Background Huntington’s disease (HD) patients exhibit skeletal muscle wasting that reduces muscle strength and as the disease progresses the muscle degeneration becomes one of the principal components of HD. Muscle pathology in HD correlates with disease duration, as well as CAG repeat length and has been suggested to result from transcriptional dysregulation and mitochondrial abnormalities in muscle fibres. So far, however, no study addressed whether mutant huntingtin (mHTT) expression is the sole cause of abnormalities in the muscle fibres, i.e. alterations of progenitor satellite cell (myoblast) differentiation into the muscle fibres that results in hindered formation and maintenance of skeletal muscle.
Aim To determine whether mHTT expression in satellite cells causes and is the principle contributor of severe muscle wasting and motor disturbances in HD.
Methods We will characterise the mechanisms and effects of mHTT expression on the proliferation, differentiation capacity and viability of satellite cells in R6/2 and BACHD mouse models of HD.
Preliminary results We show that R6/2 and BACHD mouse models exhibit the morphological changes in skeletal muscle. The qualitative histopathological analysis of gastrocnemius muscle tissue revealed chronic muscle degeneration associated with increased endomysial connective tissue, abnormal variation in fibre size in both HD mouse models.
Conclusions BACHD and R6/2 mouse models are potentially valuable for understanding HD skeletal muscle pathology, which opens up for identifying disease specific alterations and biomarkers that will aid in assessing the response to future treatment strategies.
- muscle degeneration
- satellite cells
- mutant huntingtin
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