Over the past decade several converging lines of evidence have highlighted the importance of post-transcriptional events in skeletal muscle. This level of regulation is controlled by multi-functional RNA-binding proteins and trans-acting factors. In fact, several RNA-binding proteins are implicated in neuromuscular disorders including myotonic dystrophy type I, spinal muscular atrophy and amyotrophic lateral sclerosis. Therefore, it is necessary to examine the impact of RNA-binding proteins during skeletal muscle development and plasticity in order to understand the consequences linked to their misregulation in disease. Here, we focused on the RNA-binding protein Staufen1, which assumes multiple roles in both skeletal muscle and neurons. We previously demonstrated that Staufen1 is regulated during myogenic differentiation and that its expression is increased in denervated and in myotonic dystrophy type I skeletal muscles. The increased expression of Staufen1 initially appeared beneficial for DM1 since further elevating Staufen1 levels rescued key hallmarks of the disease. However, based on the multi-functional nature of Staufen1, we hypothesized that Staufen1 acts as a disease modifier in DM1. To test this, we investigated the roles of Staufen1 in skeletal muscle biology and their implications for disease. Our data demonstrated that Staufen1 is required during the early stages of muscle development, however its expression must remain low in postnatal skeletal muscle. Interestingly, the overexpression of Staufen1 impaired myogenesis through the regulation of c-myc translation. Since the function of c-myc in oncogenesis is well described, we investigated the role of Staufen1 in cancer biology. In particular, we determined novel functions of Staufen1 in rhabdomyosarcoma tumorigenesis, thus providing the first direct evidence for Staufen1’s involvement in cancer. Moreover, based on Staufen1’s role in myogenic differentiation and in myotonic dystrophy type I, we generated muscle-specific transgenic mice to examine the impact of sustained Staufen1 expression in postnatal skeletal muscle. Staufen1 transgenic mice developed a myopathy characterized by histological and functional abnormalities via atrogene induction and the regulation of PTEN mRNAs. In parallel, we further investigated Staufen1-regulated alternative splicing and our data demonstrated that Staufen1 regulates multiple alternative splicing events in normal and myotonic dystrophy type I skeletal muscles, both beneficial and detrimental for the pathology. Collectively, these findings uncover several novel functions of Staufen1 in skeletal muscle biology and highlight Staufen1’s role as a disease modifier in DM1.

Myotonic Dystrophy Type I (DM1) is a multi-systemic genetic neuromuscular degenerative disease, has a prevalence in most populations of about 1:8000 and is caused by the nuclear retention of pathogenically expanded DMPK mRNA. A previous DM1 RNAi-kinome screen in our lab has identified kinases that reduced both count and area of DMPK mRNA foci in vitro. One such discovered kinase is PACT, which has showed to decrease foci count and area in DM1 fibroblasts by 30-50%. This study explored PACT as well as binding partner DICER involved in cellular RNA processing machinery, to highlight potential therapeutic targets in DM1. DM1 fibroblasts treated with PACT siRNA showed a non-significant trend of upregulation in MBNL1 mRNA and protein expression. PACT knockdown also showed trend of missplicing normalization in SERCA-1, more prominently seen in DM1-2000 human fibroblasts, whereas IR (insulin receptor) splicing remained unaffected. On the other hand, DICER knockdown did not have profound affect on foci integrity as well as MBNL1 RNA and protein xpressions in DM1 fibroblasts. SERCA-1 splicing in DICER siRNA treated samples also remained unchanged. We report here our findings in pursuit of potential therapeutic targets for the treatment of DM1.

Des difficultés de compréhension interpersonnelles sont régulièrement rapportées par les proches et les patients atteints de Dystrophie Myotonique de type I (DM1) ou de Dystrophie Facio-Scapulo-Humérale (FSHD). Nous nous sommes intéressés à différents facteurs qui peuvent éclairer la présence d’un contresens relationnel au sein des couples (le patient avec son conjoint). Les facteurs étudiés sont : les troubles cognitifs, l’atteinte des mimiques faciales et le style d’attachement de chacun des partenaires. La méthode utilisée est basée en partie sur l’observation de l’interaction (communication verbale et non verbale) au sein des couples lors la réalisation d’une tâche de résolution de problème. Un test de reconnaissance des émotions faciales avec des visages atteints et des visages contrôles a également été construit et proposé à 57 sujets naïfs. Les résultats observés permettent de confirmer que l’atteinte du visage et de la cognition sociale (théorie de l’esprit) ainsi que le style d’attachement des membres du couple jouent un rôle dans les difficultés à se comprendre entre partenaires de l’interaction. Il est important de sensibiliser chacun des partenaires au rôle de la communication non verbale (CNV) dans leur quotidien. La CNV transmet non seulement des informations sur l’état interne (notamment les émotions) de l’autre, mais également sur ses besoins d’attention, de soutien, de support émotionnel. / Interpersonal communication difficulties are regularly reported by individuals suffering from Myotonic Dystrophy type I (DMI) and Facioscapulohumeral muscular Dystrophy (FSHD), and their families. Our study focuses specifically on communication between patients and their spouses. In order to investigate the nature of communication difficulties, cognitive impairment, impaired facial expression and the attachment styles of subjects were examined. Our investigation procedure involved detailed observation of couples’ communication processes (verbal and non-verbal communication) while completing a problem-solving task. Furthermore, we construct a test of facial emotion recognition composed of images from the DM1 and control groups, which was administered to 57 naive subjects. Results enables us to confirm that impaired facial expression, social cognition difficulties (theory of mind) and attachment style play a major role, in the communication and comprehension difficulties reported by patients and their families. A phenomenon of relational misinterpretation seems to occur between patients and their partners. It is therefore important to raise couples’ awareness of the role of non-verbal communication in everyday life. Non-verbal communication not only provides information about an individual’s internal state (such as emotions), but also about his or her needs for attention and emotional support.