Tamoxifen Ameliorates Symptoms of Duchenne Muscular Dystrophy
Results of new study published in The American Journal of Pathology
Philadelphia, PA, January 15, 2013 – A new study has found that tamoxifen, a well-known breast cancer drug, can counteract some pathologic features in a mouse model of Duchenne muscular dystrophy (DMD). At present, no treatment is known to produce long-term improvement of the symptoms in boys with DMD, a debilitating muscular disorder that is characterized by progressive muscle wasting, respiratory and cardiac impairments, paralysis, and premature death. This study will be published in the February 2013 issue of The American Journal of Pathology.
Using the mdx5Cv mouse model of DMD, investigators found that tamoxifen, given orally for more than a year, “caused remarkable improvements of muscle force and of diaphragm and cardiac structure,” according to lead author Olivier M. Dorchies, PhD, of the Department of Pharmacology, Geneva-Lausanne School of Pharmaceutical Sciences of the University of Geneva and University of Lausanne. For instance, in the heart, fibrosis was diminished by approximately 50%. In the diaphragm, the muscle of the dystrophic mouse thought to be most like that of human DMD, tamoxifen reduced fibrosis while increasing thickness as well as the number and average diameter of muscle fibers. The net effect was that tamoxifen raised the amount of contractile tissue available for respiration by 72%.
Patients with DMD show muscle degeneration, and their muscle fibers become abnormally susceptible to stress. In this animal study, tamoxifen improved the structure of leg muscles, slowed muscle contraction, increased overall muscle function, and made leg muscles more resistant to repetitive stimulation and fatigue. In fact, tamoxifen rendered dystrophic muscles even stronger than those of non-dystrophic control mice. “Our findings of a slower rate of contraction and an enhanced resistance to fatigue in muscles from tamoxifen-treated dystrophic mice are of significance for the pathophysiology of muscular dystrophy,” say the authors.
A wire test revealed that treating male mdx5Cv mice with tamoxifen for more than a year increased the whole body strength 2- to 3-fold, close to that of normal mice.
Additional findings shed light on the mechanism of tamoxifen’s therapeutic actions. For example, plasma creatine kinase (CK) activity was found to be about 3 times higher in the dystrophic male mice than in the non-dystrophic males, and tamoxifen treatment normalized the CK levels of the dystrophic mice. The authors suggest that this effect is mediated by an estrogen receptor (ER) dependent mechanism. The study also reported for the first time that mouse dystrophic muscle is high in both ER α and β, and that tamoxifen raises levels of ERβ2 in particular. Other findings, such as increased levels of calcineurin and accumulation of several structural proteins, indicate a protective effect of tamoxifen on dystrophic muscles. The authors point out that the beneficial effects of tamoxifen were seen with muscle tissue levels much lower than those reported in previous studies of normal rodents, suggesting that doses lower than those used to treat breast cancer may be effective in the treatment of DMD.
# # #
Notes for editors
“The anti-cancer drug tamoxifen counteracts the pathology in a mouse model of Duchenne muscular dystrophy,” by Olivier M. Dorchies, Julie Reutenauer-Patte, Elyes Dahmane, et al. (DOI: http://dx.doi.org/10.1016/j.ajpath.2012.10.018). It appears in The American Journal of Pathology, Volume 182, Issue 2 (February 2013) published by Elsevier.
Full text of the article is available to credentialed journalists upon request; contact David Sampson at +1-215-239-3171 or email@example.com. Journalists wishing to interview the authors may contact Olivier M. Dorchies at +41 78 635 6811 (cell) or firstname.lastname@example.org.
About The American Journal of Pathology
The American Journal of Pathology (http://ajp.amjpathol.org), official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.
The leading global forum for reporting quality original research on cellular and molecular mechanisms of disease, The American Journal of Pathology is the most highly cited journal in Pathology – over 38,000 cites in 2011 – with an Impact Factor of 4.890 according to 2011 Journal Citation Reports®, Thomson Reuters.
Elsevier is a world-leading provider of information solutions that enhance the performance of science, health, and technology professionals, empowering them to make better decisions, deliver better care, and sometimes make groundbreaking discoveries that advance the boundaries of knowledge and human progress. Elsevier provides web-based, digital solutions — among them ScienceDirect, Scopus, Elsevier Research Intelligence,and ClinicalKey—and publishes over 2,200 journals, including The Lancet and Cell, and over 25,000 book titles, including a number of iconic reference works.
The company is part of Reed Elsevier Group PLC, a world leading provider of professional information solutions in the Science, Medical, Legal and Risk and Business sectors, which is jointly owned by Reed Elsevier PLC and Reed Elsevier NV. The ticker symbols are REN (Euronext Amsterdam), REL (London Stock Exchange), RUK and ENL (New York Stock Exchange).
+1 215 239 3171
Dr. Chhavi Chauhan
The American Journal of Pathology
+1 301 634 7953