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EMBO Mol Med. 2014 Nov;6(11):1455-75. doi: 10.15252/emmm.201404436.

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.

Author information

1
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.
2
Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris 6, Paris, France.
3
IGBMC-CNRS, UMR 7104 INSERM U964, Illkirch, France.
4
Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris 6, Paris, France Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
5
Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
6
INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.
7
National Center of Neurology and Psychiatry, Tokyo, Japan.
8
Morphology Unit, Myology Institut Pitié Salpêtrière Hospital, Paris, France.
9
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.

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.

KEYWORDS:

centronuclear myopathy; cytoskeleton; nuclear movement; triad formation

PMID:
25262827
PMCID:
PMC4237471
DOI:
10.15252/emmm.201404436
[Indexed for MEDLINE]
Free PMC Article

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