi, G., Capanni, C., Columbaro, M., Merlini, L., Mattioli, E., Sabatelli, P., Stefano Squarzoni, Manzoli, F. A., Maraldi NM, Lattanzi G, Capanni C, Columbaro M, Merlini L, Mattioli E, Sabatelli P, Squarzoni S, and Manzoli FA.
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congenital, hereditary, and neonatal diseases and abnormalities ,animal structures ,integumentary system ,Lipodystrophy ,Nuclear Envelope ,Membrane Proteins ,Nuclear Proteins ,Thymopoietins ,Aging, Premature ,Chromatin Assembly and Disassembly ,Lamin Type A ,Muscular Dystrophy, Emery-Dreifuss ,Heterochromatin ,embryonic structures ,Mutation ,Animals ,Humans - Abstract
The involvement of the nuclear envelope in the modulation of chromatin organization is strongly suggested by the increasing number of human diseases due to mutations of nuclear envelope proteins. A common feature of these diseases, named laminopathies, is the occurrence of major chromatin defects. We previously reported that cells from laminopathic patients show an altered nuclear profile, and loss or detachment of heterochromatin from the nuclear envelope. Recent evidence indicates that processing of the lamin A precursor is altered in laminopathies featuring pre-mature aging and/or lipodystrophy phenotype. In these cases, pre-lamin A is accumulated in the nucleus and heterochromatin is severely disorganized. Here we report evidence indicating that pre-lamin A is mis-localized in the nuclei of Emery-Dreifuss muscular dystrophy fibroblasts, either bearing lamin A/C or emerin mutations. Abnormal pre-lamin A-containing structures are formed following treatment with a farnesyl-transferase inhibitor, a drug that causes accumulation of pre-lamin A. Pre-lamin A-labeled structures co-localize with heterochromatin clumps. These data indicate that in almost all laminopathies the expression of the mutant lamin A precursor disrupts the organization of heterochromatin domains. Our results further show that the absence of emerin expression alters the distribution of pre-lamin A and of heterochromatin areas, suggesting a major involvement of emerin in pre-lamin A-mediated mechanisms of chromatin remodeling.
3. Metabolic activation and covalent binding to nucleic acids of pentachloroethane as short-term test of genotoxicity
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Turina, M. P., Colacci, A., Sandro Grilli, Mazzullo, M., Prodi, G., Lattanzi, G., Bonora, B., Bartoli, S., and Guidotti, L.
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Male ,Ethane ,Mice, Inbred BALB C ,Mutagenicity Tests ,Rats, Inbred Strains ,DNA ,In Vitro Techniques ,Rats ,Mice ,Species Specificity ,Hydrocarbons, Chlorinated ,Animals ,Biotransformation ,Mutagens - Abstract
The in vivo covalent binding of 14C-pentachloroethane to DNA, RNA and proteins of rats and mouse organs was detected 22 hr after i.p. injection. The covalent binding index, calculated on the liver labeling was comparable to those of compounds considered as weak-moderate initiators. Like other haloalkanes, 14C-pentachloroethane was bioactivated in in vitro cell-free system by both microsomal and cytosolic enzymatic fractions from mouse and rat organs to react covalently with DNA and other macromolecules. The binding extents obtained from in vitro incubation and the binding values detected after in vivo administration of labeled pentachloroethane were comparable each other and showed a high correlation with oncogenic potency index of this compound. This result confirms the efficiency of in vitro binding as short-term test of genotoxicity prediction.
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- 1989
4. Short-term tests of genotoxicity for 1,1,1-trichloroethane
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Turina, M. P., Colacci, A., Sandro Grilli, Mazzullo, M., Prodi, G., and Lattanzi, G.
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Male ,Mice, Inbred BALB C ,Stomach ,Proteins ,Rats, Inbred Strains ,DNA ,Kidney ,Mixed Function Oxygenases ,Rats ,Mice ,Cytosol ,Cytochrome P-450 Enzyme System ,Liver ,Gastric Mucosa ,Microsomes ,Hydrocarbons, Chlorinated ,Microsomes, Liver ,Solvents ,Animals ,RNA ,Trichloroethanes ,Carbon Radioisotopes ,Lung - Abstract
Covalent binding of 14C-1,1,1-trichloroethane to macromolecules from rat and mouse liver, kidney, lung and stomach was analyzed under the same experimental conditions previously utilized in studying 1,1-dichloroethane and 1,1,2-trichloroethane. Labeling of DNA, RNA and proteins was very low both in in vivo interaction and in in vitro microsome-mediated binding. Interaction proceeded through the involvement of the P-450-dependent mixed function oxidase system from liver microsomes and, to a lesser extent, from lung microsomes. Covalent Binding Index of 1,1,1-trichloroethane in liver DNA was typical of very weak initiators. However, overall evaluation of the short-term assays available for 1,1,1-trichloroethane leads to limited evidence of genotoxicity. On the other hand, the evidence of 1,1,1-trichloroethane carcinogenicity in animals is still inadequate.
5. In vivo and in vitro interaction of trichloroethylene with macromolecules from various organs of rat and mouse
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Mazzullo, M., Bartoli, S., Bonora, B., ANNAMARIA COLACCI, Lattanzi, G., Niero, A., Silingardi, P., and Grilli, S.
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Mice ,Cytochrome P-450 Enzyme System ,Species Specificity ,Microsomes ,Animals ,Proteins ,RNA ,Cattle ,DNA ,NADP ,Glutathione Transferase ,Rats ,Trichloroethylene - Abstract
Trichloroethylene was covalently bound in vivo to DNA, RNA and proteins of rat and mouse organs 22 hr after ip injection. The covalent binding index values of rat and mouse liver DNA classify trichloroethylene as a weak initiator. Labeling of RNA and proteins from various organs of both species was higher than that of DNA. In vitro, trichloroethylene was bioactivated by microsomal fractions dependent on cytochrome P450, mainly from liver of both species, to intermediate(s) capable of binding to exogenous DNA. No particular species-specific difference was evident except for mouse lung microsomes which were more efficient than rat lung microsomes. GSH-transferases capable of bioactivating P450-dependent were present in mouse lung microsomes and in liver microsomes of both species. These data, along those previously reported, provide sufficient evidence for a weak ability of TCY to interact covalently with DNA.
6. Long term breeding of the Lmna G609G progeric mouse: Characterization of homozygous and heterozygous models
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Giovanna Lattanzi, Francesco Prisco, Mara Sanapo, Massimiliano Baleani, Elisa Schena, Catia Barboni, Cristina Capanni, Valeria Pellegrino, Anna Festa, Michela Murdocca, Roberta Fognani, Stefano Squarzoni, Alessia Diana, Orlando Paciello, Anna Zaghini, Maria Rosaria D'Apice, Serenella Papparella, Manuela Loi, Rosaria Mecca, Nikolina Linta, Giuseppe Sarli, Julie Rambaldi, Fabio Baruffaldi, Zaghini A., Sarli G., Barboni C., Sanapo M., Pellegrino V., Diana A., Linta N., Rambaldi J., D'Apice M.R., Murdocca M., Baleani M., Baruffaldi F., Fognani R., Mecca R., Festa A., Papparella S., Paciello O., Prisco F., Capanni C., Loi M., Schena E., Lattanzi G., Squarzoni S., Zaghini, A., Sarli, G., Barboni, C., Sanapo, M., Pellegrino, V., Diana, A., Linta, N., Rambaldi, J., D'Apice, M. R., Murdocca, M., Baleani, M., Baruffaldi, F., Fognani, R., Mecca, R., Festa, A., Papparella, S., Paciello, O., Prisco, F., Capanni, C., Loi, M., Schena, E., Lattanzi, G., and Squarzoni, S.
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0301 basic medicine ,Quality of life ,congenital, hereditary, and neonatal diseases and abnormalities ,Aging ,Heterozygote ,Transgene ,Bone strength ,Biology ,Breeding ,medicine.disease_cause ,Biochemistry ,Kyphosi ,LMNA ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Endocrinology ,Progeria ,Genotype ,Genetics ,medicine ,Animals ,Molecular Biology ,Gene ,Mutation ,integumentary system ,Homozygote ,Membrane Proteins ,Cell Biology ,medicine.disease ,Lamin Type A ,Phenotype ,Disease Models, Animal ,030104 developmental biology ,Animal model breeding ,Hutchinson-Gilford Progeria Syndrome (HGPS) ,030217 neurology & neurosurgery ,Lamin - Abstract
The transgenic LmnaG609G progeric mouse represents an outstanding animal model for studying the human Hutchinson-Gilford Progeria Syndrome (HGPS) caused by a mutation in the LMNA gene, coding for the nuclear envelope protein Lamin A/C, and, as an important, more general scope, for studying the complex process governing physiological aging in humans. Here we give a comprehensive description of the peculiarities related to the breeding of LmnaG609G mice over a prolonged period of time, and of many features observed in a large colony for a 2-years period. We describe the breeding and housing conditions underlining the possible interference of the genetic background on the phenotype expression. This information represents a useful tool when planning and interpreting studies on the LmnaG609G mouse model, complementing any specific data already reported in the literature about this model since its production. It is also particularly relevant for the heterozygous mouse, which mirrors the genotype of the human pathology however requires an extended time to manifest symptoms and to be carefully studied.
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- 2019
7. Antibiotic-associated dysbiosis affects the ability of the gut microbiota to control intestinal inflammation upon fecal microbiota transplantation in experimental colitis models
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Georgia Lattanzi, Federica Facciotti, Maria Rita Giuffrè, Claudia Burrello, Francesco Strati, Jacopo Troisi, Flavio Caprioli, Meritxell Pujolassos, Strati, F, Pujolassos, M, Burrello, C, Giuffre, M, Lattanzi, G, Caprioli, F, Troisi, J, and Facciotti, F
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Male ,Microbiology (medical) ,medicine.drug_class ,Antibiotics ,IBD ,Gut microbiota ,Gut flora ,Microbiology ,digestive system ,lcsh:Microbial ecology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,fluids and secretions ,Vancomycin ,Metronidazole ,Lactobacillus ,medicine ,Animals ,Humans ,Colitis ,030304 developmental biology ,FMT ,0303 health sciences ,Antiinfective agent ,Innate immune system ,biology ,Research ,Antibiotic ,Fecal Microbiota Transplantation ,Th1 Cells ,medicine.disease ,biology.organism_classification ,Anti-Bacterial Agents ,Gastrointestinal Microbiome ,Disease Models, Animal ,iNKT ,Immunology ,Streptomycin ,Dysbiosis ,Natural Killer T-Cells ,Th17 Cells ,lcsh:QR100-130 ,Female ,030217 neurology & neurosurgery - Abstract
Background The gut microbiota plays a central role in host physiology and in several pathological mechanisms in humans. Antibiotics compromise the composition and functions of the gut microbiota inducing long-lasting detrimental effects on the host. Recent studies suggest that the efficacy of different clinical therapies depends on the action of the gut microbiota. Here, we investigated how different antibiotic treatments affect the ability of the gut microbiota to control intestinal inflammation upon fecal microbiota transplantation in an experimental colitis model and in ex vivo experiments with human intestinal biopsies. Results Murine fecal donors were pre-treated with different antibiotics, i.e., vancomycin, streptomycin, and metronidazole before FMT administration to colitic animals. The analysis of the gut microbiome, fecal metabolome, and the immunophenotyping of colonic lamina propria immune cells revealed that antibiotic pre-treatment significantly influences the capability of the microbiota to control intestinal inflammation. Streptomycin and vancomycin-treated microbiota failed to control intestinal inflammation and were characterized by the blooming of pathobionts previously associated with IBD as well as with metabolites related to the presence of oxidative stress and metabolism of simple sugars. On the contrary, the metronidazole-treated microbiota retained its ability to control inflammation co-occurring with the enrichment of Lactobacillus and of innate immune responses involving iNKT cells. Furthermore, ex vivo cultures of human intestinal lamina propria mononuclear cells and iNKT cell clones from IBD patients with vancomycin pre-treated sterile fecal water showed a Th1/Th17 skewing in CD4+ T-cell populations; metronidazole, on the other hand, induced the polarization of iNKT cells toward the production of IL10. Conclusions Diverse antibiotic regimens affect the ability of the gut microbiota to control intestinal inflammation in experimental colitis by altering the microbial community structure and microbiota-derived metabolites.
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- 2021
8. Interleukin-6 neutralization ameliorates symptoms in prematurely aged mice
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Giovanna Lattanzi, Elisa Schena, Giuseppe Sarli, Gianluca Storci, Elisabetta Mattioli, Davide Andrenacci, Anna Zaghini, Massimiliano Bonafè, Patrizia Sabatelli, Catia Barboni, Valeria Pellegrino, Vittoria Cenni, Cristina Capanni, Maria Rosaria D'Apice, Stefano Squarzoni, Mara Sanapo, Fabio Baruffaldi, Anna Festa, Squarzoni S., Schena E., Sabatelli P., Mattioli E., Capanni C., Cenni V., D'Apice M.R., Andrenacci D., Sarli G., Pellegrino V., Festa A., Baruffaldi F., Storci G., Bonafe M., Barboni C., Sanapo M., Zaghini A., and Lattanzi G.
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0301 basic medicine ,Premature aging ,anti‐aging ,Aging ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Adipose tissue ,Inflammation ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Progeria ,0302 clinical medicine ,Tocilizumab ,Internal medicine ,medicine ,cytokine ,Animals ,Humans ,accelerated aging ,cellular senescence ,Interleukin 6 ,laminopathie ,biology ,integumentary system ,Interleukin-6 ,laminopathies ,anti-aging ,nutritional and metabolic diseases ,Original Articles ,Cell Biology ,medicine.disease ,Progerin ,cytokines ,3. Good health ,030104 developmental biology ,Endocrinology ,chemistry ,ageing ,inflammation ,biology.protein ,Original Article ,medicine.symptom ,Lipodystrophy ,030217 neurology & neurosurgery ,nuclear lamina - Abstract
Hutchinson–Gilford progeria syndrome (HGPS) causes premature aging in children, with adipose tissue, skin and bone deterioration, and cardiovascular impairment. In HGPS cells and mouse models, high levels of interleukin‐6, an inflammatory cytokine linked to aging processes, have been detected. Here, we show that inhibition of interleukin‐6 activity by tocilizumab, a neutralizing antibody raised against interleukin‐6 receptors, counteracts progeroid features in both HGPS fibroblasts and LmnaG609G / G609G progeroid mice. Tocilizumab treatment limits the accumulation of progerin, the toxic protein produced in HGPS cells, rescues nuclear envelope and chromatin abnormalities, and attenuates the hyperactivated DNA damage response. In vivo administration of tocilizumab reduces aortic lesions and adipose tissue dystrophy, delays the onset of lipodystrophy and kyphosis, avoids motor impairment, and preserves a good quality of life in progeroid mice. This work identifies tocilizumab as a valuable tool in HGPS therapy and, speculatively, in the treatment of a variety of aging‐related disorders., Signs of premature ageing are improved by tocilizumab treatment. A study in a murine model of Hutchinson‐Gilford Progeria shows that neutralization of interleukin 6 preserves motor activity and slows‐down tissue deterioration.
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- 2021
9. The Foreign Body Response to an Implantable Therapeutic Reservoir in a Diabetic Rodent Model
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Chuan-En Lu, Robert Wylie, Julia Marzi, Rachel Beatty, Giulio Ghersi, Eimear B. Dolan, Shannon L. Layland, Raymond O'Connor, Ruth E. Levey, Garry P. Duffy, Eimear Wallace, Katja Schenke-Layland, Salamone M, Giulia Lattanzi, Daniel A. Carvajal Berrio, Beatty R., Lu C.-E., Marzi J., Levey R.E., Carvajal Berrio D., Lattanzi G., Wylie R., O'Connor R., Wallace E., Ghersi G., Salamone M., Dolan E.B., Layland S.L., Schenke-Layland K., and Duffy G.P.
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Type 1 diabetes ,Pathology ,medicine.medical_specialty ,Bioartificial pancreas ,business.industry ,Micro computed tomography ,foreign body response ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,Rodent model ,Rodentia ,Prostheses and Implants ,X-Ray Microtomography ,medicine.disease ,Foreign Bodies ,Diabetes mellitus ,diabetes mellitus ,Raman spectroscopy ,medicine ,Animals ,Foreign body ,micro-computed tomography ,business - Abstract
Advancements in type 1 diabetes mellitus treatments have vastly improved in recent years. The move toward a bioartificial pancreas and other fully implantable systems could help restore patient's glycemic control. However, the long-term success of implantable medical devices is often hindered by the foreign body response. Fibrous encapsulation "walls off" the implant to the surrounding tissue, impairing its functionality. In this study we aim to examine how streptozotocin-induced diabetes affects fibrous capsule formation and composition surrounding implantable drug delivery devices following subcutaneous implantation in a rodent model. After 2 weeks of implantation, the fibrous capsule surrounding the devices were examined by means of Raman spectroscopy, micro-computed tomography (μCT), and histological analysis. Results revealed no change in mean fibrotic capsule thickness between diabetic and healthy animals as measured by μCT. Macrophage numbers (CCR7 and CD163 positive) remained similar across all groups. True component analysis also showed no quantitative difference in the alpha-smooth muscle actin and extracellular matrix proteins. Although principal component analysis revealed significant secondary structural difference in collagen I in the diabetic group, no evidence indicates an influence on fibrous capsule composition surrounding the device. This study confirms that diabetes did not have an effect on the fibrous capsule thickness or composition surrounding our implantable drug delivery device. Impact Statement Understanding the impact diabetes has on the foreign body response (FBR) to our implanted material is essential for developing an effective drug delivery device. We used several approaches (Raman spectroscopy and micro-computed tomography imaging) to demonstrate a well-rounded understanding of the diabetic impact on the FBR to our devices, which is imperative for its clinical translation.
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- 2021
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10. Morphological study of TNPO3 and SRSF1 interaction during myogenesis by combining confocal, structured illumination and electron microscopy analysis
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Cristina Capanni, Nicoletta Zini, Roberta Costa, Corrado Angelini, Giovanna Lattanzi, Roberta Marozzo, Giovanna Cenacchi, Maria Teresa Rodia, Spartaco Santi, Valentina Pegoraro, Costa R., Rodia M.T., Zini N., Pegoraro V., Marozzo R., Capanni C., Angelini C., Lattanzi G., Santi S., and Cenacchi G.
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0301 basic medicine ,Cytoplasm ,TNPO3 ,Cellular differentiation ,Confocal ,Clinical Biochemistry ,Muscle disorder ,Muscle Development ,Article ,Cell Line ,Mice ,03 medical and health sciences ,0302 clinical medicine ,SR protein ,Electron microscopy ,Animals ,Molecular Biology ,Cell Nucleus ,Structured illumination microscopy ,Microscopy, Confocal ,Serine-Arginine Splicing Factors ,Myogenesis ,Chemistry ,Alternative splicing ,Cell Biology ,General Medicine ,beta Karyopherins ,Cell biology ,SRSF1 ,Microscopy, Electron ,030104 developmental biology ,Myogenesi ,RNA splicing ,030217 neurology & neurosurgery - Abstract
Transportin3 (TNPO3) shuttles the SR proteins from the cytoplasm to the nucleus. The SR family includes essential splicing factors, such as SRSF1, that influence alternative splicing, controlling protein diversity in muscle and satellite cell differentiation. Given the importance of alternative splicing in the myogenic process and in the maintenance of healthy muscle, alterations in the splicing mechanism might contribute to the development of muscle disorders. Combining confocal, structured illumination and electron microscopy, we investigated the expression of TNPO3 and SRSF1 during myogenesis, looking at nuclear and cytoplasmic compartments. We investigated TNPO3 and its interaction with SRSF1 and we observed that SRSF1 remained mainly localized in the nucleus, while TNPO3 decreased in the cytoplasm and was strongly clustered in the nuclei of differentiated myotubes. In conclusion, combining different imaging techniques led us to describe the behavior of TNPO3 and SRSF1 during myogenesis, showing that their dynamics follow the myogenic process and could influence the proteomic network necessary during myogenesis. The combination of different high-, super- and ultra-resolution imaging techniques led us to describe the behavior of TNPO3 and its interaction with SRSF1, looking at nuclear and cytoplasmic compartments. These observations represent a first step in understanding the role of TNPO3 and SRFSF1 in complex mechanisms, such as myogenesis.
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- 2021
11. Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome
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Giovanna Lattanzi, Fabrizio d'Adda di Fagagna, Peh Fern Ong, Corey Winston Jones-Weinert, Oliver Dreesen, Claudio Tripodo, Agustin Sola-Carvajal, Maria Eriksson, Francesca Rossiello, Emelie Wallén Arzt, Gwladys Revêchon, Valeria Cancila, Julio Aguado, Aguado J., Sola-Carvajal A., Cancila V., Revechon G., Ong P.F., Jones-Weinert C.W., Wallen Arzt E., Lattanzi G., Dreesen O., Tripodo C., Rossiello F., Eriksson M., and d'Adda di Fagagna F.
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0301 basic medicine ,Genome instability ,RNA, Untranslated ,DNA Repair ,General Physics and Astronomy ,Cellular homeostasis ,Antisense oligonucleotide therapy ,Mice ,0302 clinical medicine ,Progeria ,Homeostasis ,lcsh:Science ,Cellular Senescence ,Skin ,Multidisciplinary ,integumentary system ,Telomere ,Progerin ,Lamin Type A ,3. Good health ,Cell biology ,Telomeres ,Phenotype ,Premature aging ,congenital, hereditary, and neonatal diseases and abnormalities ,DNA repair ,Science ,Double-strand DNA breaks ,Biology ,Settore MED/08 - Anatomia Patologica ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cell Line ,03 medical and health sciences ,medicine ,DNA damage, Hutchinson-Gilford Progeria Syndrome ,Animals ,Cell Proliferation ,nutritional and metabolic diseases ,General Chemistry ,Oligonucleotides, Antisense ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Mutation ,lcsh:Q ,030217 neurology & neurosurgery ,Lamin ,DNA Damage - Abstract
Hutchinson–Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo., Hutchinson–Gilford progeria syndrome causes premature aging. Here the authors show that activation of the DNA damage response at dysfunctional telomeres and transcription of telomeric non-coding RNAs contributes to the pathogenesis, which can be ameliorated by treatment with sequence-specific telomeric antisense oligonucleotides.
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- 2019
12. Elevated TGF β2 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes
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Nicola Carboni, Chiara Lanzuolo, Elisa Schena, Lucio Santoro, Tiziana Mongini, Elena Biagini, Lucia Morandi, Gisèle Bonne, Giovanna Lattanzi, Lorenzo Maggi, Patrizia Sabatelli, Giulia Ricci, Lucia Ruggiero, Cristina Cappelletti, Marta Columbaro, Luisa Politano, Antoine Muchir, Giuseppe Boriani, Camilla Evangelisti, Sabino Prencipe, Gabriele Siciliano, Elena Pegoraro, Pia Bernasconi, Paola Cavalcante, Liliana Vercelli, Carmelo Rodolico, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Pisa - Università di Pisa, Second University of Naples-Caserta, University of Naples Federico II, University of Turin, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Università degli Studi di Modena e Reggio Emilia, Universita degli Studi di Padova, Istituto Nazionale Genetica Molecolare [Milano] (INGM), Fondazione Santa Lucia [IRCCS], Clinical and Behavioral Neurology [IRCCS Santa Lucia], Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Bernasconi, Pia, Carboni, Nicola, Ricci, Giulia, Siciliano, Gabriele, Politano, Luisa, Maggi, Lorenzo, Mongini, Tiziana, Vercelli, Liliana, Rodolico, Carmelo, Biagini, Elena, Boriani, Giuseppe, Ruggiero, Lucia, Santoro, Lucio, Schena, Elisa, Prencipe, Sabino, Evangelisti, Camilla, Pegoraro, Elena, Morandi, Lucia, Columbaro, Marta, Lanzuolo, Chiara, Sabatelli, Patrizia, Cavalcante, Paola, Cappelletti, Cristina, Bonne, Gisèle, Muchir, Antoine, Lattanzi, Giovanna, Bernasconi P., Carboni N., Ricci G., Siciliano G., Politano L., Maggi L., Mongini T., Vercelli L., Rodolico C., Biagini E., Boriani G., Ruggiero L., Santoro L., Schena E., Prencipe S., Evangelisti C., Pegoraro E., Morandi L., Columbaro M., Lanzuolo C., Sabatelli P., Cavalcante P., Cappelletti C., Bonne G., Muchir A., and Lattanzi G.
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0301 basic medicine ,Male ,Basic fibroblast growth factor ,LMNA ,chemistry.chemical_compound ,Mice ,Transforming growth factor beta 2 (TGF b2) ,Medicine ,Muscular Dystrophy ,Muscular dystrophy ,Emery–Dreifuss muscular dystrophy ,LMNA gene ,Cells, Cultured ,lamin A/C ,muscle fibrosis ,Mice, Knockout ,Cultured ,tendon fibrosis ,biology ,Myogenesis ,Emery-Dreifuss ,Cell Differentiation ,Middle Aged ,Muscular Dystrophy, Emery-Dreifuss ,3. Good health ,Laminopathie ,Transforming growth factor beta 2 (TGF β2) ,Fibroblast ,Female ,Interleukin 17 ,Human ,musculoskeletal diseases ,Adult ,Cells ,Knockout ,Muscle Cell ,Dilated Cardiomyopathy (CMD1A) ,Emery-Dreifuss Muscular Dystrophy type 2 (EDMD2) ,Laminopathies ,Limb-Girdle muscular Dystrophy 1B (LGMD1B) ,muscular differentiation ,03 medical and health sciences ,Transforming Growth Factor beta2 ,Young Adult ,Lamin A/C ,Muscle fibrosis ,Muscular differentiation ,Tendon fibrosis ,Animals ,Fibroblasts ,Humans ,Muscle Cells ,Tenocytes ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Interleukin 6 ,Animal ,Muscular Dystrophy, Emery-Dreifu ,business.industry ,muscle fibrosi ,Cell Biology ,Transforming growth factor beta ,Tenocyte ,medicine.disease ,030104 developmental biology ,chemistry ,biology.protein ,Cancer research ,business ,Tendon fibrosi ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF β2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF β2 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss Muscular Dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF β2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF β2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF β2-dependent mechanisms were also determined in laminopathic cells, where TGF β2 activated AKT/mTOR phosphorylation. These data show that TGF β2 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF β2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies.
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- 2018
13. The role of transposable elements activity in aging and their possible involvement in laminopathic diseases
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Valeria Cavaliere, Giovanna Lattanzi, Davide Andrenacci, Andrenacci D., Cavaliere V., and Lattanzi G.
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0301 basic medicine ,Transposable element ,Genome instability ,Aging ,Heterochromatin ,Context (language use) ,Biology ,Gene mutation ,Biochemistry ,Genome ,Genomic Instability ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Humans ,Sterile inflammation ,Gene silencing ,Constitutive heterochromatin ,Molecular Biology ,Inflammation ,fungi ,Lamins ,Cell biology ,Ageing ,030104 developmental biology ,Laminopathie ,Neurology ,DNA Transposable Elements ,DNA damage ,Transposons ,Lamin ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Eukaryotic genomes contain a large number of transposable elements, part of which are still active and able to transpose in the host genome. Mobile element activation is repressed to avoid deleterious effects, such as gene mutations or chromosome rearrangements. Control of transposable elements includes a variety of mechanisms comprising silencing pathways, which are based on the production of small non-coding RNAs. Silencing can occur either through transposable element RNA degradation or through the targeting of DNA sequences by heterochromatin formation and consequent transcriptional inhibition. Since the important role of the heterochromatin silencing, the gradual loss of heterochromatin marks in constitutive heterochromatin regions during the aging process promotes derepression of transposable elements, which is considered a cause of the progressive increase in genomic instability and of the activation of inflammatory responses. This review provides an overview of the effects of heterochromatin loss on the activity of transposable elements during the aging process and the possible impact on genome function. In this context, we discuss the possible role of the nuclear lamina, a major player in heterochromatin dynamics, in the regulation of transposable element activity and potential implications in laminopathic diseases.
- Published
- 2020
14. Potential therapeutic effects of the MTOR inhibitors for preventing ageing and progeria-related disorders
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Vittoria Cenni, Giovanna Lattanzi, Camilla Evangelisti, Evangelisti C., Cenni V., and Lattanzi G.
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0301 basic medicine ,mTOR inhibitors ,Aging ,mTOR inhibitor ,Protein Kinase Inhibitor ,Biology ,Models, Biological ,03 medical and health sciences ,Progeria ,medicine ,Animals ,Humans ,Pharmacology (medical) ,progeria‐related diseases ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,lamin A ,Pharmacology ,integumentary system ,Cell growth ,rapamycin ,Animal ,progeria-related disease ,TOR Serine-Threonine Kinases ,Autophagy ,Review‐themed Issue ,Hutchinson–Gilford Progeria syndrome (HGPS) ,medicine.disease ,Hedgehog signaling pathway ,Cell biology ,030104 developmental biology ,ageing ,Signal transduction ,Lamin ,Human - Abstract
The mammalian target of rapamycin (mTOR) pathway is an highly conserved signal transduction axis involved in many cellular processes, such as cell growth, survival, transcription, translation, apoptosis, metabolism, motility and autophagy. Recently, this signalling pathway has come to the attention of the scientific community owing to the unexpected finding that inhibition of mTOR by rapamycin, an antibiotic with immunosuppressant and chemotherapeutic properties, extends lifespan in diverse animal models. Moreover, rapamycin has been reported to rescue the cellular phenotype in a progeroid syndrome [Hutchinson–Gilford Progeria syndrome (HGPS)] that recapitulates most of the traits of physiological ageing. The promising perspectives raised by these results warrant a better understanding of mTOR signalling and the potential applications of mTOR inhibitors to counteract ageing‐associated diseases and increase longevity. This review is focused on these issues.
- Published
- 2016
15. Laminopathies and lamin-associated signaling pathways
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Giovanna Lattanzi, Cristina Capanni, Nadir M. Maraldi, Vittoria Cenni, Milena Fini, Maraldi NM, Capanni C, Cenni V, Fini M, and Lattanzi G.
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Cell signaling ,Lipodystrophy ,LAMINOPATHIES ,Emerin ,Biology ,Biochemistry ,Nuclear envelope ,Muscular Dystrophies ,Progeroid syndromes ,LMNA ,Cellular signaling ,medicine ,Animals ,Humans ,Disease ,Nuclear protein ,Molecular Biology ,Transcription factor anchorage ,Genetics ,Lamin Type B ,Nuclear Proteins ,Cell Biology ,Lamin Type A ,medicine.disease ,Nuclear matrix ,Cell biology ,Mutation ,Signal transduction ,Lamin ,Signal Transduction - Abstract
Laminopathies are genetic diseases due to mutations or altered post-translational processing of nuclear envelope/lamina proteins. The majority of laminopathies are caused by mutations in the LMNA gene, encoding lamin A/C, but manifest as diverse pathologies including muscular dystrophy, lipodystrophy, neuropathy, and progeroid syndromes. Lamin-binding proteins implicated in laminopathies include lamin B2, nuclear envelope proteins such as emerin, MAN1, LBR, and nesprins, the nuclear matrix protein matrin 3, the lamina-associated polypeptide, LAP2alpha and the transcriptional regulator FHL1. Thus, the altered functionality of a nuclear proteins network appears to be involved in the onset of laminopathic diseases. The functional interplay among different proteins involved in this network implies signaling partners. The signaling effectors may either modify nuclear envelope proteins and their binding properties, or use nuclear envelope/lamina proteins as platforms to regulate signal transduction. In this review, both aspects of lamin-linked signaling are presented and the major pathways so far implicated in laminopathies are summarized.
- Published
- 2011
16. A-type lamins and signaling: The PI 3-kinase/Akt pathway moves forward
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Nadir M. Maraldi, Jessika Bertacchini, Sandra Marmiroli, Francesca Beretti, Anto De Pol, Marianna Guida, Vittoria Cenni, Giovanna Lattanzi, Marmiroli S, Bertacchini J, Beretti F, Cenni V, Guida M, De Pol A, Maraldi NM, and Lattanzi G.
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MAPK/ERK pathway ,Cell signaling ,animal structures ,Physiology ,Clinical Biochemistry ,LAMINS PHOSPHORYLATION AKT/PKB NUCLEUS LAMINOPHATY SIGNALLING ,Biology ,Phosphatidylinositol 3-Kinases ,Animals ,Humans ,Protein kinase B ,PI3K/AKT/mTOR pathway ,integumentary system ,Kinase ,Cell Biology ,Lamin Type A ,Cell biology ,Disease Models, Animal ,Mutation ,embryonic structures ,Nuclear lamina ,Signal transduction ,Proto-Oncogene Proteins c-akt ,Lamin ,Protein Binding ,Signal Transduction - Abstract
Lamin A/C is a nuclear lamina constituent mutated in a number of human inherited disorders collectively referred to as laminopathies. The occurrence and significance of lamin A/C interplay with signaling molecules is an old question, suggested by pioneer studies performed in vitro. However, this relevant question has remained substantially unanswered, until data obtained in cellular and organismal models of laminopathies have indicated two main aspects of lamin A function. The first aspect is that lamins establish functional interactions with different protein platforms, the second aspect is that lamin A/C activity and altered function may elicit different effects in different cells and tissue types and even in different districts of the same tissue. Both these observations strongly suggest that signaling mechanisms targeting lamin A/C or its binding partners may regulate such a plastic behavior. A number of very recent data show involvement of kinases, as Akt and Erk, or phosphatases, as PP1 and PP2, in lamin A-linked cellular mechanisms. Moreover, altered activation of signaling in laminopathies and rescue of the pathological phenotype in animal models by inhibitors of signaling pathways, strongly suggest that signaling effectors related to lamin A/C may be implicated in the pathogenesis of laminopathies and may represent targets of therapeutic intervention. In face of such an open perspective of basic and applied research, we review current evidence of lamin A/C interplay with signaling molecules, with particular emphasis on the lamin A-Akt interaction and on the biological significance of their relationship. J. Cell. Physiol. 220: 553–561, 2009. © 2009 Wiley-Liss, Inc.
- Published
- 2009
17. Prelamin A is involved in early steps of muscle differentiation
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Giovanna Lattanzi, Anna Rocchi, Daria Camozzi, Roland Foisner, Marta Columbaro, Nadir M. Maraldi, Rosalba Del Coco, Katia Scotlandi, Elisabetta Mattioli, Stefano Squarzoni, Cristina Capanni, Capanni C, Del Coco R, Squarzoni S, Columbaro M, Mattioli E, Camozzi D, Rocchi A, Scotlandi K, Maraldi N, Foisner R, and Lattanzi G.
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congenital, hereditary, and neonatal diseases and abnormalities ,Time Factors ,Caveolin 3 ,Cellular differentiation ,Emerin ,Biology ,Muscle Development ,Myoblasts ,Mice ,Animals ,Humans ,Protein Precursors ,Muscle, Skeletal ,Cells, Cultured ,Cellular localization ,integumentary system ,Muscle cell differentiation ,Gene Expression Regulation, Developmental ,Membrane Proteins ,Nuclear Proteins ,Cell Differentiation ,Cell Biology ,Lamin Type A ,Cell biology ,DNA-Binding Proteins ,Biochemistry ,Nuclear lamina ,Protein Processing, Post-Translational ,C2C12 ,Lamin ,Protein Binding - Abstract
Lamin A is a nuclear lamina constituent implicated in a number of human disorders including Emery-Dreifuss muscular dystrophy. Since increasing evidence suggests a role of the lamin A precursor in nuclear functions, we investigated the processing of prelamin A during differentiation of C2C12 mouse myoblasts. We show that both protein levels and cellular localization of prelamin A are modulated during myoblast activation. Similar changes of lamin A-binding proteins emerin and LAP2alpha were observed. Furthermore, prelamin A was found in a complex with LAP2alpha in differentiating myoblasts. Prelamin A accumulation in cycling myoblasts by expressing unprocessable mutants affected LAP2alpha and PCNA amount and increased caveolin 3 mRNA and protein levels, while accumulation of prelamin A in differentiated muscle cells following treatment with a farnesyl transferase inhibitor appeared to inhibit caveolin 3 expression. Our data provide evidence for a critical role of the lamin A precursor in the early steps of muscle cell differentiation.
- Published
- 2008
18. Remodelling of the nuclear lamina during human cytomegalovirus infection: role of the viral proteins pUL50 and pUL53
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Daria Camozzi, Paola Dal Monte, Maria Paola Landini, Sara Pignatelli, Cristina Capanni, Giovanna Lattanzi, Cecilia Valvo, Camozzi D, Pignatelli S, Valvo C, Lattanzi G, Capanni C, Dal Monte P, and Landini MP
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Human cytomegalovirus ,Immunoprecipitation ,viruses ,Cytomegalovirus ,Biology ,medicine.disease_cause ,Herpesviridae ,Virus ,Viral Proteins ,Virology ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,Lung ,Cell Nucleus ,Nuclear Lamina ,Virion ,Fibroblasts ,medicine.disease ,Lamins ,medicine.anatomical_structure ,Cytoplasm ,COS Cells ,Nuclear lamina ,Nucleus ,Lamin - Abstract
A fundamental step in the efficient production of human cytomegalovirus (HCMV) progeny is viral egress from the nucleus to the cytoplasm of infected cells. In the family Herpesviridae, this process involves alteration of nuclear lamina components by two highly conserved proteins, whose homologues in HCMV are named pUL50 and pUL53. This study showed that HCMV infection induced the mislocalization of nuclear lamins and that pUL50 and pUL53 play a role in this event. At late stages of infection, both lamin A/C and lamin B showed an irregular distribution on the nuclear rim, coincident with areas of pUL53 accumulation. No variations in the total amount of nuclear lamins could be detected, supporting the view that HCMV induces a qualitative, rather than a quantitative, alteration of these cellular components, as has been suggested previously for other herpesviruses. Interestingly, pUL53, in the absence of other viral products, localized diffusely in the nucleus, whilst the co-expression and interaction of pUL53 with its partner, pUL50, restored its nuclear rim localization in distinct patches, thus indicating that pUL50 is sufficient to induce the localization of pUL53 observed during virus infection. Importantly, analysis of the nuclear lamina in the presence of pUL50–pUL53 complexes at the nuclear boundary and in the absence of other viral products showed that the two viral proteins were sufficient to promote alterations of lamins, strongly resembling those observed during HCMV infection. These results suggest that pUL50 and pUL53 may play an important role in the exit of virions from the nucleus by inducing structural modifications of the nuclear lamina.
- Published
- 2008
19. Ankrd2/ARPP is a novel Akt2 specific substrate andregulates myogenic differentiation upon cellular exposure to H(2)O(2)
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Lucio Cocco, Francesca Beretti, Sandra Marmiroli, Alberto Bavelloni, Vittoria Cenni, Nadir M. Maraldi, Francesca Tagliavini, Lucia Manzoli, Giovanna Lattanzi, Cenni V, Bavelloni A, Beretti F, Tagliavini F, Manzoli L, Lattanzi G, Maraldi NM, Cocco L, and Marmiroli S
- Subjects
Gene isoform ,ANKRD2 ,Myoblasts, Skeletal ,Muscle Proteins ,AKT2 ,Biology ,Muscle Development ,Serine ,Mice ,Myocyte ,Animals ,Humans ,Phosphorylation ,Molecular Biology ,Protein kinase B ,Cell Nucleus ,Akt ,cell signaling ,Akt kinase ,Akt substrates ,muscle fiber ,ROS ,oxidative stress ,Ankrd2 ,Nuclear Proteins ,Cell Differentiation ,Cell Biology ,Hydrogen Peroxide ,Articles ,Oxidants ,Ankdr2 ,Molecular biology ,Signaling ,Cell biology ,Repressor Proteins ,Oxidative Stress ,Protein Transport ,PHOSPHOSUBSTRATES ,C2C12 ,Proto-Oncogene Proteins c-akt ,Protein Binding - Abstract
A proteomic-based search for novel substrates of Akt was undertaken in C2C12 murine muscle cells. Our data demonstrate that Akt isoform 2 phosphorylates Ankrd2 at Serine 99 in response to H2O2 stimuli, regulating muscle differentiation rate., Activation of Akt-mediated signaling pathways is crucial for survival, differentiation, and regeneration of muscle cells. A proteomic-based search for novel substrates of Akt was therefore undertaken in C2C12 murine muscle cells exploiting protein characterization databases in combination with an anti–phospho-Akt substrate antibody. A Scansite database search predicted Ankrd2 (Ankyrin repeat domain protein 2, also known as ARPP) as a novel substrate of Akt. In vitro and in vivo studies confirmed that Akt phosphorylates Ankrd2 at Ser-99. Moreover, by kinase assay with recombinant Akt1 and Akt2, as well as by single-isoform silencing, we demonstrated that Ankrd2 is a specific substrate of Akt2. Ankrd2 is typically found in skeletal muscle cells, where it mediates the transcriptional response to stress conditions. In an attempt to investigate the physiological implications of Ankrd2 phosphorylation by Akt2, we found that oxidative stress induced by H2O2 triggers this phosphorylation. Moreover, the forced expression of a phosphorylation-defective mutant form of Ankrd2 in C2C12 myoblasts promoted a faster differentiation program, implicating Akt-dependent phosphorylation at Ser-99 in the negative regulation of myogenesis in response to stress conditions.
- Published
- 2011
20. Muscular laminopathies: role of prelamin A in early steps of muscle differentiation
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Marta Columbaro, Rosalba Del Coco, Francesco A. Manzoli, Cristina Capanni, Elisabetta Mattioli, Giovanna Lattanzi, Nadir M. Maraldi, Stefano Squarzoni, Maraldi NM, Capanni C, Del Coco R, Squarzoni S, Columbaro M, Mattioli E, Lattanzi G, and Manzoli FA.
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Emerin ,Muscle Development ,Mice ,Muscular Diseases ,Genetics ,medicine ,Myocyte ,Animals ,Humans ,Regeneration ,Muscular dystrophy ,skeletal muscle ,Protein Precursors ,Muscle, Skeletal ,Molecular Biology ,Cellular localization ,integumentary system ,Muscle cell differentiation ,Chemistry ,Nuclear Proteins ,Cell Differentiation ,medicine.disease ,Lamin Type A ,Cell biology ,Caveolin 3 ,Molecular Medicine ,C2C12 ,Lamin - Abstract
Mutations in A-type lamins or lamin-binding proteins are involved in the pathogenesis of diseases referred to as laminopathies (Worman et al., 2009). They include both tissue-specific disorders affecting striated muscle (muscular laminopathies), adipose tissue (lipodystrophic laminopathies), and syndromes in which many tissues undergo premature ageing (progeric laminopathies). Howmutations in LMNA cause diverse diseases is one of the most intriguing riddle in medical genetics. Two hypotheses have emerged to account for the molecular basis of the wide spectrum of these diseases. The mechanical stress hypothesis, mainly based on observations in cultured cells, proposes that mutations in A-type lamins lead to increased nuclear fragility and eventual nuclear disruption in tissues exposed to mechanical strain (Lammerding et al., 2005). The gene expression hypothesis suggests that mutations in A-type lamins lead to abnormal tissue-specific gene regulation. This model is based on findings that A-type lamins and associated proteins bind to chromatin and transcriptional regulators. The gene expression hypothesis does not exclude effects that mechanical stress may have on cells; in fact, both gene expression, as well as signalling pathways and mechanical integrity should be perturbed in cells carrying laminopathy mutations (Cohen et al., 2008). Furthermore, signalling pathways that culminate in transcription factor activity may also be regulated at the nuclear envelope and lamina, which act as a platform or scaffold necessary for the appropriate localization of factors important in specific tissue differentiation (Schirmer and Foisner, 2007; Pekovic and Hutchison, 2008; Andrés and Gonzalez, 2009).
- Published
- 2010
21. Lamin A precursor induces barrier-to-autointegration factor nuclear localization
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Tokuko Haraguchi, Cristina Capanni, Egon Ogris, Vittoria Cenni, Giovanna Lattanzi, Nadir M. Maraldi, Giuseppe Novelli, Stefano Squarzoni, Stefan Schüchner, Capanni C, Cenni V, Haraguchi T, Squarzoni S, Schüchner S, Ogris E, Novelli G, Maraldi NM, and Lattanzi G.
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Barrier-to-autointegration factor ,Biology ,Chromatin remodeling ,Progeria ,medicine ,Animals ,Humans ,Protein Precursors ,Nuclear protein ,Molecular Biology ,Cell Nucleus ,Genetics ,integumentary system ,Nuclear Proteins ,nutritional and metabolic diseases ,Cell Biology ,Fibroblasts ,Lamin Type A ,Progerin ,medicine.disease ,Rats ,Chromatin ,Cell biology ,DNA-Binding Proteins ,Protein Transport ,HEK293 Cells ,Settore MED/03 - Genetica Medica ,Nuclear lamina ,Protein Processing, Post-Translational ,Lamin ,Protein Binding ,Developmental Biology - Abstract
Lamin A, a protein component of the nuclear lamina, is synthesized as a precursor named prelamin A, whose multi-step maturation process involves different protein intermediates. As demonstrated in laminopathies such as familial partial lipodystrophy, mandibuloacral dysplasia, Werner syndrome, Hutchinson-Gilford progeria syndrome and restrictive dermopathy, failure of prelamin A processing results in the accumulation of lamin A protein precursors inside the nucleus which dominantly produces aberrant chromatin structure. To understand if nuclear lamina components may be involved in prelamin A chromatin remodeling effects, we investigated barrier-to-autointegration factor (BAF) localization and expression in prelamin A accumulating cells. BAF is a DNA-binding protein that interacts directly with histones, lamins and LEM-domain proteins and has roles in chromatin structure, mitosis and gene regulation. In this study, we show that the BAF heterogeneous localization between nucleus and cytoplasm observed in HEK293 cycling cells changes in response to prelamin A accumulation. In particular, we observed that the accumulation of lamin A, non-farnesylated prelamin A and farnesylated carboxymethylated lamin A precursors induce BAF nuclear translocation. Moreover, we show that the treatment of human fibroblasts with prelamin A interfering drugs results in similar changes. Finally, we report that the accumulation of progerin, a truncated form of farnesylated and carboxymethylated prelamin A identified in Hutchinson-Gilford progeria syndrome cells, induces BAF recruitment in the nucleus. These findings are supported by coimmunoprecipitation of prelamin A or progerin with BAF in vivo and suggest that BAF could mediate prelamin A-induced chromatin effects.
- Published
- 2010
22. Constitutive heterochromatin: a surprising variety of expressed sequences
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Ruggiero Caizzi, Ennio Giordano, Patrizio Dimitri, Maria Carmela Accardo, Giovanna Lattanzi, Giuseppe Biamonti, Dimitri, P, Caizzi, R, Giordano, Ennio, Carmela Accardo, M, Lattanzi, G, and Biamonti, G.
- Subjects
Genetics ,Genome evolution ,Euchromatin ,Heterochromatin ,fungi ,Chromosome Mapping ,Gene Expression ,Genomics ,Biology ,Genome ,Drosophila melanogaster ,Eukaryotic chromosome fine structure ,Constitutive heterochromatin ,Animals ,Humans ,Heterochromatin protein 1 ,Drosophila ,Genetics (clinical) ,Pericentric heterochromatin ,In Situ Hybridization, Fluorescence - Abstract
The organization of chromosomes into euchromatin and heterochromatin is amongst the most important and enigmatic aspects of genome evolution. Constitutive heterochromatin is a basic yet still poorly understood component of eukaryotic chromosomes, and its molecular characterization by means of standard genomic approaches is intrinsically difficult. Although recent evidence indicates that the presence of transcribed genes in constitutive heterochromatin is a conserved trait that accompanies the evolution of eukaryotic genomes, the term heterochromatin is still considered by many as synonymous of gene silencing. In this paper, we comprehensively review data that provide a clearer picture of transcribed sequences within constitutive heterochromatin, with a special emphasis on Drosophila and humans.
- Published
- 2008
23. Lamin A Ser404 Is a Nuclear Target of Akt Phosphorylation in C2C12 Cells
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Manfred Wehnert, Nadir M. Maraldi, Anto De Pol, Oriano Marin, Alberto Bavelloni, Francesca Beretti, Giovanna Lattanzi, Vittoria Cenni, Jessika Bertacchini, Sandra Marmiroli, Lucio Cocco, Giorgio Arrigoni, Massimo Riccio, Veena K. Parnaik, Maria Ruzzene, Cenni V, Bertacchini J, Beretti F, Lattanzi G, Bavelloni A, Riccio M, Ruzzene M, Marin O, Arrigoni G, Parnaik V, Wehnert M, Maraldi NM, de Pol A, Cocco L, and Marmiroli S
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Biology ,Kidney ,Transfection ,Biochemistry ,Cell Line ,Akt/PKB ,Myoblasts ,Mice ,proteomics ,nucleus ,Lamin A/C ,2D-electrophoresis ,phosphorylation ,Serine ,Animals ,Humans ,Protein kinase B ,Cell Nucleus ,integumentary system ,Activator (genetics) ,General Chemistry ,Lamin Type A ,Molecular biology ,Recombinant Proteins ,embryonic structures ,Phosphorylation ,Nuclear lamina ,Signal transduction ,C2C12 ,Proto-Oncogene Proteins c-akt ,Lamin - Abstract
Akt/PKB is a central activator of multiple signaling pathways coupled with a large number of stimuli. Although both localization and activity of Akt in the nuclear compartment are well-documented, most Akt substrates identified so far are located in the cytoplasm, while nuclear substrates have remained elusive. A proteomic-based search for nuclear substrates of Akt was undertaken, exploiting 2D-electrophoresis/MS in combination with an anti-Akt phosphosubstrate antibody. This analysis indicated lamin A/C as a putative substrate of Akt in C2C12 cells. In vitro phosphorylation of endogenous lamin A/C by recombinant Akt further validated this result. Moreover, by phosphopeptide analysis and point mutation, we established that lamin A/C is phosphorylated by Akt at Ser404, in an evolutionary conserved Akt motif. To delve deeper into this, we raised an antibody against the lamin A Ser404 phosphopeptide which allowed us to determine that phosphorylation of lamin A Ser404 is triggered by the well-known Akt activator insulin, and is therefore to be regarded as a physiological response. Remarkably, expression of S404A lamin A in primary cells from healthy tissue caused the nuclear abnormalities that are a hallmark of Emery-Dreifuss muscular dystrophy (EDMD) cells. Indeed, it is known that mutations at several sites in lamin A/C cause autosomal dominant EDMD. Very importantly, we show here that Akt failed to phosphorylate lamin A/C in primary cells from an EDMD-2 patient with lamin A/C mutated in the Akt consensus motif. Together, our data demonstrate that lamin A/C is a novel signaling target of Akt, and implicate Akt phosphorylation of lamin A/C in the correct function of the nuclear lamina.
- Published
- 2008
24. SREBP1 interaction with prelamin A forms: a pathogenic mechanism for lipodystrophic laminopathies
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Francesco A. Manzoli, Daria Camozzi, Cristina Capanni, Andrea Facchini, Giovanna Lattanzi, Nadir M. Maraldi, Maraldi NM, Capanni C, Lattanzi G, Camozzi D, Facchini A, and Manzoli FA.
- Subjects
Cancer Research ,Lipodystrophy ,Biology ,Models, Biological ,Mice ,3T3-L1 Cells ,Genetics ,Adipocytes ,Animals ,Humans ,Protein Precursors ,Protein Structure, Quaternary ,Molecular Biology ,Metabolic Syndrome ,Prenylation ,Mechanism (biology) ,Nuclear Proteins ,Cell Differentiation ,PRELAMIN A ,Lamin Type A ,Sterol regulatory element-binding protein ,Cell biology ,PPAR gamma ,Protein Transport ,Molecular Medicine ,Sterol Regulatory Element Binding Protein 1 - Published
- 2008
25. Laminopathies: a chromatin affair
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Patrizia Sabatelli, Cristina Capanni, Nadir M. Maraldi, Giovanna Lattanzi, Elisabetta Mattioli, Francesco A. Manzoli, Stefano Squarzoni, Marta Columbaro, Maraldi NM, Lattanzi G, Capanni C, Columbaro M, Mattioli E, Sabatelli P, Squarzoni S, and Manzoli FA.
- Subjects
Genetics ,Cancer Research ,integumentary system ,Amino acid substitution ,Biology ,Chromatin ,Lamins ,Amino Acid Substitution ,Mutation ,Mutation (genetic algorithm) ,Animals ,Humans ,Molecular Medicine ,Molecular Biology ,Lamin - Abstract
In the last 5 years, an impressive series of genetic diseases (16 distinct diseased phenotypes have been so far identified), affecting metabolic and/or developmental processes, have been demonstrated to be caused by mutation of LMNA gene and collectively referred to as laminopathies. Most of these diseases are characterized by dystrophic/degenerative processes affecting different tissues and organs. Nuclear defects, consisting in heterochromatin focal or total loss and in nuclear lamina thickening or invagination, characterize the cells from laminopathic patients. Furthermore, accumulation of pre-lamin A has been demonstrated to occur, at least in a large group of laminopathies. These findings suggest a possible pathogenic mechanism for laminopathies. The cells bearing mutated pre-lamin A could not be able to maintain the chromatin organization required by differentiation programs, which represents an epigenetic marker of each cell lineage undergoing a differentiation process. These alterations have been demonstrated to be due to a lack of mutant lamin A to physiologically interact with heterochromatin-associated proteins, including HP1. The use of specific drugs that interfere with the maturation of lamin A allowed us to demonstrate that the accumulation of farnesylated pre-lamin A induces the appearance of nuclear phenotypes similar to those occurring in progeric syndromes. Furthermore, LMNA mutations found in several laminopathies reduce the transcriptional capability of the cells accumulating pre-lamin A. Therefore, the pathogenic mechanism of laminopathies appears to involve alterations of the chromatin organization and transcriptional capability required by differentiation programs, not necessarily during early embryogenesis, in which cells lack lamin A/C, but in adult cell populations capable of differentiating under specific stimuli. These cells, that onstitute the stem reservoir of several adult tissues, and that are typically represented by mesenchymal stromal cells, in the presence of mutant lamin A/C, and of accumulating prelamin A, present phenotypic alterations of the chromatin pattern and impairment of gene expression mechanisms. This could result in an accelerated cellular senescence, which could be characterized by the presence of progerin in progeric laminopathies, and of pre-lamin A in other laminopathies, in which not all tissues but specific tissues are involved. In fact, lamins and lamin-associated proteins, by constituting a platform for the interaction with transcription factors, may contribute to a fine modulation of gene expression programs, typical of each cell lineage.
- Published
- 2006
26. Linkage of lamins to fidelity of gene transcription
- Author
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Giovanna Lattanzi, Nadir M. Maraldi, Maraldi NM, and Lattanzi G.
- Subjects
Transcription, Genetic ,Genetic Linkage ,Nuclear Envelope ,Cellular differentiation ,LAMINOPATHIES ,Muscle disorder ,Biology ,Models, Biological ,Chromatin remodeling ,LAMIN ,Gene expression ,Genetics ,Animals ,Humans ,Molecular Biology ,Transcription factor ,Cell Nucleus ,MUSCLE DISORDERS ,GENETIC DISORDER ,Nuclear Proteins ,GENE TRANSCRIPTION ,Chromatin ,Lamins ,Nuclear lamina ,Lamin - Abstract
Two major events are emerging as being involved in the fine regulatory mechanisms that control gene expression through the nuclear envelope/lamina. The first is the linkage of envelope proteins to transcription factors, most of which function as transcriptional repressors. The second is the interplay between nuclear lamina/nuclear envelope proteins and chromatin, through more or less direct interactions with DNA-binding proteins. The first mechanism appears to play a major role in tissue-specific functions, whereas the latter mechanism likely modifies higher-order chromatin organization, thus regulating differentiation and aging. This review highlights the importance of the study of a group of genetic diseases, collectively referred to as laminopathies, to understand the actual role played by lamins in ensuring the fidelity of gene expression and in modulating cell differentiation.
- Published
- 2005
27. Lamin A N-terminal phosphorylation is associated with myoblast activation: impairment in Emery-Dreifuss muscular dystrophy
- Author
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Sandra Marmiroli, Andrea Ognibene, Patrizia Sabatelli, N.M. Maraldi, Marta Columbaro, Elisabetta Mattioli, Vittoria Cenni, Stefano Squarzoni, Cristina Capanni, Gisèle Bonne, Giovanna Lattanzi, Luciano Merlini, Cenni V, Sabatelli P, Mattioli E, Marmiroli S, Capanni C, Ognibene A, Squarzoni S, Maraldi NM, Bonne G, Columbaro M, Merlini L, and Lattanzi G.
- Subjects
medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,animal structures ,Muscle Fibers, Skeletal ,Emerin ,LMNA ,Biology ,Cell Line ,Myoblasts ,HUTCHINSON-GILFORD PROGERIA ,Mice ,NUCLEAR-ENVELOPE PROTEINS ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Insulin ,Phosphorylation ,Muscular dystrophy ,Emery–Dreifuss muscular dystrophy ,Genetics (clinical) ,integumentary system ,Skeletal muscle ,Cell Differentiation ,DILATED CARDIOMYOPATHY ,Lamin Type A ,medicine.disease ,Muscular Dystrophy, Emery-Dreifuss ,Cell biology ,Endocrinology ,medicine.anatomical_structure ,Muscular Dystrophies, Limb-Girdle ,PARTIAL LIPODYSTROPHY ,embryonic structures ,Original Article ,Protein Processing, Post-Translational ,Lamin ,Signal Transduction ,Limb-girdle muscular dystrophy - Abstract
Background: Skeletal muscle disorders associated with mutations of lamin A/C gene include autosomal Emery–Dreifuss muscular dystrophy and limb girdle muscular dystrophy 1B. The pathogenic mechanism underlying these diseases is unknown. Recent data suggest an impairment of signalling mechanisms as a possible cause of muscle malfunction. A molecular complex in muscle cells formed by lamin A/C, emerin, and nuclear actin has been identified. The stability of this protein complex appears to be related to phosphorylation mechanisms. Objective: To analyse lamin A/C phosphorylation in control and laminopathic muscle cells. Methods: Lamin A/C N-terminal phosphorylation was determined in cultured mouse myoblasts using a specific antibody. Insulin treatment of serum starved myoblast cultures was carried out to evaluate involvement of insulin signalling in the phosphorylation pathway. Screening of four Emery–Dreifuss and one limb girdle muscular dystrophy 1B cases was undertaken to investigate lamin A/C phosphorylation in both cultured myoblasts and mature muscle fibres. Results: Phosphorylation of lamin A was observed during myoblast differentiation or proliferation, along with reduced lamin A/C phosphorylation in quiescent myoblasts. Lamin A N-terminus phosphorylation was induced by an insulin stimulus, which conversely did not affect lamin C phosphorylation. Lamin A/C was also hyperphosphorylated in mature muscle, mostly in regenerating fibres. Lamin A/C phosphorylation was strikingly reduced in laminopathic myoblasts and muscle fibres, while it was preserved in interstitial fibroblasts. Conclusions: Altered lamin A/C interplay with a muscle specific phosphorylation partner might be involved in the pathogenic mechanism of Emery–Dreifuss muscular dystrophy and limb girdle muscular dystrophy 1B.
- Published
- 2005
28. Laminopathies: involvement of structural nuclear proteins in the pathogenesis of an increasing number of human diseases
- Author
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Cristina Capanni, Elisabetta Mattioli, Giovanna Lattanzi, Nadir M. Maraldi, Andrea Ognibene, Stefano Squarzoni, Patrizia Sabatelli, Maraldi NM, Squarzoni S, Sabatelli P, Capanni C, Mattioli E, Ognibene A, and Lattanzi G.
- Subjects
Genetics ,Physiology ,Nuclear Envelope ,fungi ,Clinical Biochemistry ,Genetic Diseases, Inborn ,Nuclear Proteins ,Cell Biology ,Computational biology ,Biology ,Actins ,Chromatin ,Lamins ,Pathogenesis ,Gene Expression Regulation ,Hereditary Diseases ,Genes, Regulator ,Animals ,Humans ,Identification (biology) ,Nuclear protein ,Lamin - Abstract
Just at the beginning of the millennium the neologism laminopathies has been introduced in the scientific vocabulary. An exponential increase of interest on the subject started concomitantly, so that a formerly quite neglected group of rare human diseases is now widely investigated. This review will cover the history of the identification of the molecular basis for fourteen (since now) hereditary diseases arising from defects in genes that encode nuclear envelope and nuclear lamina-associated proteins and will also consider the hypotheses that can account for the role of structural nuclear proteins in the pathogenesis of diseases affecting a wide spectrum of tissues. Copyright 2004 Wiley-Liss, Inc.
- Published
- 2004
29. Different prelamin A forms accumulate in human fibroblasts: a study in experimental models and progeria
- Author
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N.M. Maraldi, Martine Auclair, Giuseppe Novelli, Mauro Magnani, Sabrina Dominici, Valentina Fiori, M Caron, Elisa Schena, Daria Camozzi, Corinne Vigouroux, Maria Rosaria D'Apice, Cristina Capanni, Giovanna Lattanzi, C. Le Dour, Dominici S, Fiori V, Magnani M, Schena E, Capanni C, Camozzi D, D'Apice MR, Le Dour C, Auclair M, Caron M, Novelli G, Vigouroux C, Maraldi NM, and Lattanzi G.
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Histology ,Protein Prenylation ,Biophysics ,Laminopathy ,Progeroid syndromes ,HIV-protease inhibitors ,Progeria ,Endopeptidases ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Protein Precursors ,Nuclear protein ,lcsh:QH301-705.5 ,anti-prelamin A antibodies ,FTI-277 ,Original Paper ,prelamin A ,integumentary system ,Chemistry ,laminopathies ,Membrane Proteins ,Metalloendopeptidases ,Nuclear Proteins ,nutritional and metabolic diseases ,Cell Biology ,Fibroblasts ,Lamin Type A ,medicine.disease ,AFCMe ,Cell biology ,lcsh:Biology (General) ,Membrane protein ,Protein prenylation ,Nuclear lamina ,Rabbits ,Lamin - Abstract
Lamin A is a component of the nuclear lamina mutated in a group of human inherited disorders known as laminopathies. Among laminopathies, progeroid syndromes and lipodystrophies feature accumulation of prelamin A, the precursor protein which, in normal cells, undergoes a multi-step processing to yield mature lamin A. It is of utmost importance to characterize the prelamin A form accumulated in each laminopathy, since existing evidence shows that drugs acting on protein processing can improve some pathological aspects. We report that two antibodies raised against differently modified prelamin A peptides show a clear specificity to full-length prelamin A or carboxymethylated farnesylated prelamin A, respectively. Using these antibodies, we demonstrated that inhibition of the prelamin A endoprotease ZMPSTE24 mostly elicits accumulation of full-length prelamin A in its farnesylated form, while loss of the prelamin A cleavage site causes accumulation of carboxymethylated prelamin A in progeria cells. These results suggest a major role of ZMPSTE24 in the first prelamin A cleavage step.
30. Emerin increase in regenerating muscle fibers
- Author
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M Rocca, Cristina Capanni, Nadir M. Maraldi, Giovanna Lattanzi, Elisabetta Mattioli, Marta Columbaro, C. Rutigliano, Patrizia Sabatelli, Stefano Squarzoni, Squarzoni S, Sabatelli P, Capanni C, Lattanzi G, Rutigliano C, Columbaro M, Mattioli E, Rocca M, and Maraldi NM.
- Subjects
Male ,Histology ,MUSCLE REGENERATOION ,Immunoblotting ,Muscle Fibers, Skeletal ,LAMINOPATHIES ,Biophysics ,Emerin ,Fluorescent Antibody Technique ,Thymopoietins ,Myoblasts ,medicine ,Animals ,Regeneration ,Myocyte ,RNA, Messenger ,Rats, Wistar ,Emery–Dreifuss muscular dystrophy ,Muscle, Skeletal ,lcsh:QH301-705.5 ,Cells, Cultured ,Cell Nucleus ,Muscle cell differentiation ,Chemistry ,MUSCLE DIFFERENTIATION ,Regeneration (biology) ,Membrane Proteins ,Nuclear Proteins ,Skeletal muscle ,Cell Differentiation ,Cell Biology ,Anatomy ,medicine.disease ,Immunohistochemistry ,Rats ,Up-Regulation ,Cell biology ,EMERIN ,medicine.anatomical_structure ,lcsh:Biology (General) ,Models, Animal ,Crush injury ,ITGA7 ,EMERY-DREIFUSS MUSCULAR DYSTROPHY - Abstract
The fate of emerin during skeletal muscle regeneration was investigated in an animal model by means of crush injury. Immunofluorescence, immunoblotting and mRNA analysis demonstrated that emerin level is increased in regenerating rat muscle fibers with respect to normal mature myofibers. This finding suggests an involvement of emerin during the muscle fiber regeneration process, in analogy with its reported involvement in muscle cell differentiation in vitro. The impairment of skeletal muscle physiological regeneration or reorganization could be a possible pathogenetic mechanism for Emery Dreifuss muscular dystrophy.
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