Widely used in the treatment of certain breast cancers, tamoxifen has already shown its ability to improve muscle cell function in two types of myopathies, including Duchenne. Today, a new study confirms the potential interest of this drug for the management of a third family of neuromuscular diseases: centronuclear myopathies. The hypothesis of a universal use of anti-cancer, for all myopathies, is more and more credible…
Myopathies include more than 200 neuromuscular diseases, most of which are of genetic origin. All are characterized by impaired muscle function, but they are distinguished by different mutations and pathophysiological mechanisms. At the Institute of Genetics and Molecular and Cellular Biology in Strasbourg, Jocelyn Laporte’s team is studying two families: centronuclear myopathies linked to gene mutations DNM2 or BIN1and myotubular myopathies linked to a mutation of MTM1. « The cellular abnormalities caused by these different mutations result in excessive activity of dynamin 2, a protein in responsible for the reorganization of the membrane of muscle cells. This phenomenon limits the ability of muscle cells to contract. », explains the researcher.
With his team, he has just shown that the administration of tamoxifen, an anti-cancer drug used in breast cancer, improves muscle contractility in an animal model of centronuclear myopathy. ” This was a so-called repositioning study, he continues. This consists of studying a molecule already on the market to find out if it could be effective in other diseases. This approach makes it possible to identify new treatments more quickly than by the traditional route, since their toxicity in humans is already known.
Encouraging clinical results
Tamoxifen has anti-estrogenic activity in breast tissue, but it also appears to have a favorable effect on muscle cell function. A few years ago, this particularity motivated researchers to evaluate the effect of tamoxifen in an animal model of Duchenne muscular dystrophy, the most common genetic muscle disease, in which a disturbance in the cohesion of muscle tissue leads to the progressive muscle degeneration. “ The convincing results that have been obtained have led to the establishment ofa clinical trialcurrently in progress »relate Jocelyn Laporte. Centronuclear myopathies and myotubular myopathies are different from Duchenne muscular dystrophy: they are not associated with muscle cell degeneration but with their very low contractility. The researcher wanted to know if the administration of tamoxifen could nevertheless have an equivalent interest in these diseases. After confirming this hypothesis in myotubular myopathies in 2018, his team therefore shows today that the drug also seems beneficial in the case of centronuclear myopathies. These demonstrations were performed in mice that model both diseases, but “ we observed the same efficacy of the molecule on human muscle cells studied in vitro. It remains to confirm these results in patients », specifies Jocelyn Laporte.
« Given the heterogeneity of the genetic, cellular and molecular abnormalities of the different myopathies that respond to tamoxifen, we also wanted to characterize the mechanisms of action of the molecule “, he continues. It appeared that it leads to an intracellular decrease in the quantity of dynamin 2, associated with that of another protein, cullin 3. When a protein is no longer functional, it is degraded by the cell. Cullin 3 tags proteins that should be sent for recycling by attaching a small molecule, ubiquitin, to them. However, the levels of these two proteins are correlated: when dynamin 2 is in excess, the level of culline 3 increases. Under tamoxifen, we observe a normalization of the level of dynamin 2 and culline 3. We therefore believe that tamoxifen improves or reinforces the degradation of dynamin 2. »
For several weeks, a clinical trial has been conducted to assess the efficacy of tamoxifen in myotubular myopathies and the researcher hopes that a new study can be quickly set up to conduct the same work in centronuclear myopathies. At the same time, he is expanding his preclinical work to new groups of myopathies. ” The clinical study which is in progress in Duchenne muscular dystrophy is showing initial encouraging results. Patients seem to recover better muscle function, without major side effects. We can therefore hope that it will be the same in centronuclear and myotubular myopathies. concludes Jocelyn Laporte.
Jocelyn Laporte is responsible for the team Pathophysiology of neuromuscular diseases at the Institute of Genetics and Molecular and Cellular Biology (IGBMC, unit 1258 Inserm/CNRS/University of Strasbourg), in Illkirch.
Source : C. Gineste et al. Tamoxifen improves muscle structure and function of Bin1– and Dnm2–related centronuclear myopathies. Brain, online edition of December 23, 2022; doi:10.1093/brain/awac489
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Source: www.inserm.fr
