title: N-WASP is required for Amphiphysin-2/BIN1-dependent nuclear positioning and triad organization in skeletal muscle and is involved in the pathophysiology of centronuclear myopathy.
abstract: Mutations in amphiphysin-2/BIN1, dynamin 2, and myotubularin are associated with centronuclear myopathy (CNM), a muscle disorder characterized by myofibers with atypical central nuclear positioning and abnormal triads. Mis-splicing of amphiphysin-2/BIN1 is also associated with myotonic dystrophy that shares histopathological hallmarks with CNM. How amphiphysin-2 orchestrates nuclear positioning and triad organization and how CNM-associated mutations lead to muscle dysfunction remains elusive. We find that N-WASP interacts with amphiphysin-2 in myofibers and that this interaction and N-WASP distribution are disrupted by amphiphysin-2 CNM mutations. We establish that N-WASP functions downstream of amphiphysin-2 to drive peripheral nuclear positioning and triad organization during myofiber formation. Peripheral nuclear positioning requires microtubule/Map7/Kif5b-dependent distribution of nuclei along the myofiber and is driven by actin and nesprins. In adult myofibers, N-WASP and amphiphysin-2 are only involved in the maintenance of triad organization but not in the maintenance of peripheral nuclear positioning. Importantly, we confirmed that N-WASP distribution is disrupted in CNM and myotonic dystrophy patients. Our results support a role for N-WASP in amphiphysin-2-dependent nuclear positioning and triad organization and in CNM and myotonic dystrophy pathophysiology.
authors.affiliation: Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris 6, Paris, France Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France sestinaf@gmail.com edgar.gomes@upmc.fr.
authors.forename: Sestina
authors.initials: S
authors.lastname: Falcone
authors.affiliation: Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris 6, Paris, France.
authors.forename: William
authors.initials: W
authors.lastname: Roman
authors.affiliation: IGBMC-CNRS, UMR 7104 INSERM U964, Illkirch, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Hnia
authors.affiliation: Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris 6, Paris, France Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Gache
authors.affiliation: Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris 6, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Didier
authors.affiliation: Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Lainé
authors.affiliation: Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris 6, Paris, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Auradé
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Marty
authors.affiliation: National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.affiliation: IGBMC-CNRS, UMR 7104 INSERM U964, Illkirch, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charlet-Berguerand
authors.affiliation: Morphology Unit, Myology Institut Pitié Salpêtrière Hospital, Paris, France.
authors.forename: Norma Beatriz
authors.initials: NB
authors.lastname: Romero
authors.affiliation: Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris 6, Paris, France.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Marazzi
authors.affiliation: Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris 6, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Sassoon
authors.affiliation: IGBMC-CNRS, UMR 7104 INSERM U964, Illkirch, France.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
authors.affiliation: Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris 6, Paris, France Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal sestinaf@gmail.com edgar.gomes@upmc.fr.
authors.forename: Edgar R
authors.initials: ER
authors.lastname: Gomes
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D006801:Humans; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000503:physiopathology*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020914:Myopathies, Structural, Congenital / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D050505:Mutant Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C495771:WASL protein, human; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal
keywords: centronuclear myopathy; cytoskeleton; nuclear movement; triad formation