title: The anticancer drug tamoxifen counteracts the pathology in a mouse model of duchenne muscular dystrophy.
abstract: 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.
authors: Department of Pharmacology, University of Geneva and University of Lausanne, Geneva, Switzerland. olivier.dorchies@unige.ch
authors: Olivier M
authors: OM
authors: Dorchies
authors: Julie
authors: J
authors: Reutenauer-Patte
authors: Elyes
authors: E
authors: Dahmane
authors: Heham M
authors: HM
authors: Ismail
authors: Olivier
authors: O
authors: Petermann
authors: Ophélie
authors: O
authors: Patthey- Vuadens
authors: Sophie A
authors: SA
authors: Comyn
authors: Elinam
authors: E
authors: Gayi
authors: Tony
authors: T
authors: Piacenza
authors: Robert J
authors: RJ
authors: Handa
authors: Laurent A
authors: LA
authors: Décosterd
authors: Urs T
authors: UT
authors: Ruegg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D001696:Biomechanical Phenomena / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D003964:Diaphragm / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005247:Feeding Behavior / Q000187:drug effects; D005355:Fibrosis; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000097:blood / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000097:blood / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D011960:Receptors, Estrogen; D013629:Tamoxifen; D003402:Creatine Kinase