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

• Published in: EMBO molecular medicine Vol. 6; no. 11; pp. 1455 - 1475
• Main Authors: Falcone, Sestina, Roman, William, Hnia, Karim, Gache, Vincent, Didier, Nathalie, Lainé, Jeanne, Auradé, Frederic, Marty, Isabelle, Nishino, Ichizo, Charlet‐Berguerand, Nicolas, Romero, Norma Beatriz, Marazzi, Giovanna, Sassoon, David, Laporte, Jocelyn, Gomes, Edgar
• Format: Journal Article
• Language: English
• Published: London EMBO Press 01.11.2014; Nature Publishing Group UK; BlackWell Publishing Ltd; Springer Nature
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adult; Centronuclear myopathy; Cytoskeleton; EMBO25; Humans; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal - physiopathology; Mutant Proteins - genetics; Mutant Proteins - metabolism; Myopathies, Structural, Congenital - physiopathology; Nuclear movement; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Research Article; Triad formation; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Wiskott-Aldrich Syndrome Protein, Neuronal - metabolism; centronuclear myopathy; nuclear movement; triad formation; cytoskeleton
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201404436

© 2014 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 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.