A032 Altered calcium signaling in skeletal muscle of R6/2 Huntington’s disease model

<h3>Background</h3> Muscle wasting is an early and prominent feature in Huntington’s disease (HD), yet the underlying mechanisms remain poorly understood. This study focuses on calcium signaling dysfunction in the skeletal muscle of the R6/2 mouse model of HD, which may contribute to muscle pathology. <h3>Aims</h3> This research aims to investigate the dysregulation of calcium signaling in the skeletal muscle of R6/2 mice and its potential role in muscle dysfunction and atrophy associated with HD. <h3>Methods</h3> R6/2 mice and wild-type (WT) littermates were used to examine calcium signaling in differentiated myotubes from the vastus lateralis muscle. Fluo-4 AM dye was used to measure real-time calcium dynamics. Fiber morphology and mutant huntingtin (mHTT) inclusions were assessed through immunohistochemistry and image analysis. Statistical analyses were conducted to compare calcium signaling parameters and fiber morphology. <h3>Results</h3> R6/2 myotubes exhibited significantly altered calcium signaling compared to WT, including reduced kurtosis and skewness, decreased range, and higher median calcium intensity at 7 days post differentiation. No significant differences in these parameters were observed at 17 days post-differentiation. Additionally, R6/2 myotubes did not display mHTT nuclear inclusions at 7 weeks with altered fiber width compared to WT and similar to WT at 17 days. <h3>Conclusions</h3> The findings suggest that calcium signaling is disrupted in R6/2 myotubes, which may contribute to the muscle pathology observed in HD. The absence of mHTT inclusions at early stages indicates that calcium dysregulation might precede their formation. Further research is required to elucidate how mHTT affects calcium dynamics and explore potential therapeutic interventions targeting calcium homeostasis in HD.