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Biochimica et biophysica acta. General subjects2016; 1861(1 Pt A); 3388-3398; doi: 10.1016/j.bbagen.2016.08.021

A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase.

Abstract: Equine type 1 polysaccharide storage myopathy (PSSM1) is associated with a missense mutation (R309H) in the glycogen synthase (GYS1) gene, enhanced glycogen synthase (GS) activity and excessive glycogen and amylopectate inclusions in muscle. Equine muscle biochemical and recombinant enzyme kinetic assays in vitro and homology modelling in silico, were used to investigate the hypothesis that higher GS activity in affected horse muscle is caused by higher GS expression, dysregulation, or constitutive activation via a conformational change. PSSM1-affected horse muscle had significantly higher glycogen content than control horse muscle despite no difference in GS expression. GS activity was significantly higher in muscle from homozygous mutants than from heterozygote and control horses, in the absence and presence of the allosteric regulator, glucose 6 phosphate (G6P). Muscle from homozygous mutant horses also had significantly increased GS phosphorylation at sites 2+2a and significantly higher AMPKα1 (an upstream kinase) expression than controls, likely reflecting a physiological attempt to reduce GS enzyme activity. Recombinant mutant GS was highly active with a considerably lower K for UDP-glucose, in the presence and absence of G6P, when compared to wild type GS, and despite its phosphorylation. Elevated activity of the mutant enzyme is associated with ineffective regulation via phosphorylation rendering it constitutively active. Modelling suggested that the mutation disrupts a salt bridge that normally stabilises the basal state, shifting the equilibrium to the enzyme's active state. This study explains the gain of function pathogenesis in this highly prevalent polyglucosan myopathy.
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Publication Date: 2016-08-31 PubMed ID: 27592162PubMed Central: PMC5148651DOI: 10.1016/j.bbagen.2016.08.021Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study explains the cause of a common glycogen storage disease in horses, known as type 1 polysaccharide storage myopathy (PSSM1), is due to the constitutive activation of a mutant glycogen synthase, an enzyme involved in the storage of glucose as glycogen.

About the Research Study

  • The research was aimed at understanding the underlying cause of equine type 1 polysaccharide storage myopathy (PSSM1), a common glycogen storage disease in horses. This condition is associated with a mutation in the glycogen synthase gene (GYS1), leading to excessive glycogen and a specific type of starch called amylopectin in muscles.
  • The researchers conducted a variety of experiments, including muscle biochemical assays, recombinant enzyme kinetic assays, and homology modeling, to test their hypothesis. The hypothesis was whether a higher activity of the glycogen synthase (GS) in the muscles of affected horses is caused by higher GS expression, dysregulation, or continuous activation due to a change in structure.

Findings of the Study

  • The study found that the muscles of PSSM1-affected horses had significantly higher glycogen content than the muscles of control horses. And this was despite no difference in GS expression, ruling out the hypothesis of enhanced GS expression being the cause.
  • A significant difference was also noted in GS activity between muscle samples of homozygous mutant horses (those with two copies of the mutation) and the control horses. The researchers observed this in both the presence and absence of the glucose 6 phosphate (G6P) regulator. This suggested that the increased GS activity results from constitutive activation due to a conformational change, rather than dysregulation.
  • A physiological attempt to reduce GS enzyme activity in homozygous mutant horses was evident by the significant increase in AMPKα1 (an upstream kinase) expression and GS phosphorylation at sites 2+2a in their muscles, when compared to controls.
  • Recombinant mutant GS, in comparison to wild type GS, showed elevated activity despite presence or absence of G6P or its phosphorylation, confirming the constitutive activation of the mutant enzyme.
  • Modeling results suggested that the mutation might be disrupting a salt bridge which normally stabilizes the enzyme’s basal state, propelling the equilibrium towards the enzyme’s active state. This finding provides an explanation for the gain of function pathogenesis in this highly prevalent glycogen storage disease.

Conclusion of the Study

  • The research concluded that constitutive activation of a mutant glycogen synthase due to a conformational change is the major cause of the higher glycogen content in the muscles of PSSM1-affected horses. Dysregulation or higher expression of GS were not found to be accountable. This research imparts crucial understanding towards the pathogenesis of this widely common equine glycogen storage disease.

Cite This Article

APA
Maile CA, Hingst JR, Mahalingan KK, O'Reilly AO, Cleasby ME, Mickelson JR, McCue ME, Anderson SM, Hurley TD, Wojtaszewski JFP, Piercy RJ. (2016). A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase. Biochim Biophys Acta Gen Subj, 1861(1 Pt A), 3388-3398. https://doi.org/10.1016/j.bbagen.2016.08.021

Publication

Biochimica et biophysica acta. General subjects
ISSN: 0304-4165
NlmUniqueID: 101731726
Country: Netherlands
Language: English
Volume: 1861
Issue: 1 Pt A
Pages: 3388-3398
PII: S0304-4165(16)30321-X

Researcher Affiliations

Maile, C A
  • Comparative Neuromuscular Diseases Laboratory, Department of Clinical Sciences and Services, Royal Veterinary College, London, UK.
Hingst, J R
  • Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
Mahalingan, K K
  • Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, USA.
O'Reilly, A O
  • School of Natural Sciences and Psychology, Liverpool John Moores University, Liverpool, UK.
Cleasby, M E
  • Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
Mickelson, J R
  • Veterinary Biomedical Sciences Department, University of Minnesota, St. Paul, MN, USA.
McCue, M E
  • Veterinary Population Medicine Department, University of Minnesota, St. Paul, MN, USA.
Anderson, S M
  • Veterinary Population Medicine Department, University of Minnesota, St. Paul, MN, USA.
Hurley, T D
  • Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, USA.
Wojtaszewski, J F P
  • Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
Piercy, R J
  • Comparative Neuromuscular Diseases Laboratory, Department of Clinical Sciences and Services, Royal Veterinary College, London, UK. Electronic address: rpiercy@rvc.ac.uk.

MeSH Terms

  • Adenylate Kinase / metabolism
  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Breeding
  • Enzyme Activation
  • Glucose Transporter Type 4 / metabolism
  • Glucose-6-Phosphate / metabolism
  • Glycogen / metabolism
  • Glycogen Storage Disease / enzymology
  • Glycogen Storage Disease / epidemiology
  • Glycogen Synthase / chemistry
  • Glycogen Synthase / genetics
  • Glycogen Synthase / metabolism
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Horses / metabolism
  • Kinetics
  • Models, Molecular
  • Muscle, Skeletal / enzymology
  • Mutant Proteins / metabolism
  • Mutation / genetics
  • Phosphorylation
  • Prevalence
  • Protein Subunits / metabolism
  • Structural Homology, Protein
  • Uridine Diphosphate Glucose / metabolism

Grant Funding

  • K08 AR055713 / NIAMS NIH HHS
  • R01 DK079887 / NIDDK NIH HHS

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Citations

This article has been cited 8 times.
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