Ramblings of a muscle-obsessed veterinary surgeon

I have a confession to make – I have a vested interest in equine muscle as it has been the focus of my PhD and now my postdoctorate. I am also a keen sportswoman, so my interest in muscle physiology is also partly selfish – I want to know how to run faster with less effort. Doesn’t everyone?

As muscle is such an important tissue (it makes up approximately 55% of equine body mass), I thought it might be worth explaining briefly how muscle contracts. It is important to understand the physiology if you are to understand the pathology.

Sliding filament theory explains how muscles contract during the cross-bridge cycle: calcium released from the sarcoplasmic reticulum (SR) binds to troponin C. This causes a conformational change in the troponin-tropomyosin complex and allows interaction between the myosin adenosine triphosphatase heads and the actin filaments.

When adenosine triphosphate is hydrolysed, energy is released. This causes a conformational change in the shape of the myosin head, allowing myosin to slide relative to actin and induce contraction.

Muscle research

A bit of trivia. By coincidence, two independent research groups at different universities (Cambridge and Massachusetts Institute of Technology; MIT) came up with what is essentially the same hypothesis for muscle contraction at exactly the same time.

Their two papers were published in the same issue of Nature in 1954. But the coincidences don’t stop there.

While the Cambridge team was led by Andrew Huxley, the MIT team was led by the unrelated Hugh Huxley – and so sliding filament theory was born, although it was not fully accepted until the 1980s, when scientific techniques meant it was possible to image and prove the theory¹.

Muscle pathology is quite common in horses, probably due to the fact they are athletes and have such a large muscle mass. When vets think of muscle disease, rhabdomyolysis is often a word that comes to mind.

Rhabdomyolysis is a Greek term meaning striated (rhabdo), muscle (myo) and breakdown (lysis), and has recently become a talking point in the CrossFit fitness programme community, too. The high incidence of rhabdomyolysis in CrossFit is due to the high intensity nature of the workout.

To raise the profile of the problem, a caricature of a clown that has rhabdomyolysis – “Uncle Rhabdo” – is seen on a lot of CrossFit websites. This slightly crude image shows the clown hooked up to a dialysis machine with damaged muscles and is often considered the unofficial mascot of CrossFit.

Exertional rhabdomyolysis (ER) is also a common problem among horses and affects a wide range of breeds (it is not just a problem of the elite athlete). Clinical signs can vary in severity and this is not always related to the severity of the disease.

I remember seeing a horse in practice that had muscle enzyme levels higher than I had seen and the horse was just a bit stiff.

It was safe to say it was a draught horse and was being terribly stoic (I can only liken it to a rugby player with blood pouring out of his or her nose, but trying to continue playing, when racehorses with ER often resemble footballers that have bumped their little toe).

I would urge vets not to rule out ER, even if the horse doesn’t appear to be demonstrating classic signs (muscle fasciculations, muscle cramps, stiffness and tachycardia). In my final week in practice, I got sent to all the “tying up” horses as my practice manager knew I had a particular interest in it, and was amazed I saw, on average, one affected horse each day.

This showed the extent to which horses suffer from ER as there is a high chance lots of people don’t telephone a vet for it or even recognise it if it’s mild.

ER is a collection of clinical signs rather than a disease per se, therefore treatment depends somewhat on the diagnosis. Diagnosis is primarily achieved by observation of characteristic clinical signs and demonstration of moderate to massively increased elevations in plasma creatine kinase and aspartate transaminase activities.

Until relatively recently, vets believed all cases of ER had a common aetiology, but now, several muscle disorders are known to result in the clinical signs of ER. I remember one year I went to see the same client every day for a week, as every day he had a new polo pony with ER.

I think the problem with polo ponies is they exert themselves for a small amount of time and are then left stood tied up for the rest of the match. They are, therefore, prime candidates for serious episodes of ER.

Muscle fibre composition, logically, may also explain the variety in clinical signs as fast muscle fibres seem to be more affected and, therefore, in my experience, horses bred for speed display worse clinical signs.

Two of the most common forms of ER are known or thought to be genetic. These are polysaccharide storage myopathy (PSSM) and recurrent exertional rhabdomyolysis (RER).

Remembering the mechanism of muscle contraction, it should not be a surprise defects in energy metabolism and calcium regulation are common causes of muscle disease and pathology.

PSSM

PSSM was first described in 1992 in Quarter horses, but has since been diagnosed in a wide range of breeds, including British native breeds. However, a particularly high prevalence exists in certain breeds, namely Quarter horses, and continental draught-related breeds.

PSSM was originally characterised by identification of abnormal glycogen deposits within skeletal muscle; however, in 2008, a missense, dominant mutation in the muscle glycogen synthase gene (GYS1) was discovered in PSSM-affected Quarter horses following genome-wide association analysis².

Subsequently, PSSM cases are now divided into two types – type one and type two. PSSM type one is those with the GYS1 mutation, while PSSM type two is all the rest (therefore it is a more heterogenous group of horses as it is probably caused by several different genetic mutations).

RER

RER commonly affects Thoroughbreds and probably several other breeds, such as Standardbreds³. The cause of this disease is still unknown and the pathogenesis is poorly understood.

It was originally believed to be a primary calcium homeostasis defect^4,5, but more recent research has suggested otherwise⁶, thereby opening the door once again for new hypotheses.

A common starting point is to turn to human research and pathology. Most genetic causes of ER in humans are primary defects in energy metabolism⁷ and, therefore, this seems like a good (albeit huge) area to start looking for the cause of RER.

Treatment

Treatment of ER is similar for all causes of the disease, mainly because no treatment exists; all vets can do is treat the clinical signs. Recommendations include cessation of exercise during the acute episodes, analgesia and, in severe cases, intravenous fluids.

Long-term management is, however, preferable. This includes regular exercise, dietary manipulation in the case of PSSM (reducing carbohydrate and increasing fat content) and use of dantrolene sodium (used under the cascade) in horses with RER, which has been shown to be efficacious⁸.

Dantrolene is used in humans and pigs with malignant hyperthermia⁹ and affects calcium release from the SR, so the positive response to dantrolene treatment in horses with RER is suggestive of a defect in calcium metabolism, even if it is not a primary one.

Future

To be honest, most owners I have experienced seem happy with this palliative approach in the short term, but after three, four or x number of episodes without a cure (and with a large vet bill), people start asking what else they can do.

Diet and exercise regimes can work wonders and often reduce the severity of, or even prevent, any further episodes, but still they are not a cure.

As a researcher who works in this area, I hope one day soon we will be able to give you some good news. In mine and several other people’s opinions, genetic therapy such as that proposed for humans with very long chain acyl-CoA dehydrogenase deficiency¹⁰ is the obvious route to go.

PSSM type one is a particularly attractive candidate for gene therapy due to its severity, lack of treatment and single genetic mutation. As for RER, hopefully, as soon as the pathology is better understood, further steps can be taken towards a cure.

Meanwhile, keep your eyes peeled for cases of ER and, hopefully, one day the R in RER can be dropped.