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

TY - JOUR

T1 - HDAC4-Myogenin Axis As an Important Marker of HD-Related Skeletal Muscle Atrophy

AU - Mielcarek, Michal

AU - Toczek, Marta

AU - Smeets, Cleo J L M

AU - Franklin, Sophie A.

AU - Bondulich, Marie K.

AU - Jolinon, Nelly

AU - Muller, Thomas

AU - Ahmed, Mhoriam

AU - Dick, James R T

AU - Piotrowska, Izabela

AU - Greensmith, Linda

AU - Smolenski, Ryszard T.

AU - Bates, Gillian

PY - 2015/3/6

Y1 - 2015/3/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84926191823&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1005021

DO - 10.1371/journal.pgen.1005021

M3 - Article

C2 - 25748626

AN - SCOPUS:84926191823

SN - 1553-7390

VL - 11

JO - PL o S Genetics

JF - PL o S Genetics

IS - 3

M1 - e1005021

ER -