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Nat Commun. 2018 Nov 19;9(1):4848. doi: 10.1038/s41467-018-07058-4.

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

Author information

1
Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne, University of Geneva, CMU 5-6, Rue Michel-Servet 1, Geneva, 1211, Switzerland.
2
Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, 67404, France.
3
Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, 67404, France.
4
Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, 67404, France.
5
Université de Strasbourg, Illkirch, 67404, France.
6
Division and Laboratory of Clinical Pharmacology, Service of Biomedicine, Department of Laboratories, Lausanne University Hospital, Lausanne, 1011, Switzerland.
7
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.
8
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.

Abstract

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.

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