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).

Team members

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. DR2 Inserm
Bouglé Adrien. PCU-PH AP-HP
Prudhon Bernard. Technician, Association Institut de Myologie
Mekzine Lylia. Research assistant Inserm
Milliet Kevin. Research assistant Inserm
Moparthi Satish. Post-doctoral researcher Inserm
Da Costa Oterelo Martins Joana . PhD student, Sorbonne Université
Benoist Marion. PhD student, Sorbonne Université
Akrouf Inès. PhD student, Sorbonne Université

Contact

Marc Bitoun
m.bitoun@institut-myologie.org
tel: 0142165718

Last publications

• Mollard A, Peccate C, Forand A, Chassagne J, Julien L, Meunier P, Guesmia Z, Marais T, Bitoun M, Piétri-Rouxel F, Benkhelifa-Ziyyat S, Lorain S.  Muscle regeneration affects Adeno Associated Virus 1 mediated transgene transcription. Sci Rep. 2022 Jun 11;12(1):9674.
• Trochet D, Prudhon B, Mekzine L, Lemaitre M, Beuvin M, Julien L, Benkhelifa-Ziyyat S, Bui MT, Romero N, Bitoun M. Benefits of therapy by dynamin-2-mutant-specific silencing are maintained with time in a mouse model of dominant centronuclear myopathy. Mol Ther Nucleic Acids. 2022 Feb 13;27:1179-1190.
• Dudhal S, Mekzine L, Prudhon B, Soocheta K, Cadot B, Mamchaoui K, Trochet D, Bitoun M. Development of versatile allele-specific siRNAs able to silence all the dominant dynamin 2 mutations. Mol Ther Nucleic Acids. 2022 Aug 13;29:733-748.
• Vassilopoulos S, Leterrier C. [Rings and braids: Correlative microscopy reveals the structure of axonal actin]. Med Sci (Paris). 2022 Feb;38(2):130-133.
• Le Dour C, Chatzifrangkeskou M, Macquart C, Magiera MM, Peccate C, Jouve C, Virtanen L, Heliö T, Aalto-Setälä K, Crasto S, Cadot B, Cardoso D, Mougenot N, Adesse D, Di Pasquale E, Hulot JS, Taimen P, Janke C, Muchir A. Actin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations. Nat Commun. 2022 Dec 22;13(1):7886. 
• Rose N, Estrada Chavez B, Sonam S, Nguyen T, Grenci G, Bigot A, Muchir A, Ladoux B, Cadot B, Le Grand F, Trichet L. Bioengineering a miniaturized in vitro 3D myotube contraction monitoring chip to model muscular dystrophies. Biomaterials. 2023 Feb;293:121935.
• Labasse C, Brochier G, Taratuto AL, Cadot B, Rendu J, Monges S, Biancalana V, Quijano-Roy S, Bui MT, Chanut A, Madelaine A, Lacène E, Beuvin M, Amthor H, Servais L, de Feraudy Y, Erro M, Saccoliti M, Neto OA, Fauré J, Lannes B, Laugel V, Coppens S, Lubieniecki F, Bello AB, Laing N, Evangelista T, Laporte J, Böhm J, Romero NB. Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies. Acta Neuropathol Commun. 2022 Jul 9;10(1):101.
• Agsu G, Gaillard J, Cadot B, Blanchoin L, Fabre E, Théry M. Reconstituting the Interaction Between Purified Nuclei and Microtubule Network. Methods Mol Biol. 2022; 2430:385-399. 
• Jacquier V, Prévot M, Gostan T, Bordonné R, Benkhelifa-Ziyyat S, Barkats M, Soret J. Splicing efficiency of minor introns in a mouse model of SMA predominantly depends on their branchpoint sequence and can involve the contribution of major spliceosome components. RNA. 2022 Mar;28(3):303-319. 
• Lionello VM, Kretz C, Edelweiss E, Crucifix C, Gómez-Oca R, Messaddeq N, Buono S, Koebel P, Massana Muñoz X, Diedhiou N, Cowling BS, Bitoun M, Laporte J. BIN1 modulation in vivo rescues dynamin-related myopathy. Proc Natl Acad Sci U S A. 2022 Mar 1;119(9):e2109576119.
• Seetharaman S, Vianay B, Roca V, Farrugia AJ, De Pascalis C, Boëda B, Dingli F, Loew D, Vassilopoulos S, Bershadsky A, Théry M, Etienne-Manneville S. Microtubules tune mechanosensitive cell responses. Nat Mater. 2022 Mar;21(3):366-377.
• El Alaoui F, Casuso I, Sanchez-Fuentes D, Arpin-Andre C, Rathar R, Baecker V, Castro A, Lorca T, Viaud J, Vassilopoulos S, Carretero-Genevrier A, Picas L. Structural organization and dynamics of FCHo2 docking on membranes. Elife. 2022 Jan 19;11:e73156.
• Venkova L, Vishen AS, Lembo S, Srivastava N, Duchamp B, Ruppel A, Williart A, Vassilopoulos S, Deslys A, Garcia Arcos JM, Diz-Muñoz A, Balland M, Joanny JF, Cuvelier D, Sens P, Piel M. A mechano-osmotic feedback couples cell volume to the rate of cell deformation. Elife. 2022 Apr 13;11:e72381.
• Iqbal MH, Revana FJR, Pradel E, Gribova V, Mamchaoui K, Coirault C, Meyer F, Boulmedais F. Brush-Induced Orientation of Collagen Fibers in Layer-by-Layer Nanofilms: A Simple Method for the Development of Human Muscle Fibers. ACS Nano. 2022 Dec 27;16(12):20034-20043.
• Viggars MR, Owens DJ, Stewart C, Coirault C, Mackey AL, Jarvis JC. PCM1 labeling reveals myonuclear and nuclear dynamics in skeletal muscle across species. Am J Physiol Cell Physiol. 2023 Jan 1;324(1):C85-C97.