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

Michal Mielcarek*, Marta Toczek, Cleo J L M Smeets, Sophie A. Franklin, Marie K. Bondulich, Nelly Jolinon, Thomas Muller, Mhoriam Ahmed, James R T Dick, Izabela Piotrowska, Linda Greensmith, Ryszard T. Smolenski, Gillian Bates

*Corresponding author for this work

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Skeletal muscle remodelling and contractile dysfunction occur through both acute and chronic disease processes. These include the accumulation of insoluble aggregates of misfolded 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 pronounced 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 HdhQ150 knock-in mouse models of HD. We found that symptomatic animals developed 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 significant reduction in muscle force, possibly as a result of a deterioration in energy metabolism 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.

Original languageEnglish
Article numbere1005021
JournalPL o S Genetics
Issue number3
Publication statusPublished - 6 Mar 2015

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