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
• PI3K/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

• 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. JCSM (2018) in press.
• Increased Serpina3n release into circulation during glucocorticoid-mediated muscle atrophy.
  Gueugneau M, d’Hose D, Barbé C, de Barsy M, Lause P, Maiter D, Bindels LB, Delzenne NM, Schaeffer L, Gangloff YG, Chambon C, Coudy-Gandilhon C, Béchet D, Thissen JP. JCSM (2018 July) Article DOI: 10.1002/jcsm.12315.
• Resistance exercise initiates mechanistic target of rapamycin (mTOR) translocation and protein complex co-localisation in human skeletal muscle.
  Song Z, Moore DR, Hodson N, Ward C, Dent JR, O’Leary MF, Shaw AM, Hamilton DL, Sarkar S, Gangloff YG, Hornberger TA, Spriet LL, Heigenhauser GJ, Andrew Philp A. Sci Rep. (2017) 7(1):5028.
• Isolation of Exosomes and Microvesicles from Cell Culture Systems to Study Prion Transmission.
  Leblanc P, Arellano-Anaya ZE, Bernard E, Gallay L, Provansal M, Lehmann S, Schaeffer L, Raposo G, Vilette D. Methods Mol Biol. (2017) 1545:153-176.
• 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.
• Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death.
  Jacquier A, Delorme C, Belotti E, Juntas-Morales R, Solé G, Dubourg O, Giroux M, Maurage CA, Castellani V, Rebelo A, Abrams A, Züchner S, Stojkovic T, Schaeffer L, Latour P. Acta Neuropathol Commun. (2017) 5(1):55..
• mTOR inactivation in myocardium from infant mice rapidly leads to dilated cardiomyopathy due to translation defects and p53/JNK-mediated apoptosis.
  Mazelin L, Panthu B, Nicot AS, Belotti E, Tintignac L, Teixeira G, Zhang Q, Risson V, Baas D, Delaune E, Derumeaux G, Taillandier D, Ohlmann T, Ovize M, Gangloff YG, Schaeffer L. J Mol Cell Cardiol. (2016) 97:213-25.
• Pak1 and CtBP1 regulate the coupling of neuronal activity to muscle chromatin and gene expression
  Thomas J-L, Moncollin V, Ravel-Chapuis A, Valente C, Corda D, Méjat A and Schaeffer L. Mol.Cell.Biol. (2015) 35(24):4110-4120.
• Histone Deacetylase 6 Is a FoxO Transcription Factor-dependent Effector in Skeletal Muscle Atrophy
  Ratti F., Ramond F, Moncollin V, Simonet T, Milan G, Méjat A, Thomas JL, Streichenberger N, Gilquin B, Matthias P, Khochbin S, Sandri M, Schaeffer L. J.Biol.Chem. (2015) 290(7):4215-24.
• Phosphorylation of NBR1 by GSK3 modulates protein aggregation
  Nicot AS, Lo Verso F, Ratti F, Pilot-Storck F, Streichenberger N, Sandri M, Schaeffer L, Goillot E. Autophagy (2014) 10(6):1036-1053..
• Drosophila Nesprin-1 controls glutamate receptors density at neuromuscular junction
  Morel V, Lepicard S, Rey A, Parmentier ML, Schaeffer L. Cell.Mol.Life.Sci (2014) 71(17):3363.
• Antibodies to clustered acetylcholine receptor: expanding the phenotype
  Devic P,Petiot P, Simonet T, Stojkovic T, Delmont E, Franques J, Magot A, Vial C, Lagrange E, Lebouvier T, Nicot AS, Risson V, Eymard B, Schaeffer L. Eur.J.Neurol (2014) 21(1):130-134.
• CKIP-1 regulates mammalian and zebrafish myoblast fusion
  Baas D, Boude S, Guiraud A, Calhabeu F, Delaune-Henry E, Pilot F, Chopin E, Machuca I, Vernay A, Bertrand S, Rual J F, Jurdic P, Hill DE, Vidal M, Schaeffer L. J.Cell.Sci. (2012) 125:3790-3800.
• Myopathy caused by mammalian target of rapamycin complex 1 (mTORC1) inactivation is not reversed by restoring mitochondrial function.
  Romanino K, Mazelin L, Albert V, Conjard-Duplany A, Lin S, Bentzinger CF, Handschin C, Puigserver P, Zorzato F, Schaeffer L, Gangloff YG, and Rüegg MA. PNAS (2011) 108(51):20808-13.
• Interactome mapping of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway identifies deformed epidermal autoregulatory factor-1 as a new glycogen synthase kinase-3 interactor
  Pilot-Storck F, Chopin E, Rual JF, Baudot A, Dobrokhotov P, Robinson-Rechavi M, Brun C, Cusick ME, Hill DE, Schaeffer L, Vidal M, Goillot E. Mol Cell Proteomics (2010) 9(7):1578-93.
• 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.
• Identification of an agrin mutation that causes congenital myasthenia and affects synapse function
  Huze C, Bauché S, Richard P, Chevessier F, Goillot E, Gaudon K, Ben Ammar A, Chaboud A, Grosjean I, Lecuyer HA, Bernard V, Rouche A, Alexandri N, Kuntzer T, Fardeau M, Fournier E, Brancaccio A, Rüegg MA, Koenig J, Eymard B, Schaeffer L, Hanta‘ D. Am J Hum Genet (2009) Epub Feb 23.
• Post synaptic chromatin is under neural control at the neuromuscular junction
  Ravel Chapuis A, Vandromme M, Thomas JL and Schaeffer L. EMBO (2007) 26(4):1117-28.
• 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.
• Expression of mutant Ets protein at the neuromuscular synapse causes alterations in morphology and gene expression
  de Kerchove d’Exaerde A., Cartaud J, Ravel-Chapuis A, Seroz T, Pasteau F, Angus LM, Jasmin B J, Changeux JP and Schaeffer L.EMBO R. (2002) 3(11):1075-81.

FUNDING