Muscle Mitochondrial Uncoupling Dismantles Neuromuscular Junction and Triggers Distal Degeneration of Motor Neurons

• DOI: 10.1371/journal.pone.0005390
• Publication Date: 2009-04-29T16:29:02Z
• Authors: Luc Dupuis; Jose-Luis Gonzale...; Andoni Echaniz-La...; Judith Eschbach; Frédérique Rene; Hugues Oudart; Benoit Halter; Caroline Huze; Laurent Schaeffer; Frédéric Bouillaud; Jean-Philippe Loe...
• Keywords: Motor Neurons; 0301 basic medicine; Evolution; [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE]; Science; Q; Amyotrophic Lateral Sclerosis; R; Neuromuscular Junction; Mice, Transgenic; Ion Channels; Mitochondria, Muscle; Mitochondrial Proteins; Mice; 03 medical and health sciences; Populations and Evolution; Nerve Degeneration; Medicine; Animals; Energy Metabolism; Muscle, Skeletal; Uncoupling Protein 1; Research Article

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.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.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.