%0 Journal Article
%T HDAC4-Myogenin Axis As an Important Marker of HD-Related Skeletal Muscle Atrophy
%A Cleo J. L. M. Smeets
%A Gillian P. Bates
%A Izabela Piotrowska
%A James R. T. Dick
%A Linda Greensmith
%A Marie K. Bondulich
%A Marta Toczek
%A Mhoriam Ahmed
%A Michal Mielcarek
%A Nelly Jolinon
%A Ryszard T. Smolenski
%A Sophie A. Franklin
%A Thomas Muller
%J -
%D 2015
%R 10.1371/journal.pgen.1005021
%X 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 HuntingtonĄ¯s disease (HD). While HD has been described primarily as a neurological disease, HD patientsĄ¯ 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
%K Skeletal muscles
%K Mouse models
%K Atrophy
%K Muscle proteins
%K Muscle contraction
%K Huntington disease
%K Muscle functions
%K Skeletal muscle fibers
%U https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005021