The University of Southampton
University of Southampton Institutional Repository

Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington's disease mutation

Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington's disease mutation
Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington's disease mutation
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.
0953-816X
3092-3114
Ribchester, Richard R.
4bcfc164-f345-4795-a337-8c8bcc3c01de
Thomson, Derek
87c32f42-a519-49ca-a2e4-5aaa5686401a
Wood, Nigel I.
48441e2c-a0f0-467a-bad8-bb5b486391cb
Hinks, Tim
7117a072-2b0a-4012-a4b5-2f70ac54711c
Gillingwater, Thomas H.
57dffa27-4b29-4612-859d-6d32686711e0
Wishart, Thomas M.
222e6d1c-5174-40f0-ba0d-8ce2cb5788e5
Court, Felipe A.
ff1a4d0b-25c8-47de-b107-db69fd9b70f3
Morton, A. Jennifer
b5621262-46ec-47f8-884e-f6847fc41386
Ribchester, Richard R.
4bcfc164-f345-4795-a337-8c8bcc3c01de
Thomson, Derek
87c32f42-a519-49ca-a2e4-5aaa5686401a
Wood, Nigel I.
48441e2c-a0f0-467a-bad8-bb5b486391cb
Hinks, Tim
7117a072-2b0a-4012-a4b5-2f70ac54711c
Gillingwater, Thomas H.
57dffa27-4b29-4612-859d-6d32686711e0
Wishart, Thomas M.
222e6d1c-5174-40f0-ba0d-8ce2cb5788e5
Court, Felipe A.
ff1a4d0b-25c8-47de-b107-db69fd9b70f3
Morton, A. Jennifer
b5621262-46ec-47f8-884e-f6847fc41386

Ribchester, Richard R., Thomson, Derek, Wood, Nigel I., Hinks, Tim, Gillingwater, Thomas H., Wishart, Thomas M., Court, Felipe A. and Morton, A. Jennifer (2004) Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington's disease mutation. European Journal of Neuroscience, 20 (11), 3092-3114. (doi:10.1111/j.1460-9568.2004.03783.x). (PMID:15579164)

Record type: Article

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.

This record has no associated files available for download.

More information

Published date: December 2004

Identifiers

Local EPrints ID: 171991
URI: http://eprints.soton.ac.uk/id/eprint/171991
ISSN: 0953-816X
PURE UUID: b2565b5d-32ad-484d-9f7a-bd62341760c7

Catalogue record

Date deposited: 27 Jan 2011 14:56
Last modified: 14 Mar 2024 02:27

Export record

Altmetrics

Contributors

Author: Richard R. Ribchester
Author: Derek Thomson
Author: Nigel I. Wood
Author: Tim Hinks
Author: Thomas H. Gillingwater
Author: Thomas M. Wishart
Author: Felipe A. Court
Author: A. Jennifer Morton

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×