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.
Subject(s)
Motor Activity/drug effects , Muscle, Skeletal/drug effects , Myopathies, Structural, Congenital/drug therapy , Protective Agents/pharmacology , Protein Tyrosine Phosphatases, Non-Receptor/genetics , Tamoxifen/pharmacology , Animals , Class II Phosphatidylinositol 3-Kinases/genetics , Class II Phosphatidylinositol 3-Kinases/metabolism , Disease Models, Animal , Disease Progression , Dynamin II/genetics , Dynamin II/metabolism , Electric Stimulation , Excitation Contraction Coupling/drug effects , Female , Gene Expression/drug effects , Genes, Lethal , Humans , Longevity/drug effects , Male , Mice , Mice, Knockout , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Myofibrils/drug effects , Myofibrils/metabolism , Myofibrils/ultrastructure , Myopathies, Structural, Congenital/genetics , Myopathies, Structural, Congenital/metabolism , Myopathies, Structural, Congenital/pathology , Protein Tyrosine Phosphatases, Non-Receptor/deficiencyABSTRACT
Drug discovery is a long, expensive and risky process. Evaluating drugs that have already been proved safe for use in humans and testing them for a new indication greatly reduces the time and monetary costs involved in finding treatments for life-threatening conditions. Here tamoxifen, a drug that is used for the treatment of breast cancer, is investigated in a mouse model of Duchenne muscular dystrophy. Tamoxifen was efficacious in countering the symptoms of the disease without affecting the underlying genetic cause. Based on these results, tamoxifen has been tested in other forms of muscle disease with success. Drug repurposing may not only be a cost-effective manner for treating a variety of diseases, it may also help us uncover common mechanisms between conditions that were previously thought to be unrelated.
Subject(s)
Muscular Dystrophy, Duchenne/drug therapy , Selective Estrogen Receptor Modulators/therapeutic use , Tamoxifen/therapeutic use , Animals , Female , Humans , Male , MiceABSTRACT
Duchenne muscular dystrophy (DMD) is a severe disorder characterized by progressive muscle wasting,respiratory and cardiac impairments, and premature death. No treatment exists so far, and the identification of active substances to fight DMD is urgently needed. We found that tamoxifen, a drug used to treat estrogen-dependent breast cancer, caused remarkable improvements of muscle force and of diaphragm and cardiac structure in the mdx(5Cv) mouse model of DMD. Oral tamoxifen treatment from 3 weeks of age for 15 months at a dose of 10 mg/kg/day stabilized myofiber membranes, normalized whole body force, and increased force production and resistance to repeated contractions of the triceps muscle above normal values. Tamoxifen improved the structure of leg muscles and diminished cardiac fibrosis by~ 50%. Tamoxifen also reduced fibrosis in the diaphragm, while increasing its thickness,myofiber count, and myofiber diameter, thereby augmenting by 72% the amount of contractile tissue available for respiratory function. Tamoxifen conferred a markedly slower phenotype to the muscles.Tamoxifen and its metabolites were present in nanomolar concentrations in plasma and muscles,suggesting signaling through high-affinity targets. Interestingly, the estrogen receptors ERa and ERb were several times more abundant in dystrophic than in normal muscles, and tamoxifen normalized the relative abundance of ERb isoforms. Our findings suggest that tamoxifen might be a useful therapy for DMD.
