Limits...
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.

Show MeSH

Related in: MedlinePlus

Neuromuscular function in the R6/2 mouse model of HD.(A) A significant decrease in the maximum twitch tension was observed for EDL and TA at 12 and 14 weeks of age. (B) A significant decrease in the maximum tetanic tension was observed for EDL and TA at 12 and 14 weeks of age. (C) The motor unit output for each experimental group is summarised in the bar chart. A significant decrease in functional motor units was observed for EDL at 12 and 14 weeks of age. (D) Examples of the motor unit trace recordings of the WT and R6/2 hind limb EDL muscles at 12 and 14 weeks of age. Error bars are SEM (n = 10). ONE-WAY ANOVA with Bonferroni post-hoc test: *p < 0.05, **p < 0.01; ***p < 0.001).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4352047&req=5

pgen.1005021.g004: Neuromuscular function in the R6/2 mouse model of HD.(A) A significant decrease in the maximum twitch tension was observed for EDL and TA at 12 and 14 weeks of age. (B) A significant decrease in the maximum tetanic tension was observed for EDL and TA at 12 and 14 weeks of age. (C) The motor unit output for each experimental group is summarised in the bar chart. A significant decrease in functional motor units was observed for EDL at 12 and 14 weeks of age. (D) Examples of the motor unit trace recordings of the WT and R6/2 hind limb EDL muscles at 12 and 14 weeks of age. Error bars are SEM (n = 10). ONE-WAY ANOVA with Bonferroni post-hoc test: *p < 0.05, **p < 0.01; ***p < 0.001).

Mentions: We also determined the maximum muscle force of TA and EDL muscles by physiological determination of single twitch (Fig. 4A) and tetanic force (Fig. 4B) in R6/2 mice. Twitch and tetanic force recordings showed that R6/2 TA muscles at 12 and 14 weeks of age were approximately 50% weaker than in their WT littermates. Moreover, physiological assessment of functional motor unit survival, revealed that there was a significant loss of motor units in R6/2 mice, which progressed from a 25% reduction at 12 weeks to over 60% loss at 14 weeks, compared to WT mice (Fig. 4C and D). These findings suggest that there is also likely to be a significant degeneration of spinal motor neurons during this period.


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)

Neuromuscular function in the R6/2 mouse model of HD.(A) A significant decrease in the maximum twitch tension was observed for EDL and TA at 12 and 14 weeks of age. (B) A significant decrease in the maximum tetanic tension was observed for EDL and TA at 12 and 14 weeks of age. (C) The motor unit output for each experimental group is summarised in the bar chart. A significant decrease in functional motor units was observed for EDL at 12 and 14 weeks of age. (D) Examples of the motor unit trace recordings of the WT and R6/2 hind limb EDL muscles at 12 and 14 weeks of age. Error bars are SEM (n = 10). ONE-WAY ANOVA with Bonferroni post-hoc 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.g004: Neuromuscular function in the R6/2 mouse model of HD.(A) A significant decrease in the maximum twitch tension was observed for EDL and TA at 12 and 14 weeks of age. (B) A significant decrease in the maximum tetanic tension was observed for EDL and TA at 12 and 14 weeks of age. (C) The motor unit output for each experimental group is summarised in the bar chart. A significant decrease in functional motor units was observed for EDL at 12 and 14 weeks of age. (D) Examples of the motor unit trace recordings of the WT and R6/2 hind limb EDL muscles at 12 and 14 weeks of age. Error bars are SEM (n = 10). ONE-WAY ANOVA with Bonferroni post-hoc test: *p < 0.05, **p < 0.01; ***p < 0.001).
Mentions: We also determined the maximum muscle force of TA and EDL muscles by physiological determination of single twitch (Fig. 4A) and tetanic force (Fig. 4B) in R6/2 mice. Twitch and tetanic force recordings showed that R6/2 TA muscles at 12 and 14 weeks of age were approximately 50% weaker than in their WT littermates. Moreover, physiological assessment of functional motor unit survival, revealed that there was a significant loss of motor units in R6/2 mice, which progressed from a 25% reduction at 12 weeks to over 60% loss at 14 weeks, compared to WT mice (Fig. 4C and D). These findings suggest that there is also likely to be a significant degeneration of spinal motor neurons during this period.

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