title: Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS), the most frequent adult onset motor neuron disease, is associated with hypermetabolism linked to defects in muscle mitochondrial energy metabolism such as ATP depletion and increased oxygen consumption. It remains unknown whether muscle abnormalities in energy metabolism are causally involved in the destruction of neuromuscular junction (NMJ) and subsequent motor neuron degeneration during ALS.
  
  
  RESULTS
  We studied transgenic mice with muscular overexpression of uncoupling protein 1 (UCP1), a potent mitochondrial uncoupler, as a model of muscle restricted hypermetabolism. These animals displayed age-dependent deterioration of the NMJ that correlated with progressive signs of denervation and a mild late-onset motor neuron pathology. NMJ regeneration and functional recovery were profoundly delayed following injury of the sciatic nerve and muscle mitochondrial uncoupling exacerbated the pathology of an ALS animal model.
  
  
  CONCLUSIONS
  These findings provide the proof of principle that a muscle restricted mitochondrial defect is sufficient to generate motor neuron degeneration and suggest that therapeutic strategies targeted at muscle metabolism might prove useful for motor neuron diseases.
authors.affiliation: Inserm, U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Strasbourg, France. ldupuis@unistra.fr
authors.forename: Luc
authors.initials: L
authors.lastname: Dupuis
authors.forename: Jose-Luis
authors.initials: JL
authors.lastname: Gonzalez de Aguilar
authors.forename: Andoni
authors.initials: A
authors.lastname: Echaniz-Laguna
authors.forename: Judith
authors.initials: J
authors.lastname: Eschbach
authors.forename: Frédérique
authors.initials: F
authors.lastname: Rene
authors.forename: Hugues
authors.initials: H
authors.lastname: Oudart
authors.forename: Benoit
authors.initials: B
authors.lastname: Halter
authors.forename: Caroline
authors.initials: C
authors.lastname: Huze
authors.forename: Laurent
authors.initials: L
authors.lastname: Schaeffer
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bouillaud
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Loeffler
mesh_terms: D000690:Amyotrophic Lateral Sclerosis; D000818:Animals; D004734:Energy Metabolism; D007473:Ion Channels / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000235:genetics*; D009046:Motor Neurons / Q000473:pathology*; D018482:Muscle, Skeletal / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology*; D009469:Neuromuscular Junction / Q000473:pathology*; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1