title: Advances in the understanding of skeletal muscle weakness in murine models of diseases affecting nerve-evoked muscle activity, motor neurons, synapses and myofibers.
abstract: Disease processes and trauma affecting nerve-evoked muscle activity, motor neurons, synapses and myofibers cause different levels of muscle weakness, i.e., reduced maximal force production in response to voluntary activation or nerve stimulation. However, the mechanisms of muscle weakness are not well known. Using murine models of amyotrophic lateral sclerosis (SOD1(G93A) transgenic mice), congenital myasthenic syndrome (AChE knockout mice and Musk(V789M/-) mutant mice), Schwartz-Jampel syndrome (Hspg2(C1532YNEO/C1532YNEO) mutant mice) and traumatic nerve injury (Neurotomized wild-type mice), we show that the reduced maximal activation capacity (the ability of the nerve to maximally activate the muscle) explains 52%, 58% and 100% of severe weakness in respectively SOD1(G93A), Neurotomized and Musk mice, whereas muscle atrophy only explains 37%, 27% and 0%. We also demonstrate that the impaired maximal activation capacity observed in SOD1, Neurotomized, and Musk mice is not highly related to Hdac4 gene upregulation. Moreover, in SOD1 and Neurotomized mice our results suggest LC3, Fn14, Bcl3 and Gadd45a as candidate genes involved in the maintenance of the severe atrophic state. In conclusion, our study indicates that muscle weakness can result from the triggering of different signaling pathways. This knowledge may be helpful in designing therapeutic strategies and finding new drug targets for amyotrophic lateral sclerosis, congenital myasthenic syndrome, Schwartz-Jampel syndrome and nerve injury.
authors.affiliation: Université Pierre et Marie Curie - Paris 6, Sorbonne Universités, UMR S794, INSERM U974, CNRS UMR 7215, Institut de Myologie, Paris F-75013, France; Université Paris Descartes, Sorbonne Paris Cité, Paris F-75006, France. Electronic address: arnaud.ferry@upmc.fr.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ferry
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, CNRS EAC 4413, Unit of Functional and Adaptive Biology, Laboratory of Stress and Pathologies of the Cytoskeleton, Paris F-75013, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Joanne
authors.affiliation: Université Pierre et Marie Curie - Paris 6, Sorbonne Universités, UMR S794, INSERM U974, CNRS UMR 7215, Institut de Myologie, Paris F-75013, France.
authors.forename: Wahiba
authors.initials: W
authors.lastname: Hadj-Said
authors.affiliation: Université Pierre et Marie Curie - Paris 6, Sorbonne Universités, UMR S794, INSERM U974, CNRS UMR 7215, Institut de Myologie, Paris F-75013, France.
authors.forename: Alban
authors.initials: A
authors.lastname: Vignaud
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, CNRS EAC 4413, Unit of Functional and Adaptive Biology, Laboratory of Stress and Pathologies of the Cytoskeleton, Paris F-75013, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Lilienbaum
authors.affiliation: Université Pierre et Marie Curie - Paris 6, Sorbonne Universités, UMR S794, INSERM U974, CNRS UMR 7215, Institut de Myologie, Paris F-75013, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hourdé
authors.affiliation: Université Pierre et Marie Curie - Paris 6, Sorbonne Universités, UMR S794, INSERM U974, CNRS UMR 7215, Institut de Myologie, Paris F-75013, France.
authors.forename: Fadia
authors.initials: F
authors.lastname: Medja
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Laboratoire de Biologie de la Nutrition EA 2498, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Noirez
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, CESeM, UMR 8194 CNRS, Paris F-75006, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Charbonnier
authors.affiliation: Universités Montpellier 1 et 2, INRA, UMR 866, Montpellier, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Chatonnet
authors.affiliation: Universitätsklinikum Erlangen, Neuropathologisches Institut, Erlangen, Germany.
authors.forename: Frederic
authors.initials: F
authors.lastname: Chevessier
authors.affiliation: Université Pierre et Marie Curie - Paris 6, INSERM U975, Centre de recherche de l'Institut Cerveau Moelle, CNRS UMR 7225, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Nicole
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, CNRS EAC 4413, Unit of Functional and Adaptive Biology, Laboratory of Stress and Pathologies of the Cytoskeleton, Paris F-75013, France.
authors.forename: Onnik
authors.initials: O
authors.lastname: Agbulut
authors.affiliation: Université Pierre et Marie Curie - Paris 6, Sorbonne Universités, UMR S794, INSERM U974, CNRS UMR 7215, Institut de Myologie, Paris F-75013, France.
authors.forename: Gillian
authors.initials: G
authors.lastname: Butler-Browne
mesh_terms: D000818:Animals; D002802:Cholinesterases / Q000235:genetics; D004195:Disease Models, Animal; D004576:Electromyography; D019054:Evoked Potentials, Motor / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000235:genetics; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology*; D018908:Muscle Weakness / Q000209:etiology*; D018482:Muscle, Skeletal / Q000503:physiopathology; D009135:Muscular Diseases / Q000150:complications* / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009210:Myofibrils / Q000473:pathology*; D009451:Neuroeffector Junction / Q000503:physiopathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000074050:TWEAK Receptor
chemical_list: D019812:Heparan Sulfate Proteoglycans; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C071927:perlecan; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D002802:Cholinesterases
keywords: Murine models; Neuromuscular diseases; Skeletal muscle weakness