Deciphering novel mechanisms and effectors contributing to muscle dysfunction in Myotonic Dystrophy Type I
Prof. Perrine Castets, University of Geneva
Abstract (Lay summary see below)
Myotonic Dystrophy type I (DM1) is a multisystemic neuromuscular disorder, which constitutes the most common form of muscular dystrophy in adults. DM1 patients display muscle wasting, weakness and inability to relax (i.e. myotonia). The pathomechanisms involve the mis-splicing of a large set of genes, leading to the deregulation of various signaling pathways in the tissues. How these changes lead to muscle dysfunction remains poorly understood. The overall aim of the project is to identify novel processes contributing to or compensating for myotonia and muscle atrophy in DM1. We previously established that the metabolic pathways, AMPK and mTORC1, are deregulated in DM1 muscle, which may contribute to muscle alterations. Moreover, in our recent study, we showed that the neuromuscular junctions (NMJs) are perturbed in HSALR mice, a mouse model for DM1. These defects may arise from the deregulation of the Ca2+/calmodulin-dependent protein kinase family (CaMK) and may contribute to muscle affection in DM1. In parallel, transcriptomic and proteomic analyses conducted with HSALR muscle allowed us to delineate candidate effectors, which may contribute to muscle dysfunction or alternatively, be part of a compensatory response limiting muscle affection in DM1. In this project, we first aim to achieve our study focusing on NMJ alterations in DM1, in order to understand the mechanisms underlying the defects observed and their contribution to muscle dysfunction. In the second axis, we aim to complete the analysis of chloride channel accessory proteins (CLCAs) identified in our omics data, as they may be important players in muscle pathophysiology in DM1. These two axes will bring new insights on the deregulations contributing to muscle impairment in DM1 and on the mechanisms liable to compensate for muscle dysfunction, which may orientate towards alternative therapeutic strategies for DM1.
Lay summary
Identification de nouveaux mécanismes contribuant à l'atteinte musculaire dans la Dystrophie Myotonique de type 1
La dystrophie myotonique de type I (DM1) est une maladie génétique affectant notamment les muscles. Les patients présentent une perte de masse musculaire (atrophie) et une contraction anormale de leurs muscles (myotonie) limitant leur autonomie. L’objectif du projet est de mieux comprendre les processus conduisant à l’atteinte musculaire chez les patients. Nos études ont montré que les jonctions neuromusculaires (i.e. les synapses connectant les neurones aux muscles – JNM) sont perturbées chez les souris HSALR, un modèle murin pour la DM1. En parallèle, nous avons identifié des effecteurs, dont la forte expression dans les muscles HSALR pourrait être un mécanisme compensatoire pour limiter la myotonie. Le but du projet est 1) de déterminer les mécanismes conduisant à l’altération des JNMs dans la DM1, et 2) d’explorer le rôle des effecteurs identifiés dans le muscle, afin de comprendre leur contribution respective à l’atteinte musculaire et de définir de nouvelles cibles thérapeutiques pour la pathologie.
Projekte
- Neue Forschungsprojekte ab 2024
- Die Bedeutung der Forschung
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