Reducing dynamin 2 expression rescues X-linked centronuclear myopathy - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Clinical Investigation Année : 2014

Reducing dynamin 2 expression rescues X-linked centronuclear myopathy

Résumé

Centronuclear myopathies (CNM) are congenital disorders associated with muscle weakness and abnormally located nuclei in skeletal muscle. An autosomal dominant form of CNM results from mutations in the gene encoding dynamin 2 (DNM2), and loss-of-function mutations in the gene encoding myotubularin (MTM1) result in X-linked CNM (XLCNM, also called myotubular myopathy), which promotes severe neonatal hypo-tonia and early death. Currently, no effective treatments exist for XLCNM. Here, we found increased DNM2 levels in XLCNM patients and a mouse model of XLCNM (Mtm1 –/y). Generation of Mtm1 –/y mice that were heterozygous for Dnm2 revealed that reduction of DNM2 in XLCNM mice restored life span, whole-body strength, and diaphragm function and increased muscle strength. Additionally, classic CNM-associated his-tological features, including fiber atrophy and nuclei mispositioning, were absent or reduced. Ultrastructur-al analysis revealed improvement of sarcomere organization and triad structures. Skeletal muscle–specific decrease of Dnm2 during embryogenesis or in young mice after disease onset revealed that the rescue associated with downregulation of Dnm2 is cell autonomous and is able to stop and potentially revert XLCNM progression. These data indicate that MTM1 and DNM2 regulate muscle organization and force through a common pathway. Furthermore, despite DNM2 being a key mechanoenzyme, its reduction is beneficial for XLCNM and represents a potential therapeutic approach for patients.
Fichier principal
Vignette du fichier
JCI71206.pdf (6.47 Mo) Télécharger le fichier
Origine : Publication financée par une institution
Loading...

Dates et versions

hal-01329329 , version 1 (09-06-2016)

Licence

Paternité

Identifiants

Citer

Belinda S Cowling, Thierry Chevremont, Ivana Prokic, Christine Kretz, Arnaud Ferry, et al.. Reducing dynamin 2 expression rescues X-linked centronuclear myopathy. Journal of Clinical Investigation, 2014, 124 (3), pp.1350-1363. ⟨10.1172/JCI71206⟩. ⟨hal-01329329⟩
248 Consultations
179 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More