Datensatz

Zusammenfassung

Skeletal muscle remodelling and contractile dysfunction occur through both acute and chronic disease processes. These include the accumulation of insoluble aggregates of mis- folded amyloid proteins that is a pathological feature of Huntington ’ s disease (HD). While HD has been described primarily as a neurological disease, HD patients ’ exhibit pro- nounced skeletal muscle atrophy. Given that huntingtin is a ubiquitously expressed protein, skeletal muscle fibres may be at risk of a cell autonomous HD-related dysfunction. However the mechanism leading to skeletal muscle abnormalities in the clinical and pre-clinical HD settings remains unknown. To unravel this mechanism, we employed the R6/2 transgenic and Hdh Q150 knock-in mouse models of HD. We found that symptomatic animals devel- oped a progressive impairment of the contractile characteristics of the hind limb muscles tibialis anterior (TA) and extensor digitorum longus (EDL), accompanied by a significant loss of motor units in the EDL. In symptomatic animals, these pronounced functional changes were accompanied by an aberrant deregulation of contractile protein transcripts and their up-stream transcriptional regulators. In addition, HD mouse models develop a sig- nificant reduction in muscle force, possibly as a result of a deterioration in energy metabo- lism and decreased oxidation that is accompanied by the re-expression of the HDAC4- DACH2-myogenin axis. These results show that muscle dysfunction is a key pathological feature of HD.