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.
Highlights
Centronuclear myopathy (CNM) is a rare neuromuscular disease associated with skeletal muscle weakness and hypotonia (Pierson et al, 2005; Nicot et al, 2007)
We observed a decrease in the thickness of the myofibers transfected with amph2 R154Q or amph2 K575X when compared to the GFP-transfected controls (Supplementary Fig S3H). These results reveal that amph2, dynamin 2, and myotubularin regulate nuclear peripheral positioning and triad organization during myofiber formation and that these functions are disrupted by mutations in amph2 associated with ARCNM
We found a novel protein that is regulated by BIN1/amphiphysin-2, named N-WASP, that is important for nuclear positioning and triad organization
Summary
Centronuclear myopathy (CNM) is a rare neuromuscular disease associated with skeletal muscle weakness and hypotonia (Pierson et al, 2005; Nicot et al, 2007). Centrally positioned nuclei in CNMs are not linked to excessive degeneration–regeneration processes. Several forms of CNM have been described in humans including the X-linked form (XLCNM, OMIM#310400), which exhibits the most severe phenotype and affects newborns, due to mutations in myotubularin (MTM1), a phosphoinositide phosphatase (Laporte et al, 1996), the autosomal dominant form (ADCNM, OMIM#160150) due to mutations in dynamin 2 (DNM2), a large GTPase (Bitoun et al, 2005), and an autosomal recessive form (ARCNM, OMIM#255200) due to mutations in AMPH2/BIN1 (Nicot et al, 2007).
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