Objective: Progressive muscle atrophy is a characteristic of Huntington's Disease (HD). Whether the atrophy is secondary to altered neuronal input or a primary effect of the mutant huntingtin (htt) found in muscle is unresolved. It has even been suggested that common pathogenic mechanisms act in neurons and skeletal muscle cells. To investigate functional changes in isolated skeletal muscle we use R6/2 mice, a well characterized murine model for HD expressing a polyglutamine-expanded N-terminal fragment of human htt. We previously observed a significant slowing of twitch force relaxation in fast skeletal muscle of these mice. In the present study we focused on the kinetics of Ca²⁺ transients elicited under similar conditions in single fast-twitch muscle fibres.

Methods: Enzymatically dissociated interosseus muscle fibres of male R6/2 with symptomatic disease and of age-matched WT mice were primary-cultured for 1 to 2 days. Ca²⁺-dependent fluorescence signals of Fura2-AM loaded cells exhibiting all-or-none responses on electric stimulation were analysed.

Results: In R6/2 mice we observed a significantly slower relaxation time course of stimulated Ca²⁺-transients compared to wild-type. The mean time constants of relaxation were 31 ms ± 7 ms (SD) for WT and 53 ms ± 38 ms for transgenic (T = 25°C) (P < 0.01).

Conclusion: In our experiments we demonstrate that R6/2 animals transgenic for mutant htt show slowed Ca²⁺-kinetics. These results indicate that altered mobilization or removal of myoplasmic Ca²⁺ is the basis of the changes observed in R6/2 skeletal muscle contraction.