title: Dystrophin restoration therapy improves both the reduced excitability and the force drop induced by lengthening contractions in dystrophic mdx skeletal muscle.
abstract: BACKGROUND
  The greater susceptibility to contraction-induced skeletal muscle injury (fragility) is an important dystrophic feature and tool for testing preclinic dystrophin-based therapies for Duchenne muscular dystrophy. However, how these therapies reduce the muscle fragility is not clear.
  
  
  METHODS
  To address this question, we first determined the event(s) of the excitation-contraction cycle which is/are altered following lengthening (eccentric) contractions in the mdx muscle.
  
  
  RESULTS
  We found that the immediate force drop following lengthening contractions, a widely used measure of muscle fragility, was associated with reduced muscle excitability. Moreover, the force drop can be mimicked by an experimental reduction in muscle excitation of uninjured muscle. Furthermore, the force drop was not related to major neuromuscular transmission failure, excitation-contraction uncoupling, and myofibrillar impairment. Secondly, and importantly, the re-expression of functional truncated dystrophin in the muscle of mdx mice using an exon skipping strategy partially prevented the reductions in both force drop and muscle excitability following lengthening contractions.
  
  
  CONCLUSIONS
  We demonstrated for the first time that (i) the increased susceptibility to contraction-induced muscle injury in mdx mice is mainly attributable to reduced muscle excitability; (ii) dystrophin-based therapy improves fragility of the dystrophic skeletal muscle by preventing reduction in muscle excitability.
authors.affiliation: Groupe Hospitalier Pitié Salpêtrière, Centre de Recherche en Myologie, CNRS, Inserm, UPMC Univ Paris 06, Sorbonne Universités, Paris, F-75013 France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Roy
authors.affiliation: Groupe Hospitalier Pitié Salpêtrière, Centre de Recherche en Myologie, CNRS, Inserm, UPMC Univ Paris 06, Sorbonne Universités, Paris, F-75013 France.
authors.forename: Fredérique
authors.initials: F
authors.lastname: Rau
authors.affiliation: Centre of Human and Aerospace Physiological Sciences, King's College London, Guy's Campus, SE3 8TL London, UK.
authors.forename: Julien
authors.initials: J
authors.lastname: Ochala
authors.affiliation: Groupe Hospitalier Pitié Salpêtrière, Centre de Recherche en Myologie, CNRS, Inserm, UPMC Univ Paris 06, Sorbonne Universités, Paris, F-75013 France.
authors.forename: Julien
authors.initials: J
authors.lastname: Messéant
authors.affiliation: Groupe Hospitalier Pitié Salpêtrière, Centre de Recherche en Myologie, CNRS, Inserm, UPMC Univ Paris 06, Sorbonne Universités, Paris, F-75013 France.
authors.forename: Bodvael
authors.initials: B
authors.lastname: Fraysse
authors.affiliation: Groupe Hospitalier Pitié Salpêtrière, Centre de Recherche en Myologie, CNRS, Inserm, UPMC Univ Paris 06, Sorbonne Universités, Paris, F-75013 France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Lainé
authors.affiliation: Biological Adaptation and Ageing, UMR CNRS 8256, Institut de Biologie Paris-Seine (IBPS), UPMC Univ Paris 06, Sorbonne Universités, Paris, F-75005 France.
authors.forename: Onnik
authors.initials: O
authors.lastname: Agbulut
authors.affiliation: Groupe Hospitalier Pitié Salpêtrière, Centre de Recherche en Myologie, CNRS, Inserm, UPMC Univ Paris 06, Sorbonne Universités, Paris, F-75013 France.
authors.forename: Gillian
authors.initials: G
authors.lastname: Butler-Browne
authors.affiliation: Groupe Hospitalier Pitié Salpêtrière, Centre de Recherche en Myologie, CNRS, Inserm, UPMC Univ Paris 06, Sorbonne Universités, Paris, F-75013 France.
authors.forename: Denis
authors.initials: D
authors.lastname: Furling
authors.affiliation: Groupe Hospitalier Pitié Salpêtrière, Centre de Recherche en Myologie, CNRS, Inserm, UPMC Univ Paris 06, Sorbonne Universités, Paris, F-75013 France ; Sorbonne Paris Cité, Université Paris Descartes, Paris, F-75006 France ; Groupe Hospitalier Pitié-Salpétrière, Institut de Myologie, F-75013 Paris, France.
authors.forename: Arnaud
authors.identifier: 0000-0002-6050-4556
authors.initials: A
authors.lastname: Ferry
mesh_terms: D000200:Action Potentials; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism*; D056966:Excitation Contraction Coupling; D020022:Genetic Predisposition to Disease; D015316:Genetic Therapy; D005822:Genetic Vectors; D018101:Mice, Inbred mdx; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D010641:Phenotype; D012342:RNA, Small Nuclear / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D016189:Dystrophin; D012342:RNA, Small Nuclear; C405487:U7 small nuclear RNA; C085339:apo-dystrophin 1