Awareness of CV risk factors is low in this high-risk population and associated with strong social inequalities. This information is alarming and will have to be addressed in order to improve outcomes in patients with CAD.

Congenital myopathies define a genetically heterogeneous group of disorders associated with severe muscle weakness, for which no therapies are currently available. Here we investigated repurposing of tamoxifen in mouse models of mild or severe forms of centronuclear myopathies (CNM) due to mutations in BIN1 (encoding amphiphysin 2) or DNM2 (encoding dynamin 2, DNM2), respectively. Exposure to tamoxifen-enriched diet from 3 weeks of age resulted in significant improvement in muscle contractility without increase in fiber size in both models, underlying an increase capacity of the muscle fiber to produce more force. In addition, the histological alterations were fully rescued in the BIN1-CNM mouse model. To assess the mechanism of the rescue, transcriptome analyses and targeted protein studies were performed. Albeit tamoxifen is known to modulate the transcriptional activity of the estrogen receptors, correction of the disease transcriptomic signature was marginal upon tamoxifen treatment. Conversely, tamoxifen lowered the abnormal increase in DNM2 protein level in both CNM models. Of note, it was previously reported that DNM2 increase is a main pathological cause of CNM. The Akt/mTOR muscle hypertrophic pathway and protein markers of the ubiquitin proteasome system, as the E3 ubiquitin ligase cullin 3, and the autophagy as p62 were all increased in both CNM models. Normalization of DNM2 level mainly correlated with normalization of cullin 3 protein level upon tamoxifen treatment, supporting the ubiquitin proteasome system is a main target for tamoxifen effect in the amelioration of these diseases. Overall, our data suggest that tamoxifen antagonizes disease development likely through DNM2 level regulation. In conclusion, the beneficial effect of tamoxifen on muscle function supports that tamoxifen may serve as a common therapy for several autosomal forms of centronuclear myopathies.

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