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

EMBO Molecular Medicine

Sestina Falcone⁵  William Roman⁵  Karim Hnia¹  Vincent Gache⁵  Nathalie Didier⁵  Jeanne Lainé²  Frederic Auradé⁵  Isabelle Marty⁴  Ichizo Nishino⁶  Nicolas Charlet-Berguerand¹  Norma Beatriz Romero³  Giovanna Marazzi⁵  David Sassoon⁵  Jocelyn Laporte¹ 

[1] IGBMC-CNRS, UMR 7104 INSERM, U964, Illkirch, France;Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France;Morphology Unit, Myology Institut, Pitié Salpêtrière Hospital, Paris, France;INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France;Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris 6, Paris, France;National Center of Neurology and Psychiatry, Tokyo, Japan

关键词: centronuclear myopathy;    cytoskeleton;    nuclear movement;    triad formation;   

DOI  :  10.15252/emmm.201404436

来源: Wiley

【 摘 要 】

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.

Synopsis

Amphiphysin-2/BIN1 is known to associate with centronuclear myopathy (CNM) and myotonic dystrophy. N-WASP is found downstream of Amphiphysin-2/BIN1 and aberrantly distributed in skeletal muscle of patients. Activation of N-WASP could provide a therapeutic option for CNM.

• Amphiphysin-2/BIN1 interacts with N-WASP in skeletal muscle.
• Amphiphysin-2/BIN1 and N-WASP are required for peripheral nuclei positioning and triad formation.
• Peripheral nuclear positioning requires microtubule/Map7/Kif5b-dependent distribution of nuclei along the myofiber and is driven by actin and nesprins.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.