PROJECTS

The team develops 3 fundamental research themes and 2 translational research themes:

• Regulation of muscle gene expression by motor innervation
• Nucleus/cytoskeleton links in synapse function
• TGFb/mTOR signaling in muscle
• Pathophysiological mechanisms of neuromuscular disorders (NMD)
• Identification of biomarkers in NMD

2005-2015 MAJOR SCIENTIFIC ACHIEVEMENTS

REGULATION OF MUSCLE GENE EXPRESSION BY MOTOR INNERVATION

• i) Histone Deacetylase 9 participates in the coupling of neuronal activity to muscle chromatin acetylation and gene expression (Méjat et al., 2005).
• ii) Post synaptic chromatin is under neural control at the neuromuscular junction (Ravel Chapuis et al., 2007).
• iii) Repression of muscle gene expression by electrical activity is mediated by the transcriptional co-repressor CtBP (Thomas et al., 2015).
• iv) The histone deacetylase HDAC6 is a new atrogene and a downstream effector of FoxO transcription factors in cellular stress response (Ratti et al., 2015).

NEUROMUSCULAR JUNCTION AND NUCLEI POSITIONING

Nesprins control nuclei position and postsynaptic receptors density in skeletal muscle (Morel et al. 2014).

DECIPHERING THE ROLE OF PI3K/MTOR SIGNALLING IN SKELETAL MUSCLE

• i) Establishing the interactome of the PI3K signaling pathway (Pilot-Storck et la., 2010).
• ii) The PH domain containing protein CKIP-1 act downstream of PI3K to link PI3K signalling and actin cytoskeleton to control muscle differentiation (Baas et al., 2012).
• iii) In adult muscle, mTOR controls both energy metabolism and dystrophin expression (Risson et al., 2009; Romanino et al., 2011).
• iv) The autophagic receptor NBR1 is regulated by GSK3-dependent phosphorylation and is deregulated in muscle proteinopathies (Nicot et al., 2014).

TRANSLATIONAL ACTIVITIES

• i) Identification of a new gene responsible for a congenital myasthenic syndrome (Huze et al., 2009).
• ii) Development of a cell based assay to detect non-conventional antibodies in French myasthenic patients (Devic et al., 2014).

SELECTED PUBLICATIONS

• Novel Intronic Mutation in VMA21 Causing Severe Phenotype of X-Linked Myopathy with Excessive Autophagy-Case Report.
  A. Pegat, N. Streichenberger, N. Lacoste, M. Hermier, R. Menassa, L. Coudert, J. Theuriet, R. Froissart, S. Terrone, F. Bouhour, L. Michel-Calemard, L. Schaeffer and A. Jacquier.
  Genes (2022) DOI: 10.3390/genes13122245
• Immune-Mediated Rippling Muscle Disease Associated With Thymoma and Anti-MURC/Cavin-4 Autoantibodies.
  J. Svahn , L. Coudert , N. Streichenberger, A. Kraut , A. Gravier-Dumonceau-Mazelier, L. Rotard , L. Calemard-Michel, R. Menassa, E. Errazuriz-Cerda, L. Chalabreysse, A. Osseni, C. Vial, L. Jomir, F. Tronc, D. Le Duy, E. Bernard, V. Gache, Y. Couté, V. Jacquemond, L. Schaeffer, P. Leblanc.
  Neurology: Neuroimmunology & Neuroinflammation (2023) DOI: 10.1212/NXI.0000000000200068
• Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation.
  A. Osseni, A. Ravel-Chapuis, E. Belotti, I. Scionti, Y-G. Gangloff, V. Moncollin, L. Mazelin, R. Mounier, P. Leblanc, B. J. Jasmin & L. Schaeffer.
  Nature Communications (2022) DOI: 10.1038/s41467-022-34831-3
• Expanding the phenotypic variability of MORC2 gene mutations: From Charcot-Marie-Tooth disease to late-onset pure motor neuropathy.
  A. Jacquier, S. Ribault, M. Mendes, N. Lacoste, V. Risson, J. Carras, P. Latour, A. Nadaj-Pakleza, T. Stojkovic, L. Schaeffer.
  Human Mutation (2022) DOI: 10.1002/humu.24445
• Severe congenital myasthenic syndromes caused by agrin mutations affecting secretion by motoneurons.
  A. Jacquier · V. Risson · T. Simonet 1,2 · F. Roussange · N. Lacoste · S. Ribault · J. Carras · J. Theuriet · E. Girard · I. Grosjean · L. Le Goff · S. Kröger · J. Meltoranta · S. Bauché · D. Sternberg · E. Fournier· A. Kostera-Pruszczyk ·E. O’Connor · B. Eymard · H. Lochmüller · C. Martinat · L. Schaeffer.
  Acta Neuropathologica (2022) doi: 0.1007/s00401-022-02475-8
• The ESCRT-0 subcomplex component Hrs/Hgs is a master regulator of myogenesis via modulation of signaling and degradation pathways.
  L. Coudert, A. Osseni, Y. G. Gangloff, L. Schaeffer and P. Leblanc.
  BMC Biology (2021) doi: 10.1186/s12915-021-01091.
• HDAC6 regulates microtubule stability and clustering of AChRs at neuromuscular junctions.
  Osseni A, Ravel-Chapuis A, Thomas JL, Gache V, Schaeffer L, Jasmin BJ.
  J Cell Biol (2020) doi: 10.1083/jcb/201901099.
• H2A.Z is dispensable for both basal and activated transcription in post-mitotic mouse muscles.
  Belotti E, Lacoste N, Simonet T, Papin C, Padmanabhan K, Scionti I, Gangloff YG, Ramos L, Dalkara D, Hamiche A, Dimitrov S and Schaeffer L.
  Nucleic Acids Research (2020) doi: 10.1093/nar/gkaa157.
• Phosphorylated and aggregated TDP-43 with seeding properties are induced upon mutant Huntingtin (mHtt) polyglutamine expression in human cellular models.
  Coudert L, Nonaka T, Bernard E, Hasegawa M, Schaeffer L, Leblanc P
  Cell Mol Life Sci. (2019) doi: 10.1007/s00018-019-03059-8.
• Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis.
  Zhang Q, Duplany A, Moncollin V, Mouradian S, Goillot E, Mazelin L, Gauthier K, Streichenberger N, Angleraux C, Chen J, Ding S, Schaeffer L, Gangloff YG.
  J Cachexia Sarcopenia Muscle (2019) 10:35-53. DOI: 10.1002/jcsm.12336.
• LSD1 Controls Timely MyoD Expression via MyoD Core Enhancer Transcription.
  Scionti I, Hayashi S, Mouradian S, Girard E, Esteves de Lima J, Morel V, Simonet T, Wurmser M, Maire P, Ancelin K, Metzger E, Schüle R, Goillot E, Relaix F, Schaeffer L.
  Cell Rep. (2017) 18(8):1996-2006.
• Muscle inactivation of mTOR causes metabolic defects and dystrophin downregulation leading to a severe myopathy.
  Risson V, Mazelin L, Roceri M, Sanchez H, Moncollin V, Corneloup C, Richard-Bulteau H, Vignaud A, Baas D, Defour A, Freyssenet D, Tanti J-F, Le-Marchand-Brustel Y, Ferrier B, Duplany A, Romanino K, Bauché S, Hanta? D, Mueller M, Kozma SC, Thomas G, Rüegg MA, Ferry A, Pende M, Bigard X, Koulmann N, Schaeffer L, Gangloff YG.
  J.Cell.Biol. (2009) 187:859-874.
• Histone Deacetylase 9 participates in the coupling of neuronal activity to muscle chromatin acetylation and gene expression.
  Méjat A, Ramond F, Bassel Duby R, Khochbin S, Olson EN, and Schaeffer L.
  Nature Neurosci (2005) 8(3):313-21.

FUNDING