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Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy.
Journal article

Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy.

  • Gayi E Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne, University of Geneva, CMU 5-6, Rue Michel-Servet 1, Geneva, 1211, Switzerland.
  • Neff LA Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne, University of Geneva, CMU 5-6, Rue Michel-Servet 1, Geneva, 1211, Switzerland.
  • Massana Muñoz X Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, 67404, France.
  • Ismail HM Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne, University of Geneva, CMU 5-6, Rue Michel-Servet 1, Geneva, 1211, Switzerland.
  • Sierra M Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne, University of Geneva, CMU 5-6, Rue Michel-Servet 1, Geneva, 1211, Switzerland.
  • Mercier T Division and Laboratory of Clinical Pharmacology, Service of Biomedicine, Department of Laboratories, Lausanne University Hospital, Lausanne, 1011, Switzerland.
  • Décosterd LA Division and Laboratory of Clinical Pharmacology, Service of Biomedicine, Department of Laboratories, Lausanne University Hospital, Lausanne, 1011, Switzerland.
  • Laporte J Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, 67404, France.
  • Cowling BS Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, 67404, France.
  • Dorchies OM Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne, University of Geneva, CMU 5-6, Rue Michel-Servet 1, Geneva, 1211, Switzerland. olivier.dorchies@unige.ch.
  • Scapozza L Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne, University of Geneva, CMU 5-6, Rue Michel-Servet 1, Geneva, 1211, Switzerland. leonardo.scapozza@unige.ch.
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  • 2018-11-20
Published in:
  • Nature communications. - 2018
Animals
Class II Phosphatidylinositol 3-Kinases
Disease Models, Animal
Disease Progression
Dynamin II
Electric Stimulation
Excitation Contraction Coupling
Female
Gene Expression
Genes, Lethal
Humans
Longevity
Male
Mice
Mice, Knockout
Motor Activity
Muscle, Skeletal
Myofibrils
Myopathies, Structural, Congenital
Protective Agents
Protein Tyrosine Phosphatases, Non-Receptor
Tamoxifen
English X-linked myotubular myopathy (XLMTM, also known as XLCNM) is a severe congenital muscular disorder due to mutations in the myotubularin gene, MTM1. It is characterized by generalized hypotonia, leading to neonatal death of most patients. No specific treatment exists. Here, we show that tamoxifen, a well-known drug used against breast cancer, rescues the phenotype of Mtm1-deficient mice. Tamoxifen increases lifespan several-fold while improving overall motor function and preventing disease progression including lower limb paralysis. Tamoxifen corrects functional, histological and molecular hallmarks of XLMTM, with improved force output, myonuclei positioning, myofibrillar structure, triad number, and excitation-contraction coupling. Tamoxifen normalizes the expression level of the XLMTM disease modifiers DNM2 and PI3KC2B, likely contributing to the phenotypic rescue. Our findings demonstrate that tamoxifen is a promising candidate for clinical evaluation in XLMTM patients.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/103614
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