Team leader : Marc Bitoun
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.
One archetypal example is illustrated by the Dynamin 2-related centronuclear myopathy (CNM). There is no available treatment and the pathomechanisms are still not fully understood for this disease characterized by abnormal nuclear centralization. The team has a long-lasting interest in the dominant CNM exemplified by identification of the causing gene, characterization of clinical and histopathological phenotypes, development of animal models, characterization of the role of the endocytosis machinery in muscle, identification of several pathomechanisms and development of gene-based therapies. The objectives of the team are: i) to dissect fundamental mechanisms of muscle cells, relevant to primarily understand the dominant CNM, and beyond, numerous other neuromuscular disorders, and ii) to develop experimental therapies for the dominant CNM.
In this context, the following projects are developed:
- Defining the role of the endocytosis machinery in muscle (S. Vassilopoulos).
- Investigating the connections between cytoskeletons and nuclear envelope (B. Cadot, more information in https://cadotbruno.com/).
- Understanding the Mechanobiology in healthy and pathological muscle (C. Coirault).
- Studying the pathomechanisms and developing therapies for dominant CNM (D. Trochet)
- Optimizing the AAV-mediated transduction efficacy in pathological muscle (S. Benkhelifa-Ziyyat).
- Characterizing the histopathological features of congenital myopathies (N. Romero, see also the page dedicated to the morphological unit of the Institute).
Bitoun Marc. DR2 Inserm, team leader
Coirault Catherine. DR2 Inserm
Trochet Delphine. CR Association Institut de Myologie
Benkhelifa-Ziyyat Sofia. CR Association Institut de Myologie
Cadot Bruno. CR Association Institut de Myologie
Vassilopoulos Stéphane. CR1 Inserm
Romero Norma. PH AP-HP
Prudhon Bernard. Technician, Association Institut de Myologie
Swati Dudhal. Post-doctoral Researcher
Moulay Gilles. Post-doctoral Researcher
Lemerle Eline. PhD student, Sorbonne Université
Darrigrand Jean-François. PhD student, Sorbonne Université
Chassagne Julie. PhD student, Sorbonne Université
Saline Jabr. PhD student, Sorbonne Université
- Fongy A, Falcone S, Laine J, Prudhon B, Martins-Bach A, Bitoun M (2019) Nuclear defects in skeletal muscle from a Dynamin 2-linked centronuclear myopathy mouse model. Sci Rep 9: 1580
- Franck A, Laine J, Moulay G, Lemerle E, Trichet M, Gentil C, Benkhelifa-Ziyyat S, Lacene E, Bui MT, Brochier G, Guicheney P, Romero NB, Bitoun M, Vassilopoulos S (2019) Clathrin plaques and associated actin anchor intermediate filaments in skeletal muscle. Mol Biol Cell 30: 579-590
- Julien L, Chassagne J, Peccate C, Lorain S, Pietri-Rouxel F, Danos O, Benkhelifa-Ziyyat S (2018) RFX1 and RFX3 Transcription Factors Interact with the D Sequence of Adeno-Associated Virus Inverted Terminal Repeat and Regulate AAV Transduction. Sci Rep 8: 210
- Trochet D, Prudhon B, Beuvin M, Peccate C, Lorain S, Julien L, Benkhelifa-Ziyyat S, Rabai A, Mamchaoui K, Ferry A, Laporte J, Guicheney P, Vassilopoulos S, Bitoun M (2018) Allele-specific silencing therapy for Dynamin 2-related dominant centronuclear myopathy. EMBO Mol Med 10: 239-253
- De Jong A, Carreira S, Na N, Carillion A, Jiang C, Beuvin M, Lacorte JM, Bonnefont-Rousselot D, Riou B, Coirault C (2017) Diaphragmatic function is enhanced in fatty and diabetic fatty rats. PLoS One 12: e0174043
- Gache V, Gomes ER, Cadot B (2017) Microtubule motors involved in nuclear movement during skeletal muscle differentiation. Mol Biol Cell 28: 865-874
- Roman W, Martins JP, Carvalho FA, Voituriez R, Abella JVG, Santos NC, Cadot B, Way M, Gomes ER (2017) Myofibril contraction and crosslinking drive nuclear movement to the periphery of skeletal muscle. Nat Cell Biol 19: 1189-1201
- Schwartz C, Fischer M, Mamchaoui K, Bigot A, Lok T, Verdier C, Duperray A, Michel R, Holt I, Voit T, Quijano-Roy S, Bonne G, Coirault C (2017) Lamins and nesprin-1 mediate inside-out mechanical coupling in muscle cell precursors through FHOD1. Sci Rep 7: 1253
- Gimpel P, Lee YL, Sobota RM, Calvi A, Koullourou V, Patel R, Mamchaoui K, Nedelec F, Shackleton S, Schmoranzer J, Burke B, Cadot B, Gomes ER (2017) Nesprin-1alpha-Dependent Microtubule Nucleation from the Nuclear Envelope via Akap450 Is Necessary for Nuclear Positioning in Muscle Cells. Curr Biol 27: 2999-3009 e2999
- Fraysse B, Guicheney P, Bitoun M (2016) Calcium homeostasis alterations in a mouse model of the Dynamin 2-related centronuclear myopathy. Biol Open 5: 1691-1696
- Fischer M, Rikeit P, Knaus P, Coirault C (2016) YAP-Mediated Mechanotransduction in Skeletal Muscle. Front Physiol 7: 41
- Trochet D, Prudhon B, Jollet A, Lorain S, Bitoun M (2016) Reprogramming the Dynamin 2 mRNA by Spliceosome-mediated RNA Trans-splicing. Mol Ther Nucleic Acids 5: e362
- Vilmont V, Cadot B, Ouanounou G, Gomes ER (2016) A system to study mechanisms of neuromuscular junction development and maintenance. Development 143: 2464-2477
- Vilmont V, Cadot B, Vezin E, Le Grand F, Gomes ER (2016) Dynein disruption perturbs post-synaptic components and contributes to impaired MuSK clustering at the NMJ: implication in ALS. Sci Rep 6: 27804
- Cadot B, Gache V, Gomes ER (2015) Moving and positioning the nucleus in skeletal muscle – one step at a time. Nucleus; 6(5):373-8
- Michelet P, Carreira S, Demoule A, Amour J, Langeron O, Riou B, Coirault C (2015) Effects of acute respiratory and metabolic acidosis on diaphragm muscle obtained from rats. Anesthesiology 122: 876-883
- Trochet D, Prudhon B, Vassilopoulos S, Bitoun M (2015) Therapy for Dominant Inherited Diseases by Allele-Specific RNA Interference: Successes and Pitfalls. Curr Gene Ther 15: 503-510
- Bertrand AT, Ziaei S, Ehret C, Duchemin H, Mamchaoui K, Bigot A, Mayer M, Quijano-Roy S, Desguerre I, Laine J, Ben Yaou R, Bonne G, Coirault C (2014) Cellular microenvironments reveal defective mechanosensing responses and elevated YAP signaling in LMNA-mutated muscle precursors. J Cell Sci 127: 2873-2884
- Cadot B, Gache V, Gomes ER (2014) Fast, multi-dimensional and simultaneous kymograph-like particle dynamics (SkyPad) analysis. PLoS One 9: e89073
- Guellich A, Negroni E, Decostre V, Demoule A, Coirault C (2014) Altered cross-bridge properties in skeletal muscle dystrophies. Front Physiol 5: 393
- Vassilopoulos S, Gentil C, Laine J, Buclez PO, Franck A, Ferry A, Precigout G, Roth R, Heuser JE, Brodsky FM, Garcia L, Bonne G, Voit T, Pietri-Rouxel F, Bitoun M (2014) Actin scaffolding by clathrin heavy chain is required for skeletal muscle sarcomere organization. J Cell Biol 205: 377-393