hide
Free keywords:
-
Abstract:
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.
