Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons.
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.
Dupuis
Luc
L
Inserm, U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Strasbourg, France. ldupuis@unistra.fr
Gonzalez de Aguilar
Jose-Luis
JL
Echaniz-Laguna
Andoni
A
Eschbach
Judith
J
Rene
Frédérique
F
Oudart
Hugues
H
Halter
Benoit
B
Huze
Caroline
C
Schaeffer
Laurent
L
Bouillaud
Frédéric
F
Loeffler
Jean-Philippe
JP
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
D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1