Tamoxifen improves muscle structure and function of Bin1- and Dnm2-related centronuclear myopathies.

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

ORAI1 inhibition as an efficient preclinical therapy for tubular aggregate myopathy and Stormorken syndrome.

Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by childhood-onset muscle weakness and a variable occurrence of multisystemic signs, including short stature, thrombocytopenia, and hyposplenism. TAM/STRMK is caused by gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1, both of which regulate Ca2+ homeostasis through the ubiquitous store-operated Ca2+ entry (SOCE) mechanism. Functional experiments in cells have demonstrated that the TAM/STRMK mutations induce SOCE overactivation, resulting in excessive influx of extracellular Ca2+. There is currently no treatment for TAM/STRMK, but SOCE is amenable to manipulation. Here, we crossed Stim1R304W/+ mice harboring the most common TAM/STRMK mutation with Orai1R93W/+ mice carrying an ORAI1 mutation partially obstructing Ca2+ influx. Compared with Stim1R304W/+ littermates, Stim1R304W/+Orai1R93W/+ offspring showed a normalization of bone architecture, spleen histology, and muscle morphology; an increase of thrombocytes; and improved muscle contraction and relaxation kinetics. Accordingly, comparative RNA-Seq detected more than 1,200 dysregulated genes in Stim1R304W/+ muscle and revealed a major restoration of gene expression in Stim1R304W/+Orai1R93W/+ mice. Altogether, we provide physiological, morphological, functional, and molecular data highlighting the therapeutic potential of ORAI1 inhibition to rescue the multisystemic TAM/STRMK signs, and we identified myostatin as a promising biomarker for TAM/STRMK in humans and mice.

[Omics to serve myology]. / Les omiques au service de la myologie.

Despite efforts in biomedical research, pathophysiological mechanisms and therapeutic targets of diseases remain difficult to identify. The development of high-throughput techniques led to the advent of innovatve technologies called omics. They aim at characterizing as exhaustively as possible a set of molecules: genes, RNAs, proteins, metabolites, etc. These a priori methods allow a precise molecular characterization of diseases and a better understanding of complex pathophysiological mechanisms. In this paper, we will review most omics approaches, their integration and their applications in the context of myology.

Title: Les omiques au service de la myologie. Abstract: Malgré les efforts de la recherche biomédicale, les mécanismes pathologiques et les cibles thérapeutiques des maladies restent difficiles à identifier. L'essor des technologies à haut débit a conduit au développement de technologies innovantes dites « omiques ¼ (omics en langue anglaise). Elles visent à caractériser de manière exhaustive un ensemble de molécules : gènes, ARN, protéines, métabolites, etc. Ces méthodes sans a priori permettent une caractérisation moléculaire fine des maladies et une meilleure compréhension des mécanismes physiopathologiques complexes. Dans cet article, nous ferons un tour d'horizon des approches omiques, de leur intégration et de leurs applications dans le contexte de la myologie.