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 i...
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doaj-2e994e21daa34b18b313e1754ba3e4142020-11-24T20:41:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-01-0144e539010.1371/journal.pone.0005390Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons.Luc DupuisJose-Luis Gonzalez de AguilarAndoni Echaniz-LagunaJudith EschbachFrédérique ReneHugues OudartBenoit HalterCaroline HuzeLaurent SchaefferFrédéric BouillaudJean-Philippe LoefflerBACKGROUND: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. METHODOLOGY/PRINCIPAL FINDINGS: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/SIGNIFICANCE: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.http://europepmc.org/articles/PMC2671839?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Luc Dupuis Jose-Luis Gonzalez de Aguilar Andoni Echaniz-Laguna Judith Eschbach Frédérique Rene Hugues Oudart Benoit Halter Caroline Huze Laurent Schaeffer Frédéric Bouillaud Jean-Philippe Loeffler |
spellingShingle |
Luc Dupuis Jose-Luis Gonzalez de Aguilar Andoni Echaniz-Laguna Judith Eschbach Frédérique Rene Hugues Oudart Benoit Halter Caroline Huze Laurent Schaeffer Frédéric Bouillaud Jean-Philippe Loeffler Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons. PLoS ONE |
author_facet |
Luc Dupuis Jose-Luis Gonzalez de Aguilar Andoni Echaniz-Laguna Judith Eschbach Frédérique Rene Hugues Oudart Benoit Halter Caroline Huze Laurent Schaeffer Frédéric Bouillaud Jean-Philippe Loeffler |
author_sort |
Luc Dupuis |
title |
Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons. |
title_short |
Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons. |
title_full |
Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons. |
title_fullStr |
Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons. |
title_full_unstemmed |
Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons. |
title_sort |
muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2009-01-01 |
description |
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. METHODOLOGY/PRINCIPAL FINDINGS: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/SIGNIFICANCE: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. |
url |
http://europepmc.org/articles/PMC2671839?pdf=render |
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