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

Mielcarek M, Toczek M, Smeets CJ, Franklin SA, Bondulich MK, Jolinon N, Muller T, Ahmed M, Dick JR, Piotrowska I, Greensmith L, Smolenski RT, Bates GP - PLoS Genet. (2015)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.

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.

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Related in: MedlinePlus

Transcriptional deregulation of gene markers involved in skeletal muscle atrophy.(A) AChR (nicotinic acetylcholine receptor), (B) Caspase8, (C) Mck (muscle creatine kinase) and (D) Foxo-3 (Forkhead box O3) transcripts were significantly deregulated in various muscles of the HD mouse models. All Taqman qPCR values were normalized to the geometric mean of three housekeeping genes: Atp5b, Yhwaz and Rpl13a. Error bars are SEM (n = 6). Student’s t-test: *p < 0.05, **p < 0.01; ***p < 0.001.
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pgen.1005021.g006: Transcriptional deregulation of gene markers involved in skeletal muscle atrophy.(A) AChR (nicotinic acetylcholine receptor), (B) Caspase8, (C) Mck (muscle creatine kinase) and (D) Foxo-3 (Forkhead box O3) transcripts were significantly deregulated in various muscles of the HD mouse models. All Taqman qPCR values were normalized to the geometric mean of three housekeeping genes: Atp5b, Yhwaz and Rpl13a. Error bars are SEM (n = 6). Student’s t-test: *p < 0.05, **p < 0.01; ***p < 0.001.

Mentions: To further examine the degree of skeletal muscle pathology, we determined the expression levels of additional genes that are typically altered in atrophied muscles. We found that AChR (nicotinic acetylcholine receptor) (Fig. 6A) was significantly up-regulated in all muscle types examined from mouse models. Usually, muscle atrophy is accompanied by a significant up-regulation of caspases [40]. Indeed, we found Caspase8 transcripts significantly up-regulated in the aged HdhQ150 muscles but not in those from the R6/2 mice (Fig. 6B). Similarly, we found Foxo-3 (Forkhead box O3) transcripts (Fig. 6D) to be markedly up-regulated, while Mck (muscle creatinine kinase) mRNA (Fig. 6C) was decreased in all of the muscle types examines from the R6/2 and HdhQ150 mice.


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

Mielcarek M, Toczek M, Smeets CJ, Franklin SA, Bondulich MK, Jolinon N, Muller T, Ahmed M, Dick JR, Piotrowska I, Greensmith L, Smolenski RT, Bates GP - PLoS Genet. (2015)

Transcriptional deregulation of gene markers involved in skeletal muscle atrophy.(A) AChR (nicotinic acetylcholine receptor), (B) Caspase8, (C) Mck (muscle creatine kinase) and (D) Foxo-3 (Forkhead box O3) transcripts were significantly deregulated in various muscles of the HD mouse models. All Taqman qPCR values were normalized to the geometric mean of three housekeeping genes: Atp5b, Yhwaz and Rpl13a. Error bars are SEM (n = 6). Student’s t-test: *p < 0.05, **p < 0.01; ***p < 0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352047&req=5

pgen.1005021.g006: Transcriptional deregulation of gene markers involved in skeletal muscle atrophy.(A) AChR (nicotinic acetylcholine receptor), (B) Caspase8, (C) Mck (muscle creatine kinase) and (D) Foxo-3 (Forkhead box O3) transcripts were significantly deregulated in various muscles of the HD mouse models. All Taqman qPCR values were normalized to the geometric mean of three housekeeping genes: Atp5b, Yhwaz and Rpl13a. Error bars are SEM (n = 6). Student’s t-test: *p < 0.05, **p < 0.01; ***p < 0.001.
Mentions: To further examine the degree of skeletal muscle pathology, we determined the expression levels of additional genes that are typically altered in atrophied muscles. We found that AChR (nicotinic acetylcholine receptor) (Fig. 6A) was significantly up-regulated in all muscle types examined from mouse models. Usually, muscle atrophy is accompanied by a significant up-regulation of caspases [40]. Indeed, we found Caspase8 transcripts significantly up-regulated in the aged HdhQ150 muscles but not in those from the R6/2 mice (Fig. 6B). Similarly, we found Foxo-3 (Forkhead box O3) transcripts (Fig. 6D) to be markedly up-regulated, while Mck (muscle creatinine kinase) mRNA (Fig. 6C) was decreased in all of the muscle types examines from the R6/2 and HdhQ150 mice.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.

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.

Show MeSH
Related in: MedlinePlus