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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

Deterioration of the energy metabolism and decrease in oxidation in the EDL and TA of HD mouse models.Concentrations of (A) ATP (B) NADH (C) alanine and (D) glutamate 13C enrichment in skeletal muscle extracts after administration of 1–13C glucose in WT and HD mice. 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.g005: Deterioration of the energy metabolism and decrease in oxidation in the EDL and TA of HD mouse models.Concentrations of (A) ATP (B) NADH (C) alanine and (D) glutamate 13C enrichment in skeletal muscle extracts after administration of 1–13C glucose in WT and HD mice. Error bars are SEM (n = 6). Student’s t-test: *p < 0.05, **p < 0.01; ***p < 0.001.

Mentions: Physiological changes in skeletal muscle are often caused or associated with metabolic alterations. Therefore, we analysed two aspects of metabolism in the EDL and TA muscles. First we estimated the steady-state concentration of the major components of energy equilibrium that include creatine metabolites and adenine nucleotides. Analysis of ATP, phosphocreatine and related metabolites revealed a substantial depletion of the energy equilibrium in EDL and TA in both HD mouse models (Fig. 5A and B and Table 1). The phosphocreatine/creatine ratio as well as ADP and AMP levels were significantly decreased (Table 1) in both types of muscle in R6/2 and HdhQ150 mice. Besides the energy equilibrium, the total pools of the adenine nucleotides were also consistently depleted (Fig. 5 and Table 1) while changes in the redox status were less evident (Fig. 5B). A similar pattern of metabolic changes was found in the slow type soleus muscles of the HD mouse models (S1 Table). The second metabolic aspect concerned the evaluation of the substrate preference shift in these muscles. To address this, glycolysis was assessed by measuring the 13C alanine enrichment while the changes in Krebs cycle were estimated based on 13C glutamate levels after administration of 1–13C glucose. The analysis revealed that the EDL muscle showed a slower glycolytic flux from exogenous glucose as well less oxidation of glucose in both HD mouse models (Fig. 5C and D) while the TA the muscle remained unchanged (Fig. 5C and D).


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)

Deterioration of the energy metabolism and decrease in oxidation in the EDL and TA of HD mouse models.Concentrations of (A) ATP (B) NADH (C) alanine and (D) glutamate 13C enrichment in skeletal muscle extracts after administration of 1–13C glucose in WT and HD mice. 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.g005: Deterioration of the energy metabolism and decrease in oxidation in the EDL and TA of HD mouse models.Concentrations of (A) ATP (B) NADH (C) alanine and (D) glutamate 13C enrichment in skeletal muscle extracts after administration of 1–13C glucose in WT and HD mice. Error bars are SEM (n = 6). Student’s t-test: *p < 0.05, **p < 0.01; ***p < 0.001.
Mentions: Physiological changes in skeletal muscle are often caused or associated with metabolic alterations. Therefore, we analysed two aspects of metabolism in the EDL and TA muscles. First we estimated the steady-state concentration of the major components of energy equilibrium that include creatine metabolites and adenine nucleotides. Analysis of ATP, phosphocreatine and related metabolites revealed a substantial depletion of the energy equilibrium in EDL and TA in both HD mouse models (Fig. 5A and B and Table 1). The phosphocreatine/creatine ratio as well as ADP and AMP levels were significantly decreased (Table 1) in both types of muscle in R6/2 and HdhQ150 mice. Besides the energy equilibrium, the total pools of the adenine nucleotides were also consistently depleted (Fig. 5 and Table 1) while changes in the redox status were less evident (Fig. 5B). A similar pattern of metabolic changes was found in the slow type soleus muscles of the HD mouse models (S1 Table). The second metabolic aspect concerned the evaluation of the substrate preference shift in these muscles. To address this, glycolysis was assessed by measuring the 13C alanine enrichment while the changes in Krebs cycle were estimated based on 13C glutamate levels after administration of 1–13C glucose. The analysis revealed that the EDL muscle showed a slower glycolytic flux from exogenous glucose as well less oxidation of glucose in both HD mouse models (Fig. 5C and D) while the TA the muscle remained unchanged (Fig. 5C and D).

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