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.

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

“…In DMD muscle, the fast twitch type II fibers are the first group to break down, while the slow type I fibers remain are the last group to be affected (48). A previous study of skeletal muscle fiber types revealed a greater number of slow, type I fibers in the soleus muscles of Dmd mdx-5Cv mice (49). We tested whether any of the beneficial effects observed in the Dmd mdx-5Cv Tg(Cmk-Mir486) mice might be due to changes in muscle fiber type composition.…”

Tamoxifen regulation of sphingolipid metabolism—Therapeutic implications

“…Additional works also illustrate the benefits of tamoxifen in colorectal cancer [50-52] perhaps demonstrating the need for an in depth evaluation in this area. Other, more recent findings suggest that tamoxifen might be of utility in treating Duchenne muscular dystrophy [53]. Toremifene, a chlorinated derivative of tamoxifen (Fig.…”

Retracted: ‘The effects of Duchenne muscular dystrophy on the performance of the stomatognathic system: case–control study’, by Ferreira B., Da Silva G.P., Gonçalves C.R., et al.

“…In the absence of dystrophin, the tissue suffers from calcium overload, oxidative stress, and impaired mitochondrial functions, leading to muscle cell death. 35 Any changes in chewing muscles can affect the pattern of masticatory movements and its efficiency. 30 The decrease in masticatory efficiency can lead to improper diet, which, over time, can generate a malnutrition to patients with DMD.…”