Author: "Jeanne Lainé" / Publication Year Range: Last 10 years - Searchworks@Jio Institute Digital Library Search Results

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27 results on '"Jeanne Lainé"'

1. Muscle cells of sporadic amyotrophic lateral sclerosis patients secrete neurotoxic vesicles

Author: Laura Le Gall, William J. Duddy, Cecile Martinat, Virginie Mariot, Owen Connolly, Vanessa Milla, Ekene Anakor, Zamalou G. Ouandaogo, Stephanie Millecamps, Jeanne Lainé, Udaya Geetha Vijayakumar, Susan Knoblach, Cedric Raoul, Olivier Lucas, Jean Philippe Loeffler, Peter Bede, Anthony Behin, Helene Blasco, Gaelle Bruneteau, Maria Del Mar Amador, David Devos, Alexandre Henriques, Adele Hesters, Lucette Lacomblez, Pascal Laforet, Timothee Langlet, Pascal Leblanc, Nadine Le Forestier, Thierry Maisonobe, Vincent Meininger, Laura Robelin, Francois Salachas, Tanya Stojkovic, Giorgia Querin, Julie Dumonceaux, Gillian Butler Browne, Jose‐Luis González De Aguilar, Stephanie Duguez, and Pierre Francois Pradat
Subjects: Secreted vesicles, Cell–cell communication, MND, sporadic ALS, Diseases of the musculoskeletal system, RC925-935, Human anatomy, QM1-695
Abstract: Abstract Background The cause of the motor neuron (MN) death that drives terminal pathology in amyotrophic lateral sclerosis (ALS) remains unknown, and it is thought that the cellular environment of the MN may play a key role in MN survival. Several lines of evidence implicate vesicles in ALS, including that extracellular vesicles may carry toxic elements from astrocytes towards MNs, and that pathological proteins have been identified in circulating extracellular vesicles of sporadic ALS patients. Because MN degeneration at the neuromuscular junction is a feature of ALS, and muscle is a vesicle‐secretory tissue, we hypothesized that muscle vesicles may be involved in ALS pathology. Methods Sporadic ALS patients were confirmed to be ALS according to El Escorial criteria and were genotyped to test for classic gene mutations associated with ALS, and physical function was assessed using the ALSFRS‐R score. Muscle biopsies of either mildly affected deltoids of ALS patients (n = 27) or deltoids of aged‐matched healthy subjects (n = 30) were used for extraction of muscle stem cells, to perform immunohistology, or for electron microscopy. Muscle stem cells were characterized by immunostaining, RT‐qPCR, and transcriptomic analysis. Secreted muscle vesicles were characterized by proteomic analysis, Western blot, NanoSight, and electron microscopy. The effects of muscle vesicles isolated from the culture medium of ALS and healthy myotubes were tested on healthy human‐derived iPSC MNs and on healthy human myotubes, with untreated cells used as controls. Results An accumulation of multivesicular bodies was observed in muscle biopsies of sporadic ALS patients by immunostaining and electron microscopy. Study of muscle biopsies and biopsy‐derived denervation‐naïve differentiated muscle stem cells (myotubes) revealed a consistent disease signature in ALS myotubes, including intracellular accumulation of exosome‐like vesicles and disruption of RNA‐processing. Compared with vesicles from healthy control myotubes, when administered to healthy MNs the vesicles of ALS myotubes induced shortened, less branched neurites, cell death, and disrupted localization of RNA and RNA‐processing proteins. The RNA‐processing protein FUS and a majority of its binding partners were present in ALS muscle vesicles, and toxicity was dependent on the expression level of FUS in recipient cells. Toxicity to recipient MNs was abolished by anti‐CD63 immuno‐blocking of vesicle uptake. Conclusions ALS muscle vesicles are shown to be toxic to MNs, which establishes the skeletal muscle as a potential source of vesicle‐mediated toxicity in ALS.
Published: 2022
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2. Caveolae and Bin1 form ring-shaped platforms for T-tubule initiation

Author: Eline Lemerle, Jeanne Lainé, Marion Benoist, Gilles Moulay, Anne Bigot, Clémence Labasse, Angéline Madelaine, Alexis Canette, Perrine Aubin, Jean-Michel Vallat, Norma B Romero, Marc Bitoun, Vincent Mouly, Isabelle Marty, Bruno Cadot, Laura Picas, and Stéphane Vassilopoulos
Subjects: caveolae, T-tubules, caveolin 3, correlative microscopy, caveolinopathies, Medicine, Science, Biology (General), QH301-705.5
Abstract: Excitation-contraction coupling requires a highly specialized membrane structure, the triad, composed of a plasma membrane invagination, the T-tubule, surrounded by two sarcoplasmic reticulum terminal cisternae. Although the precise mechanisms governing T-tubule biogenesis and triad formation remain largely unknown, studies have shown that caveolae participate in T-tubule formation and mutations of several of their constituents induce muscle weakness and myopathies. Here, we demonstrate that, at the plasma membrane, Bin1 and caveolae composed of caveolin-3 assemble into ring-like structures from which emerge tubes enriched in the dihydropyridine receptor. Bin1 expression lead to the formation of both rings and tubes and we show that Bin1 forms scaffolds on which caveolae accumulate to form the initial T-tubule. Cav3 deficiency caused by either gene silencing or pathogenic mutations results in defective ring formation and perturbed Bin1-mediated tubulation that may explain defective T-tubule organization in mature muscles. Our results uncover new pathophysiological mechanisms that may prove relevant to myopathies caused by Cav3 or Bin1 dysfunction.
Published: 2023
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3. Correction: Activated dendritic cells modulate proliferation and differentiation of human myoblasts

Author: Leandro Ladislau, Débora M. Portilho, Tristan Courau, Alhondra Solares-Pérez, Elisa Negroni, Jeanne Lainé, David Klatzmann, Adriana Bonomo, Yves Allenbach, Olivier Benveniste, Ingo Riederer, Wilson Savino, Vincent Mouly, Gillian Butler-Browne, and Claudia F. Benjamim
Subjects: Cytology, QH573-671
Published: 2022
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4. Ultrastructural and dynamic studies of the endosomal compartment in Down syndrome

Author: Alexandra Botté, Jeanne Lainé, Laura Xicota, Xavier Heiligenstein, Gaëlle Fontaine, Amal Kasri, Isabelle Rivals, Pollyanna Goh, Orestis Faklaris, Jack-Christophe Cossec, Etienne Morel, Anne-Sophie Rebillat, Dean Nizetic, Graça Raposo, and Marie-Claude Potier
Subjects: Down syndrome, Alzheimer’s disease, Early endosomes, Endocytosis, Electron microscopy, Super-resolution microscopy, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Enlarged early endosomes have been visualized in Alzheimer’s disease (AD) and Down syndrome (DS) using conventional confocal microscopy at a resolution corresponding to endosomal size (hundreds of nm). In order to overtake the diffraction limit, we used super-resolution structured illumination microscopy (SR-SIM) and transmission electron microscopies (TEM) to analyze the early endosomal compartment in DS. By immunofluorescence and confocal microscopy, we confirmed that the volume of Early Endosome Antigen 1 (EEA1)-positive puncta was 13–19% larger in fibroblasts and iPSC-derived neurons from individuals with DS, and in basal forebrain cholinergic neurons (BFCN) of the Ts65Dn mice modelling DS. However, EEA1-positive structures imaged by TEM or SR-SIM after chemical fixation had a normal size but appeared clustered. In order to disentangle these discrepancies, we imaged optimally preserved High Pressure Freezing (HPF)-vitrified DS fibroblasts by TEM and found that early endosomes were 75% denser but remained normal-sized. RNA sequencing of DS and euploid fibroblasts revealed a subgroup of differentially-expressed genes related to cargo sorting at multivesicular bodies (MVBs). We thus studied the dynamics of endocytosis, recycling and MVB-dependent degradation in DS fibroblasts. We found no change in endocytosis, increased recycling and delayed degradation, suggesting a “traffic jam” in the endosomal compartment. Finally, we show that the phosphoinositide PI (3) P, involved in early endosome fusion, is decreased in DS fibroblasts, unveiling a new mechanism for endosomal dysfunctions in DS and a target for pharmacotherapy.
Published: 2020
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5. Differential physiological roles for BIN1 isoforms in skeletal muscle development, function and regeneration

Author: Ivana Prokic, Belinda S. Cowling, Candice Kutchukian, Christine Kretz, Hichem Tasfaout, Vincent Gache, Josiane Hergueux, Olivia Wendling, Arnaud Ferry, Anne Toussaint, Christos Gavriilidis, Vasugi Nattarayan, Catherine Koch, Jeanne Lainé, Roy Combe, Laurent Tiret, Vincent Jacquemond, Fanny Pilot-Storck, and Jocelyn Laporte
Subjects: myotubular myopathy, centronuclear myopathy, xlmtm, sh3 domain, bar domain, myotonic dystrophy, triad, dynamin, myoblast fusion, animal model, Medicine, Pathology, RB1-214
Abstract: Skeletal muscle development and regeneration are tightly regulated processes. How the intracellular organization of muscle fibers is achieved during these steps is unclear. Here, we focus on the cellular and physiological roles of amphiphysin 2 (BIN1), a membrane remodeling protein mutated in both congenital and adult centronuclear myopathies (CNM), that is ubiquitously expressed and has skeletal muscle-specific isoforms. We created and characterized constitutive muscle-specific and inducible Bin1 homozygous and heterozygous knockout mice targeting either ubiquitous or muscle-specific isoforms. Constitutive Bin1-deficient mice died at birth from lack of feeding due to a skeletal muscle defect. T-tubules and other organelles were misplaced and altered, supporting a general early role for BIN1 in intracellular organization, in addition to membrane remodeling. Although restricted deletion of Bin1 in unchallenged adult muscles had no impact, the forced switch from the muscle-specific isoforms to the ubiquitous isoforms through deletion of the in-frame muscle-specific exon delayed muscle regeneration. Thus, ubiquitous BIN1 function is necessary for muscle development and function, whereas its muscle-specific isoforms fine tune muscle regeneration in adulthood, supporting that BIN1 CNM with congenital onset are due to developmental defects, whereas later onset may be due to regeneration defects.
Published: 2020
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6. Development of the excitation-contraction coupling machinery and its relation to myofibrillogenesis in human iPSC-derived skeletal myocytes

Author: Jeanne Lainé, Gunnar Skoglund, Emmanuel Fournier, and Nacira Tabti
Subjects: iPS-derived skeletal muscle cells, Excitation-contraction coupling, Human-induced pluripotent stem cells, RyR1, Cav1.1, Ca2+ signaling, Diseases of the musculoskeletal system, RC925-935
Abstract: Abstract Background Human induced pluripotent stem cells-derived myogenic progenitors develop functional and ultrastructural features typical of skeletal muscle when differentiated in culture. Besides disease-modeling, such a system can be used to clarify basic aspects of human skeletal muscle development. In the present study, we focus on the development of the excitation-contraction (E-C) coupling, a process that is essential both in muscle physiology and as a tool to differentiate between the skeletal and cardiac muscle. The occurrence and maturation of E-C coupling structures (Sarcoplasmic Reticulum-Transverse Tubule (SR-TT) junctions), key molecular components, and Ca2+ signaling were examined, along with myofibrillogenesis. Methods Pax7+-myogenic progenitors were differentiated in culture, and developmental changes were examined from a few days up to several weeks. Ion channels directly involved in the skeletal muscle E-C coupling (RyR1 and Cav1.1 voltage-gated Ca2+ channels) were labeled using indirect immunofluorescence. Ultrastructural changes of differentiating cells were visualized by transmission electron microscopy. On the functional side, depolarization-induced intracellular Ca2+ transients mediating E-C coupling were recorded using Fura-2 ratiometric Ca2+ imaging, and myocyte contraction was captured by digital photomicrography. Results We show that the E-C coupling machinery occurs and operates within a few days post-differentiation, as soon as the myofilaments align. However, Ca2+ transients become effective in triggering myocyte contraction after 1 week of differentiation, when nascent myofibrils show alternate A-I bands. At later stages, myofibrils become fully organized into adult-like sarcomeres but SR-TT junctions do not reach their triadic structure and typical A-I location. This is mirrored by the absence of cross-striated distribution pattern of both RyR1 and Cav1.1 channels. Conclusions The E-C coupling machinery occurs and operates within the first week of muscle cells differentiation. However, while early development of SR-TT junctions is coordinated with that of nascent myofibrils, their respective maturation is not. Formation of typical triads requires other factors/conditions, and this should be taken into account when using in-vitro models to explore skeletal muscle diseases, especially those affecting E-C coupling.
Published: 2018
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7. Screening identifies small molecules that enhance the maturation of human pluripotent stem cell-derived myotubes

Author: Sridhar Selvaraj, Ricardo Mondragon-Gonzalez, Bin Xu, Alessandro Magli, Hyunkee Kim, Jeanne Lainé, James Kiley, Holly Mckee, Fabrizio Rinaldi, Joy Aho, Nacira Tabti, Wei Shen, and Rita CR Perlingeiro
Subjects: induced pluripotent stem cells, myotubes, maturation, small molecules, myogenic differentiation, 3D culture, Medicine, Science, Biology (General), QH301-705.5
Abstract: Targeted differentiation of pluripotent stem (PS) cells into myotubes enables in vitro disease modeling of skeletal muscle diseases. Although various protocols achieve myogenic differentiation in vitro, resulting myotubes typically display an embryonic identity. This is a major hurdle for accurately recapitulating disease phenotypes in vitro, as disease commonly manifests at later stages of development. To address this problem, we identified four factors from a small molecule screen whose combinatorial treatment resulted in myotubes with enhanced maturation, as shown by the expression profile of myosin heavy chain isoforms, as well as the upregulation of genes related with muscle contractile function. These molecular changes were confirmed by global chromatin accessibility and transcriptome studies. Importantly, we also observed this maturation in three-dimensional muscle constructs, which displayed improved in vitro contractile force generation in response to electrical stimulus. Thus, we established a model for in vitro muscle maturation from PS cells.
Published: 2019
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8. MBNL‐dependent impaired development within the neuromuscular system in myotonic dystrophy type 1

Author: Julie Tahraoui‐Bories, Antoine Mérien, Anchel González‐Barriga, Jeanne Lainé, Céline Leteur, Hélène Polvèche, Alexandre Carteron, Juliette Duchesne De Lamotte, Camille Nicoleau, Jérome Polentes, Margot Jarrige, Mário Gomes‐Pereira, Erwann Ventre, Pauline Poydenot, Denis Furling, Laurent Schaeffer, Claire Legay, Cécile Martinat, Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), IPSEN Innovation, Immunité infection vaccination (I2V), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Institut NeuroMyoGène (INMG), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Saints-Pères Paris Institute for Neurosciences (SPPIN - UMR 8003), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: Histology, Neurology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Physiology (medical), [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Neurology (clinical), Pathology and Forensic Medicine
Abstract: Myotonic dystrophy type I (DM1) is one the most frequent muscular dystrophies in adults. Although DM1 has long been considered mainly a muscle disorder, growing evidence suggests the involvement of peripheral nerves in the pathogenicity of DM1 raising the question of whether motoneurons (MNs) actively contribute to neuromuscular defects in DM1.By using micropatterned 96-well plates as a co-culture platform, we generated a functional neuromuscular model combining DM1 and MBNL-knock-out human induced pluripotent stem cells-derived MNs and human healthy skeletal muscle cells.This approach led to the identification of pre-synaptic defects which affect the formation or stability of the neuromuscular junction at an early developmental stage. These neuropathological defects could be reproduced by the loss of RNA-binding MBNL proteins, whose loss of function in vivo is associated with muscular defects associated with DM1. These experiments indicate that the functional defects associated with MNs can be directly attributed to MBNL family proteins. Comparative transcriptomic analyses also revealed specific neuronal-related processes regulated by these proteins that are commonly misregulated in DM1.Beyond the application to DM1, our approach to generating a robust and reliable human neuromuscular system should facilitate disease modelling studies and drug screening assays.
Published: 2023
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9. Caveolae and Bin1 form ring-shaped platforms for T-tubule initiation

Author: Eline Lemerle, Jeanne Lainé, Gilles Moulay, Anne Bigot, Clémence Labasse, Angeline Madelaine, Alexis Canette, Perrine Aubin-Tessier, Jean-Michel Vallat, Norma Romero, Marc Bitoun, Vincent Mouly, Isabelle Marty, Bruno Cadot, Laura Picas, and Stéphane Vassilopoulos
Abstract: Excitation-contraction coupling requires a highly specialized membrane structure, the triad, composed of a plasma membrane invagination, the T-tubule, surrounded by two sarcoplasmic reticulum terminal cisternae. Although the precise mechanisms governing T-tubule biogenesis and triad formation remain largely unknown, studies have shown that caveolae participate in T-tubule formation and mutations of several of their constituents induce muscle weakness and myopathies. Here, we demonstrate that, at the plasma membrane, caveolae composed of caveolin-3 and Bin1 assemble into ring-like structures from which emerge tubes enriched in the dihydropyridine receptor. Overexpression of Bin1 lead to the formation of both rings and tubes and we show that Bin1 forms scaffolds on which caveolae accumulate to form the initial T-tubule. Cav3 deficiency caused by either gene silencing or pathogenic mutations cause defective ring formation and perturbed Bin1-mediated tubulation that may explain defective T-tubule organization in mature muscles. Our results uncover new pathophysiological mechanisms that may prove relevant to myopathies caused by Cav3 or Bin1.
Published: 2022
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10. Status and role of PABPN1 nuclear aggregates in Oculopharyngeal Muscular Dystrophy

Author: Boulinguiez, Alexis, Roth, Fanny, Dhiab, Jamila, Mouigni, Hadidja, Lassche, Saskia, Elisa, Negroni, Muraine, Laura, Marhic, Alix, Oliver, Alison, Jeanne, Lainé, Rouche, Andrée, K O'Ferrall, Erin, Engelen, Bazielvan, Ottenheijm, Coen A.C., Greif, Hagar, Blumen, Sergiu, St Guily, Jean, Périé, Sophie, Butler-Browne, Gillian S., Mouly, Vincent, Trollet, Capucine, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), CHU Tenon [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: [SDV]Life Sciences [q-bio]
Published: 2022

11. Muscle cells of sporadic ALS patients secrete neurotoxic vesicles

Author: Ouandaogo Zg, Meininger, P. Laforêt, Jeanne Lainé, Langlet T, Leblanc P, David Devos, Behin A, Gall Ll, Julie Dumonceaux, Stéphanie Millecamps, Le Forestier N, O. Lucas, Jean-Philippe Loeffler, Del Mar Amador M, Udaya Geetha Vijayakumar, Pierre-François Pradat, Stephanie Duguez, T. Maisonobe, Browne Gb, Giorgia Querin, C. Martinat, Cédric Raoul, Milla, Ekene Anakor, González De Aguilar J, William Duddy, Owen Connolly, Lucette Lacomblez, Gaëlle Bruneteau, Blasco H, Peter Bede, Mariot, S. Knoblach, François Salachas, Adele Hesters, Laura Robelin, Alexandre Henriques, and T. Stojkovic
Subjects: medicine.anatomical_structure, Myogenesis, medicine, Skeletal muscle, Myocyte, Motor neuron, Amyotrophic lateral sclerosis, Gene mutation, Biology, medicine.disease, Neuromuscular junction, Immunostaining, Cell biology
Abstract: BackgroundThe cause of the motor neuron (MN) death that drives terminal pathology in Amyotrophic Lateral Sclerosis (ALS) remains unknown, and it is thought that the cellular environment of the MN may play a key role in MN survival. Several lines of evidence implicate vesicles in ALS, including that extracellular vesicles may carry toxic elements from astrocytes towards motor neurons, and that pathological proteins have been identified in circulating extracellular vesicles of sporadic ALS patients. Since MN degeneration at the neuromuscular junction is a feature of ALS, and muscle is a vesicle-secretory tissue, we hypothesized that muscle vesicles may be involved in ALS pathology.MethodsSporadic ALS patients were confirmed to be ALS according to El Escorial criteria, were genotyped to test for classic gene mutations associated with ALS, and physical function was assessed using the ALSFRS-R score. Muscle biopsies of either mildly affected deltoids of ALS patients (n=27) or deltoids of aged-matched healthy subjects (n=30) were used for extraction of muscle stem cells, to perform immunohistology, or for electron microscopy. Muscle stem cells were characterized by immunostaining, RTqPCR and transcriptomic analysis. Secreted muscle vesicles were characterized by proteomic analysis, Western blot, NanoSight, and electron microscopy. The effects of muscle vesicles isolated from the culture medium of ALS and healthy myotubes were tested on healthy human-derived iPSC motor neurons and on healthy human myotubes, with untreated cells used as controls.ResultsAn accumulation of multivesicular bodies was observed in muscle biopsies of sporadic ALS patients by immunostaining and electron microscopy. Study of muscle biopsies and biopsy-derived denervation-naïve differentiated muscle stem cells (myotubes) revealed a consistent disease signature in ALS myotubes, including intracellular accumulation of exosome-like vesicles and disruption of RNA-processing. Compared to vesicles from healthy control myotubes, when administered to healthy motor neurons the vesicles of ALS myotubes induced shortened, less branched neurites, cell death, and disrupted localization of RNA and RNA-processing proteins. The RNA-processing protein FUS and a majority of its binding partners were present in ALS muscle vesicles, and toxicity was dependent on the expression level of FUS in recipient cells. Toxicity to recipient motor neurons was abolished by anti-CD63 immuno-blocking of vesicle uptake.ConclusionALS muscle vesicles are shown to be toxic to motor neurons, which establishes the skeletal muscle as a potential source of vesicle-mediated toxicity in ALS.One Sentence SummaryMuscle cells of ALS patients secrete vesicles that are toxic to motor neurons
Published: 2021
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12. Alternative splicing of clathrin heavy chain contributes to the switch from coated pits to plaques

Author: Stéphane Vassilopoulos, Christophe Leterrier, Masayuki Nakamori, Ichizo Nishino, Florent Dingli, Denis Furling, Mégane Lemaître, Jeanne Lainé, Ghislaine Caillol, Kamel Mamchaoui, Damarys Loew, Laura Julien, Marc Bitoun, Gilles Moulay, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Osaka University [Osaka], National Center of Neurology and Psychiatry, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], ANR-14-CE12-0001,EndoMechano,Rôle des protéines de l'endocytose dans la mécano-transduction des cellules musculaires(2014), ANR-14-CE12-0009,Dynamuscle,Role de la dynamine 2 dans le muscle normal et pathologique(2014), ANR-16-CE17-0018,SEDUCE,utilisation des cellules souches pour identifier des composés thérapeutiques visant les anomalies de splice(2016), vassilopoulos, stéphane, Appel à projets générique - Rôle des protéines de l'endocytose dans la mécano-transduction des cellules musculaires - - EndoMechano2014 - ANR-14-CE12-0001 - Appel à projets générique - VALID, Appel à projets générique - Role de la dynamine 2 dans le muscle normal et pathologique - - Dynamuscle2014 - ANR-14-CE12-0009 - Appel à projets générique - VALID, utilisation des cellules souches pour identifier des composés thérapeutiques visant les anomalies de splice - - SEDUCE2016 - ANR-16-CE17-0018 - AAPG2016 - VALID, and Centre de Recherche en Myologie
Subjects: Adult, Male, Physiology, [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Development, Endocytosis, Clathrin, Clathrin coat, Article, Mice, Young Adult, 03 medical and health sciences, Exon, 0302 clinical medicine, Animals, Humans, Child, Tissue homeostasis, 030304 developmental biology, 0303 health sciences, Trafficking, biology, Cell Membrane, Alternative splicing, Coated Pits, Cell-Membrane, Exons, Cell Biology, Cell biology, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Alternative Splicing, Clathrin Heavy Chains, RNA splicing, biology.protein, Female, CLTC, 030217 neurology & neurosurgery
Abstract: A single alternatively spliced exon in the CLTC gene contributes to clathrin coat organization. This event participates in the plasticity from clathrin-coated pits to plaques, structures that are essential for muscle fiber function and maintenance., Clathrin function directly derives from its coat structure, and while endocytosis is mediated by clathrin-coated pits, large plaques contribute to cell adhesion. Here, we show that the alternative splicing of a single exon of the clathrin heavy chain gene (CLTC exon 31) helps determine the clathrin coat organization. Direct genetic control was demonstrated by forced CLTC exon 31 skipping in muscle cells that reverses the plasma membrane content from clathrin plaques to pits and by promoting exon inclusion that stimulated flat plaque assembly. Interestingly, mis-splicing of CLTC exon 31 found in the severe congenital form of myotonic dystrophy was associated with reduced plaques in patient myotubes. Moreover, forced exclusion of this exon in WT mice muscle induced structural disorganization and reduced force, highlighting the contribution of this splicing event for the maintenance of tissue homeostasis. This genetic control on clathrin assembly should influence the way we consider how plasticity in clathrin-coated structures is involved in muscle development and maintenance., Graphical Abstract
Published: 2020
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13. Pharmacological modulation of the ER stress response ameliorates oculopharyngeal muscular dystrophy

Author: George Dickson, Fanny Roth, Jeanne Lainé, Victor Ythier, Emmanuelle Abgueguen, Alberto Malerba, Ngoc Lu-Nguyen, Pradeep Harish, Martine Simonelig, Susan Jarmin, Cécile Voisset, Alexandrine Mahoudeau, Elisa Negroni, Vincent Mouly, Gillian Butler-Browne, Philippe Guedat, Capucine Trollet, Jamila Dhiab, Ornella Cappellari, Royal Holloway, University of London, Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UMRS974, Université Pierre et Marie Curie - Paris 6 (UPMC), Royal Veterinary College [London], University of London [London], Inflectis Bioscience, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), UMR1078S-ECLA, Faculté de Médecine, and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: X-Box Binding Protein 1, Protein Folding, XBP1, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Protein aggregation, Poly(A)-Binding Protein I, Oculopharyngeal muscular dystrophy, Mice, Protein Aggregates, 03 medical and health sciences, Muscular Dystrophy, Oculopharyngeal, Genetics, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Guanabenz Acetate, Phosphorylation, Muscular dystrophy, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), 0303 health sciences, Guanabenz, Endoplasmic reticulum, 030305 genetics & heredity, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Medicine, Endoplasmic Reticulum Stress, medicine.disease, Fibrosis, 3. Good health, Cell biology, Alternative Splicing, Disease Models, Animal, Unfolded Protein Response, Unfolded protein response, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract: Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease leading to ptosis, dysphagia and proximal limb muscles at later stages. A short abnormal (GCN) triplet expansion in the polyA-binding protein nuclear 1 (PABPN1) gene leads to PABPN1-containing aggregates in the muscles of OPMD patients. Here we demonstrate that treating mice with guanabenz acetate (GA), an FDA-approved antihypertensive drug, reduces the size and number of nuclear aggregates, improves muscle force, protects myofibers from the pathology-derived turnover and decreases fibrosis. GA targets various cell processes, including the unfolded protein response (UPR), which acts to attenuate endoplasmic reticulum (ER) stress. We demonstrate that GA increases both the phosphorylation of the eukaryotic translation initiation factor 2α subunit and the splicing of Xbp1, key components of the UPR. Altogether these data show that modulation of protein folding regulation is beneficial for OPMD and promote the further development of GA or its derivatives for treatment of OPMD in humans. Furthermore, they support the recent evidences that treating ER stress could be therapeutically relevant in other more common proteinopathies.
Published: 2019
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14. Clathrin plaques and associated actin anchor intermediate filaments in skeletal muscle

Author: Jeanne Lainé, Pascale Guicheney, Guy Brochier, Stéphane Vassilopoulos, Mai Thao Bui, Agathe Franck, E. Lacène, Eline Lemerle, Norma B. Romero, Marc Bitoun, Gilles Moulay, Sofia Benkhelifa-Ziyyat, Michael Trichet, Christel Gentil, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-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), Neurobiologie et diversité cellulaire (NDC), ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Centre de recherche en myologie, 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), Microscopie Electronique [IBPS] (IBPS-ME), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Morphologie Neuromusculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Coeur, Muscle et Vaisseaux, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gestionnaire, Hal Sorbonne Université, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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 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 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)-CHU Pitié-Salpêtrière [AP-HP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche en Myologie, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Intermediate Filaments, macromolecular substances, Clathrin, Desmin, 03 medical and health sciences, Dynamin II, 0302 clinical medicine, medicine, Animals, Humans, Intermediate filament, Muscle, Skeletal, Molecular Biology, Actin, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Dynamin, Mice, Knockout, 0303 health sciences, Costameres, Sarcolemma, biology, Skeletal muscle, Cell Biology, Articles, Actins, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Cell Biology of Disease, Mutation, biology.protein, 030217 neurology & neurosurgery, Wiskott-Aldrich Syndrome Protein, Myopathies, Structural, Congenital
Abstract: International audience; Clathrin plaques are stable features of the plasma membrane observed in several cell types. They are abundant in muscle, where they localize at costameres that link the contractile apparatus to the sarcolemma and connect the sarcolemma to the basal lamina. Here, we show that clathrin plaques and surrounding branched actin filaments form microdomains that anchor a three-dimensional desmin intermediate filament (IF) web. Depletion of clathrin plaque and branched actin components causes accumulation of desmin tangles in the cytoplasm. We show that dynamin 2, whose mutations cause centronuclear myopathy (CNM), regulates both clathrin plaques and surrounding branched actin filaments, while CNM-causing mutations lead to desmin disorganization in a CNM mouse model and patient biopsies. Our results suggest a novel paradigm in cell biology, wherein clathrin plaques act as platforms capable of recruiting branched cortical actin, which in turn anchors IFs, both essential for striated muscle formation and function.
Published: 2019
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15. Differential physiological role of BIN1 isoforms in skeletal muscle development, function and regeneration

Author: Vincent Gache, Arnaud Ferry, Fanny Pilot-Storck, Olivia Wendling, Vincent Jacquemond, Vasugi Nattarayan, Jeanne Lainé, Jocelyn Laporte, Christine Kretz, Hichem Tasfaout, Roy Combe, Josiane Hergueux, Anne Toussaint, Christos Gavriilidis, Catherine Koch, Belinda S. Cowling, Candice Kutchukian, Ivana Prokic, Laurent Tiret, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Clinique de la Souris (ICS), Biologie du système neuromusculaire - Biology of the neuromuscular system [Maisons-Alfort] (BNMS - Team 10), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), École nationale vétérinaire d'Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), 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, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Gestionnaire, HAL Sorbonne Université 5, BLANC - Mécano-sensation et mécano-stabilisation au cours de la morphogenèse embryonnaire - - SenStable2011 - ANR-11-BSV2-0023 - BLANC - VALID, ANR-11-BSV2-0023,SenStable,Mécano-sensation et mécano-stabilisation au cours de la morphogenèse embryonnaire(2011), and Université de Lyon
Subjects: XLMTM, [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, lcsh:Medicine, Medicine (miscellaneous), Muscle Development, centronuclear myopathy, SH3 domain, Myoblast fusion, 0302 clinical medicine, Immunology and Microbiology (miscellaneous), myoblast fusion, Protein Isoforms, myotubular myopathy, ComputingMilieux_MISCELLANEOUS, Sequence Deletion, 0303 health sciences, triad, Homozygote, Exons, Cell biology, medicine.anatomical_structure, Organ Specificity, Knockout mouse, Intracellular, Research Article, lcsh:RB1-214, Gene isoform, Neuroscience (miscellaneous), Nerve Tissue Proteins, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, dynamin, lcsh:Pathology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Regeneration, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Centronuclear myopathy, Muscle, Skeletal, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Dynamin, myotonic dystrophy, Tumor Suppressor Proteins, Regeneration (biology), animal model, lcsh:R, Skeletal muscle, Feeding Behavior, medicine.disease, Survival Analysis, Mice, Inbred C57BL, Animals, Newborn, BAR domain, 030217 neurology & neurosurgery
Abstract: Skeletal muscle development and regeneration are tightly regulated processes. How the intracellular organization of muscle fibers is achieved during these steps is unclear. Here, we focus on the cellular and physiological roles of amphiphysin 2 (BIN1), a membrane remodeling protein mutated in both congenital and adult centronuclear myopathies (CNM), that is ubiquitously expressed and has skeletal muscle-specific isoforms. We created and characterized constitutive muscle-specific and inducible Bin1 homozygous and heterozygous knockout mice targeting either ubiquitous or muscle-specific isoforms. Constitutive Bin1-deficient mice died at birth from lack of feeding due to a skeletal muscle defect. T-tubules and other organelles were misplaced and altered, supporting a general early role for BIN1 in intracellular organization, in addition to membrane remodeling. Although restricted deletion of Bin1 in unchallenged adult muscles had no impact, the forced switch from the muscle-specific isoforms to the ubiquitous isoforms through deletion of the in-frame muscle-specific exon delayed muscle regeneration. Thus, ubiquitous BIN1 function is necessary for muscle development and function, whereas its muscle-specific isoforms fine tune muscle regeneration in adulthood, supporting that BIN1 CNM with congenital onset are due to developmental defects, whereas later onset may be due to regeneration defects., Summary: The BIN1 gene, mutated in centronuclear myopathies, expresses ubiquitous and muscle-specific isoforms. It is shown here that ubiquitous isoforms are necessary for muscle development, whereas muscle-specific isoforms fine-tune muscle regeneration.
Published: 2020
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16. Screening identifies small molecules that enhance the maturation of human pluripotent stem cell-derived myotubes

Author: Wei Shen, Bin Xu, Fabrizio Rinaldi, Jeanne Lainé, Alessandro Magli, James Kiley, Joy Aho, Sridhar Selvaraj, Ricardo Mondragon-Gonzalez, Rita C.R. Perlingeiro, Hyunkee Kim, Nacira Tabti, and Holly Mckee
Subjects: Pluripotent Stem Cells, 3D culture, 0301 basic medicine, induced pluripotent stem cells, QH301-705.5, Science, Muscle Fibers, Skeletal, Drug Evaluation, Preclinical, myogenic differentiation, Biology, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Myosin, medicine, Humans, Biology (General), Induced pluripotent stem cell, Cells, Cultured, General Immunology and Microbiology, maturation, Myogenesis, General Neuroscience, Skeletal muscle, Cell Differentiation, General Medicine, Stem Cells and Regenerative Medicine, Embryonic stem cell, Cell biology, small molecules, 030104 developmental biology, medicine.anatomical_structure, myotubes, Intercellular Signaling Peptides and Proteins, Medicine, Stem cell, Developmental biology, 030217 neurology & neurosurgery, Research Article, Developmental Biology, Human
Abstract: Targeted differentiation of pluripotent stem (PS) cells into myotubes enables in vitro disease modeling of skeletal muscle diseases. Although various protocols achieve myogenic differentiation in vitro, resulting myotubes typically display an embryonic identity. This is a major hurdle for accurately recapitulating disease phenotypes in vitro, as disease commonly manifests at later stages of development. To address this problem, we identified four factors from a small molecule screen whose combinatorial treatment resulted in myotubes with enhanced maturation, as shown by the expression profile of myosin heavy chain isoforms, as well as the upregulation of genes related with muscle contractile function. These molecular changes were confirmed by global chromatin accessibility and transcriptome studies. Importantly, we also observed this maturation in three-dimensional muscle constructs, which displayed improved in vitro contractile force generation in response to electrical stimulus. Thus, we established a model for in vitro muscle maturation from PS cells.
Published: 2019
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17. Author response: Screening identifies small molecules that enhance the maturation of human pluripotent stem cell-derived myotubes

Author: Hyunkee Kim, Nacira Tabti, Holly Mckee, Ricardo Mondragon-Gonzalez, Alessandro Magli, Wei Shen, James Kiley, Bin Xu, Fabrizio Rinaldi, Joy Aho, Jeanne Lainé, Sridhar Selvaraj, and Rita C.R. Perlingeiro
Subjects: Chemistry, Myogenesis, Induced pluripotent stem cell, Small molecule, Cell biology
Published: 2019
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18. Guanabenz treatment improves Oculopharyngeal muscular dystrophy phenotype

Author: Ornella Cappellari, Cécile Voisset, Ngoc Lu-Nguyen, Guedat P, Abgueguen E, Alberto Malerba, Gillian Butler-Browne, Fanny Roth, Mahoudeau A, Jamila Dhiab, Martine Simonelig, Susan Jarmin, Mouly, Jeanne Lainé, George Dickson, Capucine Trollet, Pradeep Harish, Ythier, and Elisa Negroni
Subjects: XBP1, Chemistry, Endoplasmic reticulum, medicine.disease, Cell biology, Oculopharyngeal muscular dystrophy, Pharyngeal muscles, medicine.anatomical_structure, medicine, Unfolded protein response, Guanabenz Acetate, Guanabenz, Cellular model, medicine.drug
Abstract: Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease affecting most profoundly eyelid and pharyngeal muscles, leading respectively to ptosis and dysphagia, and proximal limb muscles at later stages. A short abnormal (GCG) triplet expansion in the polyA– binding protein nuclear 1 (PABPN1) gene leads to PABPN1-containing aggregates in the muscles of OPMD patients. It is commonly accepted that aggregates themselves, the aggregation process and/or the early oligomeric species of PABPN1 are toxic in OPMD. Decreasing PABPN1 aggregate load in animal models of OPMD ameliorates the muscle phenotype. In order to identify a potential therapeutic molecule that would prevent and reduce aggregates, we tested guanabenz acetate (GA), an FDA-approved antihypertensive drug, in OPMD cells as well as in the A17 OPMD mouse model. We demonstrate that treating mice with GA reduces the size and number of nuclear aggregates, improves muscle force, protects myofibres from the pathology-derived turnover and decreases fibrosis. GA is known to target various cell processes, including the unfolded protein response (UPR), which acts to attenuate endoplasmic reticulum (ER) stress. Here we used a cellular model of OPMD to demonstrate that GA increases both the phosphorylation of the eukaryotic translation initiator factor 2α subunit (eIF2α) and the splicing of Xbp1, key components of the UPR. Altogether these data suggest that modulation of protein folding regulation can be beneficial for OPMD and support the further development of guanabenz or its derivatives for treatment of OPMD in humans.Significance StatementOculopharyngeal muscular dystrophy (OPMD) is a rare late onset incurable genetic disease characterized by the formation of insoluble aggregates in skeletal muscles. It has been shown that the reduction of aggregates correlates with an improvement of the disease. Here we used a mouse model of OPMD to show that Guanabenz acetate, the active constituent of a marketed but recently discontinued drug for hypertension, decreases the number and the size of aggregates after systemic delivery and improves many aspects of the disease. We also describe experimental evidences explaining the mechanism behind the efficacy of such compound for OPMD.
Published: 2018
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19. Mechanosensitive clathrin platforms anchor desmin intermediate filaments in skeletal muscle

Author: Marc Bitoun, Agathe Franck, Gilles Moulay, Jeanne Lainé, Pascale Guicheney, Thao Bui M, Norma B. Romero, Michaël Trichet, Guy Brochier, E. Lacène, Stéphane Vassilopoulos, Sabrina Sacconi, Anais Fongy, Anne Bigot, Mouly, Sofia Benkhelifa-Ziyyat, Christel Gentil, and Catherine Coirault
Subjects: 0303 health sciences, biology, Myogenesis, Chemistry, macromolecular substances, Clathrin, Cell biology, 03 medical and health sciences, 0302 clinical medicine, biology.protein, Mechanosensitive channels, Desmin, Cytoskeleton, Intermediate filament, 030217 neurology & neurosurgery, Actin, 030304 developmental biology, Dynamin
Abstract: Large flat clathrin plaques are stable features of the plasma membrane associated with sites of strong adhesion suggesting that they could also play a role in force transduction. Here, we analyzed how clathrin plaques interact with the cytoskeleton and how they respond to mechanical cues in skeletal muscle myotubes. We show that branched actin networks surrounding clathrin plaques are directly regulated by dynamin 2, anchor intermediate filaments and sequester YAP at the plasma membrane. Dynamin 2, clathrin and desmin intermediate filaments are all required for basal YAP nucleocytoplasmic distribution and efficient nuclear translocation in response to mechanical stimuli. Dynamin 2 mutations that are responsible for centronuclear myopathy in humans disorganize the desmin network and deregulate YAP signaling both in vitro and in vivo. Thus, clathrin plaques and associated dynamin 2 are defined here as a new sensor conveying mechanical cues and integrate cell signaling with cytoskeletal regulation.
Published: 2018
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20. Activated dendritic cells modulate proliferation and differentiation of human myoblasts

Author: Débora M. Portilho, Leandro Ladislau, Adriana Bonomo, Tristan Courau, Gillian Butler-Browne, Claudia F. Benjamim, Olivier Benveniste, Alhondra Solares-Pérez, Vincent Mouly, Wilson Savino, Yves Allenbach, Ingo Riederer, Jeanne Lainé, David Klatzmann, Elisa Negroni, Universidade Federal do Rio de Janeiro (UFRJ), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Myologie (IM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Instituto Oswaldo Cruz / Oswaldo Cruz Institute [Rio de Janeiro] (IOC), Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Instituto de Biofísica Carlos Chagas Filho [Rio de Janeiro] (IBCCF / UFRJ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratory on Thymus Research - Department of Immunology / Laboratório de Pesquisas sobre o Timo - Departamento de Imunologia [Rio de Janeiro], Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Fundação Oswaldo Cruz (FIOCRUZ), This work was supported by Fiocruz, CNPq (Brazil), CAPES/FAPERJ, Pronex/FAPERJ and CNPq/Ciências sem Fronteiras Programs. The CAPES/COFECUB, Fiocruz/Inserm, Sorbonne Universités/Faperj French/Brazilian joint programs. The Association Française contre les Myopathies (AFM-Telethon, France), the European Union (MYORES, 6th FP, contract 511978), and FOCEM (Mercosul)., Gestionnaire, HAL Sorbonne Université 5, and Centre de Recherche en Myologie
Subjects: 0301 basic medicine, Adult, Lipopolysaccharides, Male, Cancer Research, Myoblast proliferation, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Myoblasts, Skeletal, Immunology, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, [SCCO]Cognitive science, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Myocyte, Humans, Myoblast migration, lcsh:QH573-671, Cell Proliferation, Chemistry, Myogenesis, lcsh:Cytology, Regeneration (biology), Infant, Newborn, Cell Differentiation, Cell Biology, Dendritic Cells, Middle Aged, Antigens, Differentiation, Muscle atrophy, Cell biology, Myotube differentiation, 030104 developmental biology, Cytokine secretion, Female, medicine.symptom
Abstract: Idiopathic Inflammatory Myopathies (IIMs) are a heterogeneous group of autoimmune diseases affecting skeletal muscle tissue homeostasis. They are characterized by muscle weakness and inflammatory infiltration with tissue damage. Amongst the cells in the muscle inflammatory infiltration, dendritic cells (DCs) are potent antigen-presenting and key components in autoimmunity exhibiting an increased activation in inflamed tissues. Since, the IIMs are characterized by the focal necrosis/regeneration and muscle atrophy, we hypothesized that DCs may play a role in these processes. Due to the absence of a reliable in vivo model for IIMs, we first performed co-culture experiments with immature DCs (iDC) or LPS-activated DCs (actDC) and proliferating myoblasts or differentiating myotubes. We demonstrated that both iDC or actDCs tightly interact with myoblasts and myotubes, increased myoblast proliferation and migration, but inhibited myotube differentiation. We also observed that actDCs increased HLA-ABC, HLA-DR, VLA-5, and VLA-6 expression and induced cytokine secretion on myoblasts. In an in vivo regeneration model, the co-injection of human myoblasts and DCs enhanced human myoblast migration, whereas the absolute number of human myofibres was unchanged. In conclusion, we suggest that in the early stages of myositis, DCs may play a crucial role in inducing muscle-damage through cell–cell contact and inflammatory cytokine secretion, leading to muscle regeneration impairment.
Published: 2018
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21. A simple shortcut for observing unroofed cells by either TEM or SEM

Author: Agathe Franck, Jeanne Lainé, Marc Bitoun, Ghislaine Frébourg, Michaël Trichet, Stéphane Vassilopoulos, Microscopie Electronique [IBPS] (IBPS-ME), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio], Unroofing, Electron microscopy, Biology
Abstract: DOI: 10.1002/9783527808465.EMC2016.5846; International audience; The “unroofing” technique has been successfully used to observe the cytoplasmic side of the plasma membrane (PM) using either light or electron microscopy. Combined to transmission electron microscopy (TEM), it is an invaluable method to reveal the composition of the PM and to directly observe macromolecular complexes including the cytoskeleton and endocytic membrane invaginations. This method has been optimized over decades to preserve membranes close to their native states by the combination of quick freezing of exposed membranes, followed by deep etching and rotary replication (the so-called “QF-DE-RR” technique). However, a serious setback in implementing unroofing combined with QF-DE-RR stems from the necessity to use complicated apparatus, such as quick freezing and freeze-fracturing devices, along with strong expertise to handle them. Moreover, the technical complexity renders these techniques time consuming and reduces the number of samples that can be processed simultaneously. Here, we present a simple and straightforward protocol for observation of the cytoplasmic side of plasma membrane which only requires chemical treatment of samples prior to replication This method has been optimized towards sample preparation at room temperature, chemical fixation, dehydration, solvent drying and sequential metal coating. Moreover, this technique is easily amenable to higher throughput. We compared either TEM or high resolution SEM analysis of unroofed membranes from adherent cells and show the advantages and disadvantages of each technique towards visualization of the cytoskeleton and different endocytic structures such as clathrin coated pits and caveolae.
Published: 2016
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22. Dystrophin restoration therapy improves both the reduced excitability and the force drop induced by lengthening contractions in dystrophic mdx skeletal muscle

Author: Denis Furling, Gillian Butler-Browne, Onnik Agbulut, Bodvael Fraysse, Jeanne Lainé, Arnaud Ferry, Julien Ochala, Frédérique Rau, Pauline Roy, Julien Messéant, Centre de recherche en myologie, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre of Human and Aerospace Physiological Sciences, King‘s College London, Physiopathologie et biothérapie: cellules souches, développement et cancer, Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches et Biothérapies (CSB), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Association française contre les myopathies ( AFM-Téléthon ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cellules Souches et Biothérapies ( CSB ), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing ( B2A ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Université Paris Descartes - Paris 5 ( UPD5 )
Subjects: 0301 basic medicine, medicine.medical_specialty, Time Factors, Duchenne muscular dystrophy, Genetic Vectors, Neuromuscular transmission, Action Potentials, Biology, Dystrophin, 03 medical and health sciences, 0302 clinical medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Internal medicine, RNA, Small Nuclear, medicine, Eccentric, Animals, Orthopedics and Sports Medicine, Genetic Predisposition to Disease, Muscle Strength, Muscular dystrophy, Muscle, Skeletal, Molecular Biology, Excitation Contraction Coupling, Research, Skeletal muscle, Cell Biology, Anatomy, Genetic Therapy, Dependovirus, medicine.disease, Exon skipping, Up-Regulation, Muscular Dystrophy, Duchenne, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Phenotype, biology.protein, Mice, Inbred mdx, Myofibril, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: BackgroundThe greater susceptibility to contraction-induced skeletal muscle injury (fragility) is an important dystrophic feature and tool for testing preclinic dystrophin-based therapies for Duchenne muscular dystrophy. However, how these therapies reduce the muscle fragility is not clear.MethodsTo address this question, we first determined the event(s) of the excitation-contraction cycle which is/are altered following lengthening (eccentric) contractions in the mdx muscle.ResultsWe found that the immediate force drop following lengthening contractions, a widely used measure of muscle fragility, was associated with reduced muscle excitability. Moreover, the force drop can be mimicked by an experimental reduction in muscle excitation of uninjured muscle. Furthermore, the force drop was not related to major neuromuscular transmission failure, excitation-contraction uncoupling, and myofibrillar impairment. Secondly, and importantly, the re-expression of functional truncated dystrophin in the muscle of mdx mice using an exon skipping strategy partially prevented the reductions in both force drop and muscle excitability following lengthening contractions.ConclusionWe demonstrated for the first time that (i) the increased susceptibility to contraction-induced muscle injury in mdx mice is mainly attributable to reduced muscle excitability; (ii) dystrophin-based therapy improves fragility of the dystrophic skeletal muscle by preventing reduction in muscle excitability.
Published: 2016
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23. Nuclear PABPN1 aggregates in OPMD: correlation study and therapy

Author: Jeanne Lainé, Fanny Roth, Pradeep Harish, Alberto Malerba, Susan Jarmin, George Dickson, Gillian Butler-Browne, Gonzalo Córdova, N. Nguyen, J. Lacau St Guily, A. Oliver, Capucine Trollet, Sophie Périé, A. Chappell, and Ornella Cappellari
Subjects: Correlation, Pathology, medicine.medical_specialty, Neurology, Chemistry, Pediatrics, Perinatology and Child Health, medicine, Neurology (clinical), Genetics (clinical)
Published: 2017
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24. Two novel COLVI long chains in zebrafish that are essential for muscle development

Author: Laetitia Ramanoudjame, Marjory Fleury, Claire Rocancourt, Valérie Allamand, Lucette Joassard, Jeanne Lainé, Sorana Ciura, C. Gartioux, Edor Kabashi, Arnaud F. Klein, Xavier Cousin, Laura Lyphout, Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Ecotoxicologie - Groupe Ecophysiologie des poissons, Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Physiologie et Génomique des Poissons (LPGP), Institut National de la Recherche Agronomique (INRA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Santé et de la Recherche Médicale (Inserm), Association Française contre les Myopathies (AFM), Sorbonne Universités – UPMC, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Laboratoire d'Écotoxicologie (LEX), Biogéochimie et Ecotoxicologie (BE), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Recherche Agronomique (INRA)
Subjects: Morpholino, muscle, growth, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Gene Expression, poisson zèbre, Collagen Type VI, Muscle disorder, Biology, Muscle Development, développement musculaire, poisson, Collagen VI, cyprinidae, Genetics, Animals, Amino Acid Sequence, Molecular Biology, Gene, Zebrafish, Phylogeny, Genetics (clinical), fish, Myogenesis, Morphant, General Medicine, Zebrafish Proteins, biology.organism_classification, Phenotype, croissance, danio rerio, myologie, myogenesis, Sequence Alignment, danio devario, expression des gènes
Abstract: Collagen VI (COLVI), a protein ubiquitously expressed in connective tissues, is crucial for structural integrity, cellular adhesion, migration and survival. Six different genes are recognized in mammalians, encoding six COLVI-chains that assemble as two 'short' (α1, α2) and one 'long' chain (theoretically any one of α3-6). In humans, defects in the most widely expressed heterotrimer (α123), due to mutations in the COL6A1-3 genes, cause a heterogeneous group of neuromuscular disorders, collectively termed COLVI-related muscle disorders. Little is known about the function(s) of the recently described α4-6 chains and no mutations have been detected yet. In this study, we characterized two novel COLVI long chains in zebrafish that are most homologous to the mammalian α4 chain; therefore, we named the corresponding genes col6a4a and col6a4b. These orthologues represent ancestors of the mammalian Col6a4-6 genes. By in situ hybridization and RT-qPCR, we unveiled a distinctive expression kinetics for col6a4b, compared with the other col6a genes. Using morpholino antisense oligonucleotides targeting col6a4a, col6a4b and col6a2, we modelled partial and complete COLVI deficiency, respectively. All morphant embryos presented altered muscle structure and impaired motility. While apoptosis was not drastically increased, autophagy induction was defective in all morphants. Furthermore, motoneuron axon growth was abnormal in these morphants. Importantly, some phenotypical differences emerged between col6a4a and col6a4b morphants, suggesting only partial functional redundancy. Overall, our results further confirm the importance of COLVI in zebrafish muscle development and may provide important clues for potential human phenotypes associated with deficiency of the recently described COLVI-chains.
Published: 2015
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25. Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy

Author: Olivier Delalande, Joelle Marie, Florent Dingli, Maurice S. Swanson, Denis Furling, Ludovic Arandel, George Dickson, Kuang-Yung Lee, Cécile Peccate, Arnaud Jollet, Laetitita Ramanoudjame, Stéphanie Lorain, Takis Athanasopoulos, Taeyoung Koo, Edor Kabashi, Elisabeth Le Rumeur, Arnaud Ferry, Damarys Loew, Jeanne Lainé, Frédérique Rau, Valérie Allamand, Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), département de physiologie, Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Spectrométrie de Masse des Protéines, Institut Curie [Paris], Department of Molecular Genetics and Microbiology and the Center for NeuroGenetics, University of Florida [Gainesville] (UF), Department of Neurology, Chang Gung Memorial Hospital [Taipei] (CGMH), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), School of Biological Sciences, Royal Holloway [University of London] (RHUL), This work was supported by the Association Française contre les Myopathies/AFM-Telethon (D.F.), UPMC Emergence (D.F.) and NIH AR046799 (M.S.S) grants., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, General Physics and Astronomy, Muscle Proteins, Dystrophin, chemistry.chemical_compound, Exon, Mice, 0302 clinical medicine, Tandem Mass Spectrometry, MBNL1, Homeostasis, Myotonic Dystrophy, Zebrafish, 0303 health sciences, Multidisciplinary, Gene Expression Regulation, Developmental, RNA-Binding Proteins, Exons, Immunohistochemistry, Cell biology, Sarcoplasmic Reticulum, Biological sciences, RNA splicing, RNA Splicing Factors, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, RNA Splicing, Biology, Real-Time Polymerase Chain Reaction, Myotonic dystrophy, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Medical research, medicine, Animals, Humans, Immunoprecipitation, 030304 developmental biology, Alternative splicing, Membrane Proteins, General Chemistry, Zebrafish Proteins, medicine.disease, biology.organism_classification, Molecular biology, Microscopy, Electron, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, 030217 neurology & neurosurgery, Chromatography, Liquid
Abstract: Myotonic Dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors resulting in alternative splicing misregulation and muscular dysfunction. Here we show that the abnormal splicing of DMD exon 78 found in dystrophic muscles of DM1 patients is due to the functional loss of MBNL1 and leads to the re-expression of an embryonic dystrophin in place of the adult isoform. Forced expression of embryonic dystrophin in zebrafish using an exon-skipping approach severely impairs the mobility and muscle architecture. Moreover, reproducing Dmd exon 78 missplicing switch in mice induces muscle fibre remodelling and ultrastructural abnormalities including ringed fibres, sarcoplasmic masses or Z-band disorganization, which are characteristic features of dystrophic DM1 skeletal muscles. Thus, we propose that splicing misregulation of DMD exon 78 compromises muscle fibre maintenance and contributes to the progressive dystrophic process in DM1., The splicing of the penultimate exon of the dystrophin gene is developmentally regulated. Here the authors show that the dysregulation of this exon's splicing leads to the expression of an embryonic dystrophin form with a C-terminus distinct from the adult isoform, which leads to muscle wasting in zebrafish and mice.
Published: 2015
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26. Secretion of toxic exosomes by muscle cells of ALS patients: role in ALS pathogenesis

Author: M. Del Mar Adamor, F. Ratti, Jeanne Lainé, S. Roquevière, L. Le Gall, A. Cécile Durieux, A. Mejat, Pierre-François Pradat, Laura Robelin, Zamalou Gisele Ouandaogo, G. Butler Browne, J.-L. Gonzalez De Aguilar, William Duddy, Stephanie Duguez, C. Martinat, and Lucette Lacomblez
Subjects: Pathogenesis, Neurology, business.industry, Pediatrics, Perinatology and Child Health, Immunology, Myocyte, Medicine, Secretion, Neurology (clinical), business, Genetics (clinical), Microvesicles
Published: 2017
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27. Optimized method for extraction of exosomes from human primary muscle cells

Author: Laura Le Gall, Zamalou Gisele Ouandaogo, Ekene Anakor, Owen Connolly, Gillian Butler Browne, Jeanne Laine, William Duddy, and Stephanie Duguez
Subjects: Extracellular vesicle, Muscle exosome extraction in vitro, Muscle secretome, Diseases of the musculoskeletal system, RC925-935
Abstract: Abstract Skeletal muscle is increasingly considered an endocrine organ secreting myokines and extracellular vesicles (exosomes and microvesicles), which can affect physiological changes with an impact on different pathological conditions, including regenerative processes, aging, and myopathies. Primary human myoblasts are an essential tool to study the muscle vesicle secretome. Since their differentiation in conditioned media does not induce any signs of cell death or cell stress, artefactual effects from those processes are unlikely. However, adult human primary myoblasts senesce in long-term tissue culture, so a major technical challenge is posed by the need to avoid artefactual effects resulting from pre-senescent changes. Since these cells should be studied within a strictly controlled pre-senescent division count (30 times fewer differentiated myoblasts than what is required for the ultracentrifugation method. In addition, exosomes could still be integrated into recipient cells such as human myotubes or iPSC-derived motor neurons. Modified polymer-based precipitation combined with extra washing steps optimizes exosome yield from a lower number of differentiated myoblasts and less conditioned medium, avoiding senescence and allowing the execution of multiple experiments without exhausting the proliferative capacity of the myoblasts.
Published: 2020
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27 results on '"Jeanne Lainé"'

1. Muscle cells of sporadic amyotrophic lateral sclerosis patients secrete neurotoxic vesicles

2. Caveolae and Bin1 form ring-shaped platforms for T-tubule initiation

3. Correction: Activated dendritic cells modulate proliferation and differentiation of human myoblasts

4. Ultrastructural and dynamic studies of the endosomal compartment in Down syndrome

5. Differential physiological roles for BIN1 isoforms in skeletal muscle development, function and regeneration

6. Development of the excitation-contraction coupling machinery and its relation to myofibrillogenesis in human iPSC-derived skeletal myocytes

7. Screening identifies small molecules that enhance the maturation of human pluripotent stem cell-derived myotubes

8. MBNL‐dependent impaired development within the neuromuscular system in myotonic dystrophy type 1

9. Caveolae and Bin1 form ring-shaped platforms for T-tubule initiation

10. Status and role of PABPN1 nuclear aggregates in Oculopharyngeal Muscular Dystrophy

11. Muscle cells of sporadic ALS patients secrete neurotoxic vesicles

12. Alternative splicing of clathrin heavy chain contributes to the switch from coated pits to plaques

13. Pharmacological modulation of the ER stress response ameliorates oculopharyngeal muscular dystrophy

14. Clathrin plaques and associated actin anchor intermediate filaments in skeletal muscle

15. Differential physiological role of BIN1 isoforms in skeletal muscle development, function and regeneration

16. Screening identifies small molecules that enhance the maturation of human pluripotent stem cell-derived myotubes

17. Author response: Screening identifies small molecules that enhance the maturation of human pluripotent stem cell-derived myotubes

18. Guanabenz treatment improves Oculopharyngeal muscular dystrophy phenotype

19. Mechanosensitive clathrin platforms anchor desmin intermediate filaments in skeletal muscle

20. Activated dendritic cells modulate proliferation and differentiation of human myoblasts

21. A simple shortcut for observing unroofed cells by either TEM or SEM

22. Dystrophin restoration therapy improves both the reduced excitability and the force drop induced by lengthening contractions in dystrophic mdx skeletal muscle

23. Nuclear PABPN1 aggregates in OPMD: correlation study and therapy

24. Two novel COLVI long chains in zebrafish that are essential for muscle development

25. Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy

26. Secretion of toxic exosomes by muscle cells of ALS patients: role in ALS pathogenesis

27. Optimized method for extraction of exosomes from human primary muscle cells

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