What’s new in muscle research? [H&H VIP]

  • Muscular disorders can take many forms, from slight stiffness and spasmodic pain to a more serious and debilitating condition now linked — unlikely as it might sound — with the seeds of sycamore trees.

    Luckily, our understanding of these equine muscle diseases – known as myopathies – has evolved considerably over the past few years. Exertional rhabdomyolysis (ER), often called tying-up, was once thought to be a single disease entity. But it is now clear, from the evaluation of skeletal muscle biopsy samples, that there are several very different muscle disorders that can lead to the common clinical signs.

    Typically, horses that tie-up display stiffness and pain and may be reluctant to move during or shortly after exercise. Yet some of the more subtle clinical signs, such as poor performance or mild gait abnormalities, may not point to skeletal muscle disease and might easily be overlooked.

    Some horses probably tie-up because of over-exertion. As in humans, however, horses prone to tying-up often have a proven or a likely genetic basis to their disease.

    To date, two inherited conditions have been identified — RER and a similar condition known as polysaccharide storage myopathy (PSSM). Sequencing of the horse’s genome was completed in 2007, a milestone in the quest to unravel the genetic origin of these muscular conditions.

    With further research into cause and possible treatments now coming to fruition, it’s time to take a look at what’s new in the world of muscular disorders.

    It’s in their genes (probably)
    Recurrent exertional rhabdomyolysis, which typically affects part and full thoroughbreds but possibly other breeds as well, has been considered a hereditary disease due to the pattern of inheritance in certain breeding lines.

    Researchers at the University of Minnesota in the USA have recently identified a region of the horse’s genome – on the 16th chromosome – highly associated with the disease. Now experts are trying to hone in and identify the gene mutation.

    Other genomic regions might also be involved. If these “causative genes” can be identified, specific diagnostic tests and potentially novel therapeutic treatments can be developed for this common condition.

    More is not necessarily better
    The condition polysaccharide storage myopathy occurs in a wide variety of breeds and results in abnormal carbohydrate inclusions (storage of carbohydrates) within the horse’s skeletal muscle which interfere with normal muscle function and can result in varied clinical signs from poor performance to tying-up.

    In 2008 a mutation in a gene known as GYS1 was identified in horses with PSSM. This has led to the classification of two types of PSSM: type one that refers to horses with the gene mutation, while type two applies to horses that also have the characteristic carbohydrate inclusions but lack the gene mutation.

    As not all horses with PSSM have this specific gene mutation, it seems that there are additional and currently unidentified causes.

    Recent work by our research group at the Royal Veterinary College (RVC) investigated the effect of this gene mutation on the severity of muscle pathology in type one PSSM. Because each horse possesses two copies of the gene, affected horses can inherit one or two copies of the causative gene mutation.

    Our study revealed that if a horse inherits two mutant copies – one each from his sire and dam – he will develop more severe pathological changes in muscle than a horse that inherits only one.

    Interestingly, the extent of the carbohydrate inclusions seen on muscle biopsy does not always correlate with routine bloodwork. This emphasises the importance of muscle biopsy and genetic testing for determining severity and making informed decisions with regards to prognosis, training and breeding.

    Benefits of a biopsy
    Muscle biopsy remains the mainstay of diagnosis when an associated genetic mutation has not been identified. The procedure is well-tolerated and performed under standing sedation, and can yield valuable diagnostic information.

    Claire Massey and other colleagues at the RVC’s Comparative Neuromuscular Diseases laboratory reported a case with a vacuolar myopathy, a muscle condition seen in humans but not previously described in the horse.

    The unusual pathology was identified in a muscle biopsy submission from an eight-year-old warmblood gelding with a history of mild, intermittent ER.

    This highlights the importance of submitting clinical samples to obtain an accurate diagnosis and optimise patient management.

    As more samples are evaluated our understanding of equine muscle diseases should grow, with less common or currently unrecognised conditions not being overlooked.

    Where are we now?
    With many different causes of muscle disease in the horse now recognised, genetic testing and muscle biopsy can be valuable tools for vets — particularly in the investigation of animals that experience repeated bouts of tying-up.

    Treatments and management that are suitable for one disease might not necessarily be optimal for others, so accurate diagnosis can help in making specific recommendations.

    Despite the progress made over the past few years, considerably more work is required to further elucidate disease mechanisms and devise treatments that will help more horses with these common and painful disorders in the future.

    Read more about muscular problems

    This article was first published in Horse & Hound magazine (24 July 2014)