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 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 the endocytosis machinery in mechanobiology at the costameres in healthy and pathological muscles with a particular focus on its adhesive properties and the interplay with mechanosensitive pathways. We also want to better understand how alternative splicing events of the endocytosis machinery cooperates, upon differentiation, to govern clathrin structural diversity (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).
- By combining genetic modifications, live imaging, biophysics, cellular and animal models, we aim at deciphering the pivotal influence of the nucleo-cytoskeleton connection on cell phenotype and genome organization in particular in the context of muscle formation and cardiomyopathy (Bruno Cadot).
- 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 & 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).
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
Cadot Bruno, 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
Marc Bitoun: firstname.lastname@example.org
tel: +33 0 1 42 16 57 18
- 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.