Mechanism behind common form of tying up in horses revealed

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Histological detail of muscle from a horse with severe type1 polysaccharide storage myopathy, revealing the polyglucosan inclusions and muscle fibre disruption. Left - H&E stain; right – PAS stain.
Histological detail of muscle from a horse with severe type1 polysaccharide storage myopathy, revealing the polyglucosan inclusions and muscle fibre disruption. Left – H&E stain; right – PAS stain.

The molecular mechanism that underpins a common form of “tying up” has been identified by an international team of researchers.

Type 1 Polysaccharide Storage Myopathy (PSSM1) particularly affects Quarter horses and draught breeds.

The genetic cause of the disease was discovered in 2008 by researchers at the University of Minnesota, who found that affected animals have a mutation of a key enzyme (glycogen synthase) which is involved in energy metabolism. This leads to increased storage of glycogen and an abnormal type of polysaccharide, a form of carbohydrate.  The mutation is inherited in dominant fashion – which means that only one copy of the gene needs to be inherited to cause the disease.

Until now, no-one knew the precise mechanism by which the mutation caused increased enzyme activity in muscles. Postdoctoral Research Fellow Dr Charlotte Maile and Professor Richard Piercy at the Comparative Neuromuscular Diseases Laboratory at the Royal Veterinary College, London, led an international team of scientists from the University of Copenhagen, University of Minnesota, Indiana University School of Medicine and Liverpool John Moore’s University, to discover the answer.

Dr Charlotte Maile and Professor Richard Piercy at the Royal Veterinary College, London.
Dr Charlotte Maile and Professor Richard Piercy at the Royal Veterinary College, London.

They found that the mutation leads to a change in the enzyme’s structure which leaves it permanently active, so it cannot be switched off. This hyperactivity of mutant equine enzyme explains the increased muscle glycogen and the accumulation of polysaccharide that leads to the clinical problems in affected horses. A full report of the research is published in the journal Biochimica et Biophysica Acta.

This breakthrough in the understanding of PSSM1 might lead to the development of novel treatments for this debilitating disease. It helps explain why some forms of treatment might be ineffective. RVC researchers are now working towards improved treatments and management of this disorder.

“PSSM1 is a very common disease, especially in some breeds. Finally, we know the reason why these horses store excessive glycogen and polysaccharide in their muscles,” Maile said.

“Our goal now is to use this information in designing new treatments and management strategies.”

Piercy said that managing horses who tie-up is hard, and some recommended treatments work poorly in some animals.

“By revealing the precise mechanism for this form of tying up, our work should make a real difference. Our hope is that by targeting specific approaches to the problem, – rather than a ‘one treatment fits all’ – horse welfare will be improved allowing them to get back to exercise, which has to be good for the horse and their owner.”

The work was partly funded by the Petplan Charitable Trust and the Morris Animal Foundation.

A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase. Maile CA, Hingst JR, Mahalingan KK, O’Reilly AO, Cleasby ME, Mickelson JR, McCue ME, Anderson SM, Hurley TD, Wojtaszewski JF, Piercy RJ. Biochim Biophys Acta. (2016). doi: 10.1016/j.bbagen.2016.08.021

Equine Science Update

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