Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Next-Generation Sequencing in Medicine (Upcoming)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Reducing dynamin 2 expression rescues X-linked centronuclear myopathy
Belinda S. Cowling, … , Norma B. Romero, Jocelyn Laporte
Belinda S. Cowling, … , Norma B. Romero, Jocelyn Laporte
Published February 24, 2014
Citation Information: J Clin Invest. 2014;124(3):1350-1363. https://doi.org/10.1172/JCI71206.
View: Text | PDF
Research Article

Reducing dynamin 2 expression rescues X-linked centronuclear myopathy

  • Text
  • PDF
Abstract

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 hypotonia 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 histological features, including fiber atrophy and nuclei mispositioning, were absent or reduced. Ultrastructural 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.

Authors

Belinda S. Cowling, Thierry Chevremont, Ivana Prokic, Christine Kretz, Arnaud Ferry, Catherine Coirault, Olga Koutsopoulos, Vincent Laugel, Norma B. Romero, Jocelyn Laporte

×

Figure 4

Improved muscle strength and endurance of Mtm1–/y mice with reduced DNM2 expression.

Options: View larger image (or click on image) Download as PowerPoint
Improved muscle strength and endurance of Mtm1–/y mice with reduced DNM2...
(A) The string test was performed on mice weekly from 3 to 8 weeks. A fall was considered equal to 20 seconds. (B) The absolute maximal force of the TA muscle was measured in 8-week-old and 16-week-old mice. (C) Specific maximal force of the TA. Mtm1–/y mice usually die before 16 weeks and were therefore not measured at that age. (D) Fatigue in TA muscle, measured as the time taken to reach 50% of maximum muscle force. Muscle fatigue was unable to be measured in Mtm1–/y mice at 8 weeks due to extreme muscle weakness. All graphs depict mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. n = minimum 5 mice per group.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts