Morphological and functional changes in skeletal muscle of the Huntington's disease mouse model R6/2 suggest selective changes in fast-twitch fibres

Skeletal muscle atrophy in Huntington's disease is usually thought to be secondary to the onset of neurological symptoms. We have studied morphological and physiological changes in skeletal muscle of the R6/2 mouse model 12–16 weeks of age. Morphological changes include an increase in centrally located nuclei and activated nuclei. In addition fibre size varies widely in the R6/2 skeletal muscle and some muscle fibres show an increase in subsarcolemmal mitochondria. Electron microscopy pictures of 12 weeks old muscle detected enlarged mitochondria and widening of the z-disc in a subset of muscle fibres with neighbouring normal looking fibres. Isometric force induced by electrical stimulation was recorded in both slow (M. soleus) and fast twitch muscle M. extensor digitorum longus (EDL). The time to peak of twitch contractions was unchanged in the transgenic mice. The half time of twitch and tetanus relaxation was increased in EDL, even more so after fatiguing stimulation leading to 50% force reduction. The force-frequency relation was found to be shifted to lower frequencies. No corresponding alterations were observed in the M.soleus. To study excitation-contraction coupling, voltage clamp experiments combined with Ca2+ recording were performed on enzymatically isolated fibres of the fast interosseus muscle. The voltage dependence of Ca2+ release showed a slight negative shift and Ca2+ transient amplitudes were reduced. Confocal scanning microscopy revealed a significantly reduced activity of localized intracellular Ca2+ transients (sparks) triggered by hyperosmotic solutions. Together, these results indicate that functional changes in R6/2 muscle are confined to the fast-type muscle fibres and affect properties of the Ca2+ turnover system.