title: Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington's disease mutation.
abstract: Huntington's disease (HD) is a neurodegenerative disorder with complex symptoms dominated by progressive motor dysfunction. Skeletal muscle atrophy is common in HD patients. Because the HD mutation is expressed in skeletal muscle as well as brain, we wondered whether the muscle changes arise from primary pathology. We used R6/2 transgenic mice for our studies. Unlike denervation atrophy, skeletal muscle atrophy in R6/2 mice occurs uniformly. Paradoxically however, skeletal muscles show age-dependent denervation-like abnormalities, including supersensitivity to acetylcholine, decreased sensitivity to mu-conotoxin, and anode-break action potentials. Morphological abnormalities of neuromuscular junctions are also present, particularly in older R6/2 mice. Severely affected R6/2 mice show a progressive increase in the number of motor endplates that fail to respond to nerve stimulation. Surprisingly, there was no constitutive sprouting of motor neurons in R6/2 muscles, even in severely atrophic muscles that showed other denervation-like characteristics. In fact, there was an age-dependent loss of regenerative capacity of motor neurons in R6/2 mice. Because muscle fibers appear to be released from the activity-dependent cues that regulate membrane properties and muscle size, and motor axons and nerve terminals become impaired in their capacity to release neurotransmitter and to respond to stimuli that normally evoke sprouting and adaptive reinnervation, we speculate that in these mice there is a progressive dissociation of trophic signalling between motor neurons and skeletal muscle. However, irrespective of the cause, the abnormalities at neuromuscular junctions we report here are likely to contribute to the pathological phenotype in R6/2 mice, particularly in late stages of the disease.
authors.affiliation: Division of Neuroscience, University of Edinburgh, George Square, Edinburgh EH8 9JZ, UK.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Ribchester
authors.forename: Derek
authors.initials: D
authors.lastname: Thomson
authors.forename: Nigel I
authors.initials: NI
authors.lastname: Wood
authors.forename: Tim
authors.initials: T
authors.lastname: Hinks
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gillingwater
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wishart
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Court
authors.forename: A Jennifer
authors.initials: AJ
authors.lastname: Morton
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002038:Bungarotoxins / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002802:Cholinesterases / Q000378:metabolism; D020916:Conotoxins / Q000494:pharmacology; D008058:Dihydrolipoamide Dehydrogenase / Q000378:metabolism; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D004576:Electromyography / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008141:Lordosis / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000502:physiology; D046529:Microscopy, Electron, Transmission / Q000379:methods; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology* / Q000503:physiopathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009469:Neuromuscular Junction / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D009418:S100 Proteins / Q000378:metabolism; D013997:Time Factors; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D002038:Bungarotoxins; D002121:Calcium Channel Blockers; D020916:Conotoxins; D008562:Membrane Glycoproteins; D018727:Muscarinic Antagonists; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D009418:S100 Proteins; C489615:Sv2b protein, mouse; D025801:Ubiquitin; D001285:Atropine; D008058:Dihydrolipoamide Dehydrogenase; D002802:Cholinesterases; D000109:Acetylcholine