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PLoS Genet. 2015 Mar 6;11(3):e1005021. doi: 10.1371/journal.pgen.1005021. eCollection 2015 Mar.

HDAC4-myogenin axis as an important marker of HD-related skeletal muscle atrophy.

Author information

1
Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
2
Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland.
3
Sobell Department of Motor Neuroscience and Movement Disorders and MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.
4
MRC National Institute for Medical Research, London, United Kingdom.
5
Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland; Department of Surgery and Translational Medicine, University of Milano-Bicocca, Milano, Italy.

Abstract

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.

PMID:
25748626
PMCID:
PMC4352047
DOI:
10.1371/journal.pgen.1005021
[Indexed for MEDLINE]
Free PMC Article

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