The R6/2 mouse line is transgenic for the first exon of the human huntingtin gene with an expanded (>150) CAG repeat. R6/2 mice develop a complex progressive neurological phenotype from around 3-4 weeks of age, that ultimately involves severe motor and cognitive dysfunction. The mice lose weight from 8 weeks of age and die of unknown causes between 16 and 18 weeks of age. From about 10 weeks of age, skeletal muscles begin to show conspicuous atrophy and ubiquitinated inclusions in myonuclei. In the present study we asked whether the progressive muscle atrophy is a consequence of progressive disuse or denervation. Behavioural observations, including measurements of forelimb grip strength, indicated that most symptomatic R6/2 mice were motivated and capable of sustained use of voluntary muscle. This was confirmed by sustained isometric tetanic tension measured in isolated hindlimb muscles after killing of the animals by cervical dislocation (in accordance with Home Office Schedule 1). Intracellular recordings from isolated flexor digitorum brevis (FDB) muscles showed robust evoked synaptic transmission at virtually all neuromuscular junctions: fewer than 10% of fibres failed to respond to nerve stimulation in R6/2 mice aged over 15 weeks. As expected from the degree of muscle atrophy, FDB muscle fibre input resistance and MEPP amplitude were significantly increased, by about two fold (P<0.01 in both cases; Mann-Whitney test). Resting membrane potentials became significantly less negative than normal as the muscle atrophy progressed with age, and membrane time constants were also prolonged (P<0.01; Mann-Whitney test). Immunocytochemistry and confocal fluorescence microscopy showed that virtually all neuromuscular junctions were normally innervated, and there were few discernible abnormalities in organisation of either axons, myelin, nerve terminals, terminal Schwann cells, ACh receptors or ACh esterase. However, although innervated, most atrophic R6/2 muscles were resistant to block by the muscle NaV1.4 channel antagonist µ-conotoxin GIIIB. They also produced contractures in response to bath-applied ACh, or to ACh applied iontophoretically to extrajunctional muscle fibre membranes. Junctional fibroblasts were also spread over the muscle fibre surfaces. We suggest that in skeletal muscle, transgenic expression of protein with an expanded polyglutamine repeat induces an innervation-independent and activity-independent switch from the normal physiological state to one resembling that induced by prolonged paralysis or muscle denervation.