Muscle cell organization and therapy of dominant centronuclear myopathy

Muscle cell organization and therapy of dominant centronuclear myopathy

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
  • 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).


Equipe Bitoun
Marc Bitoun


Marc Bitoun


Main publications

  1. Moulay, G, Lainé, J, Lemaître, M, Nakamori, M, Nishino, I, Caillol, G et al.. Alternative splicing of clathrin heavy chain contributes to the switch from coated pits to plaques. J Cell Biol. 2020;219 (9):. doi: 10.1083/jcb.201912061. PubMed PMID:32642759 PubMed Central PMC7480091.
  2. Vassilopoulos, S, Gibaud, S, Jimenez, A, Caillol, G, Leterrier, C. Ultrastructure of the axonal periodic scaffold reveals a braid-like organization of actin rings. Nat Commun. 2019;10 (1):5803. doi: 10.1038/s41467-019-13835-6. PubMed PMID:31862971 PubMed Central PMC6925202.
  3. Ferrari, R, Martin, G, Tagit, O, Guichard, A, Cambi, A, Voituriez, R et al.. MT1-MMP directs force-producing proteolytic contacts that drive tumor cell invasion. Nat Commun. 2019;10 (1):4886. doi: 10.1038/s41467-019-12930-y. PubMed PMID:31653854 PubMed Central PMC6814785.
  4. Essawy, N, Samson, C, Petitalot, A, Moog, S, Bigot, A, Herrada, I et al.. An Emerin LEM-Domain Mutation Impairs Cell Response to Mechanical Stress. Cells. 2019;8 (6):. doi: 10.3390/cells8060570. PubMed PMID:31185657 PubMed Central PMC6628311.
  5. Ali, T, Bednarska, J, Vassilopoulos, S, Tran, M, Diakonov, IA, Ziyadeh-Isleem, A et al.. Correlative SICM-FCM reveals changes in morphology and kinetics of endocytic pits induced by disease-associated mutations in dynamin. FASEB J. 2019;33 (7):8504-8518. doi: 10.1096/fj.201802635R. PubMed PMID:31017801 PubMed Central PMC6593877.
  6. Fongy, A, Falcone, S, Lainé, J, Prudhon, B, Martins-Bach, A, Bitoun, M et al.. Nuclear defects in skeletal muscle from a Dynamin 2-linked centronuclear myopathy mouse model. Sci Rep. 2019;9 (1):1580. doi: 10.1038/s41598-018-38184-0. PubMed PMID:30733559 PubMed Central PMC6367339.
  7. Franck, A, Lainé, J, Moulay, G, Lemerle, E, Trichet, M, Gentil, C et al.. Clathrin plaques and associated actin anchor intermediate filaments in skeletal muscle. Mol Biol Cell. 2019;30 (5):579-590. doi: 10.1091/mbc.E18-11-0718. PubMed PMID:30601711 PubMed Central PMC6589689.
  8. Torrino, S, Shen, WW, Blouin, CM, Mani, SK, Viaris de Lesegno, C, Bost, P et al.. EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription. J Cell Biol. 2018;217 (12):4092-4105. doi: 10.1083/jcb.201801122. PubMed PMID:30348749 PubMed Central PMC6279385.
  9. Maib, H, Ferreira, F, Vassilopoulos, S, Smythe, E. Cargo regulates clathrin-coated pit invagination via clathrin light chain phosphorylation. J Cell Biol. 2018;217 (12):4253-4266. doi: 10.1083/jcb.201805005. PubMed PMID:30228161 PubMed Central PMC6279376.
  10. Le Dinh, M, Carreira, S, Obert, J, Gayan-Ramirez, G, Riou, B, Beuvin, M et al.. Prolonged mechanical ventilation worsens sepsis-induced diaphragmatic dysfunction in the rat. PLoS One. 2018;13 (8):e0200429. doi: 10.1371/journal.pone.0200429. PubMed PMID:30067847 PubMed Central PMC6070213.
  11. Julien, L, Chassagne, J, Peccate, C, Lorain, S, Piétri-Rouxel, F, Danos, O et al.. RFX1 and RFX3 Transcription Factors Interact with the D Sequence of Adeno-Associated Virus Inverted Terminal Repeat and Regulate AAV Transduction. Sci Rep. 2018;8 (1):210. doi: 10.1038/s41598-017-18604-3. PubMed PMID:29317724 PubMed Central PMC5760533.
  12. Randrianarison-Huetz, V, Papaefthymiou, A, Herledan, G, Noviello, C, Faradova, U, Collard, L et al.. Srf controls satellite cell fusion through the maintenance of actin architecture. J Cell Biol. 2018;217 (2):685-700. doi: 10.1083/jcb.201705130. PubMed PMID:29269426 PubMed Central PMC5800804.
  13. Trochet, D, Prudhon, B, Beuvin, M, Peccate, C, Lorain, S, Julien, L et al.. Allele-specific silencing therapy for Dynamin 2-related dominant centronuclear myopathy. EMBO Mol Med. 2018;10 (2):239-253. doi: 10.15252/emmm.201707988. PubMed PMID:29246969 PubMed Central PMC5801507.
  14. Gimpel, P, Lee, YL, Sobota, RM, Calvi, A, Koullourou, V, Patel, R et al.. Nesprin-1α-Dependent Microtubule Nucleation from the Nuclear Envelope via Akap450 Is Necessary for Nuclear Positioning in Muscle Cells. Curr Biol. 2017;27 (19):2999-3009.e9. doi: 10.1016/j.cub.2017.08.031. PubMed PMID:28966089 PubMed Central PMC5640514.
  15. Roman, W, Martins, JP, Carvalho, FA, Voituriez, R, Abella, JVG, Santos, NC et al.. Myofibril contraction and crosslinking drive nuclear movement to the periphery of skeletal muscle. Nat Cell Biol. 2017;19 (10):1189-1201. doi: 10.1038/ncb3605. PubMed PMID:28892082 PubMed Central PMC5675053.
  16. Schwartz, C, Fischer, M, Mamchaoui, K, Bigot, A, Lok, T, Verdier, C et al.. Lamins and nesprin-1 mediate inside-out mechanical coupling in muscle cell precursors through FHOD1. Sci Rep. 2017;7 (1):1253. doi: 10.1038/s41598-017-01324-z. PubMed PMID:28455503 PubMed Central PMC5430732.
  17. De Jong, A, Carreira, S, Na, N, Carillion, A, Jiang, C, Beuvin, M et al.. Diaphragmatic function is enhanced in fatty and diabetic fatty rats. PLoS One. 2017;12 (3):e0174043. doi: 10.1371/journal.pone.0174043. PubMed PMID:28328996 PubMed Central PMC5362060.
  18. Gache, V, Gomes, ER, Cadot, B. Microtubule motors involved in nuclear movement during skeletal muscle differentiation. Mol Biol Cell. 2017;28 (7):865-874. doi: 10.1091/mbc.E16-06-0405. PubMed PMID:28179457 PubMed Central PMC5385935.
  19. Fraysse, B, Guicheney, P, Bitoun, M. Calcium homeostasis alterations in a mouse model of the Dynamin 2-related centronuclear myopathy. Biol Open. 2016;5 (11):1691-1696. doi: 10.1242/bio.020263. PubMed PMID:27870637 PubMed Central PMC5155535.
  20. Trochet, D, Prudhon, B, Jollet, A, Lorain, S, Bitoun, M. Reprogramming the Dynamin 2 mRNA by Spliceosome-mediated RNA Trans-splicing. Mol Ther Nucleic Acids. 2016;5 (9):e362. doi: 10.1038/mtna.2016.67. PubMed PMID:27623444 PubMed Central PMC5056991.

Agence nationale de la recherche
Inserm Transfert
SU Emergence
Myotubular trust
Campus France

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