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HDAC4-Myogenin Axis As an Important Marker of HD-Related Skeletal Muscle Atrophy

Mielcarek, M., Toczek, M., Smeets, C. J. L. M., Franklin, S. A., Bondulich, M. K., Jolinon, N., Muller, T., Ahmed, M., Dick, J. R. T., Piotrowska, I., Greensmith, L., Smolenski, R. T., & Bates, G. P. (2015). HDAC4-Myogenin Axis As an Important Marker of HD-Related Skeletal Muscle Atrophy. PLoS Genetics, 11(3): e1005021. doi:10.1371/journal.pgen.1005021.
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.
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