Team 2- Muscle cell organization and therapy of dominant centronuclear myopathy

Team leaders : Marc Bitoun & Stéphane Vassilopoulos

Strengthening knowledge on fundamental aspects of muscle biology is one central challenge in order to decipher pathomechanisms and identify targets for therapeutic intervention for neuromuscular disorders. This is particularly true for diseases due to mutations in genes encoding proteins with pleiotropic roles such as autosomal dominant centronuclear myopathy (CNM) due to mutation of the ubiquitously expressed Dynamin 2 (DMN2) involved in endocytosis, intracellular membrane trafficking and cytoskeleton regulation. In this context, the objectives of the team are: i) to dissect fundamental mechanisms of muscle cells, relevant to understand the dominant CNM, and beyond, numerous other neuromuscular disorders, and ii) to develop experimental therapies for the dominant CNM and study the adeno-associated virus (AAV) vectors fate in pathological muscles to optimize AAV-mediated therapies for neuromuscular disorders. With these objectives, we are developing several projects:

  • Role of endocytosis and autophagy machinery in muscle physiology under healthy and pathological conditions. We are particularly interested in the adhesive properties of clathrin structures at costameres and their interaction with mechanosensitive pathways. Additionally, we investigate the mechanisms of autophagy in muscle cells, focusing on how the autophagy machinery can be leveraged for therapeutic purposes in conditions such as centronuclear myopathy and Duchenne muscular dystrophy. (Satish Moparthi and Stéphane Vassilopoulos).
  • Role of mechanical stress in muscle homeostasis and growth under physiological and pathological conditions, with a particular focus on the force-mediated regulation of plasma membrane and nuclear stiffness and deformations, chromatin and histone modifications, and genetic programs in muscle cells. We also want to determine how muscle differentiation impacts nuclear characteristics (Catherine Coirault).
  • The cellular and molecular mechanisms involved in ventilation-induced diaphragm dysfunction in particular during aging, and the muscle dysfunction occurring in patients in intensive care unit (Catherine Coirault and Adrien Bouglé).
  • Preclinical development of the allele-specific silencing therapy for the dominant CNM and other DNM2-linked diseases and first proof of concept of allele-specific therapy for other dominant diseases. In addition, we want to develop pharmacological therapy for the DNM2-linked CNM patients (Delphine Trochet and Marc Bitoun).
  • In order to optimize AAV-based therapies, we want to identify cellular factors impacting the efficiency of AAV-mediated transduction in diseased muscles. We are focusing on mechanisms regulating the AAV intracellular trafficking and to improve AAV-mediated therapies in DMD and CNM animal models by pharmacological co-treatments (Sofia Benkhelifa-Ziyyat).

 

Team members

Marc Bitoun, Research Director Inserm, co-team leader
Stéphane Vassilopoulos, Research Director Inserm, co-team leader
Catherine Coirault, Research Director Inserm
DelphineTrochet, Researcher Association Institut de Myologie
Benkhelifa-Ziyyat Sofia, Researcher Association Institut de Myologie
Bernard Prudhon, Technician, Association Institut de Myologie
Lylia Mekzine, Research associate Inserm
Marion Benoist, PhD student, Sorbonne University
Kevin Milliet, Master student
Inès Akrouf, PhD student, Sorbonne University
Joana Martins, PhD student, Sorbonne University
Moparthi Satish. Post-doc. Inserm  

 

Contact

Marc Bitoun: m.bitoun@institut-myologie.org
tel: +33 0 1 42 16 57 18

 

Last publications