Muscling in on the Cause of Tying-Up

1. Introduction and History of Tying-Up

Horses are supreme athletes whose beauty and performance depends on their powerful musculature. Through careful genetic selection, equine breeders have shaped muscle form and function to produce breeds with muscles fine-tuned for extreme endurance, an elegant piaffe, or a bold stretch across the finish line. Along with selection for positive traits, deleterious traits can also be inadvertently incorporated into the genome. Even minor or intermittent perturbations in muscle function can have a major impact in horses because they are constantly being exercised and pushed toward maximal performance. Fortunately, muscle remains a highly plastic tissue that is capable of adjusting in response to growth, hormonal influences, exercise, disease, and diet. Thus, horses may be able to compensate for deleterious traits if appropriate changes in environment, diet, and training are instituted. The past 30 years have offered exciting discoveries with regard to equine muscle form and function, genomics, inherited causes of muscle disorders, and regimens to manage these traits. These scientific advances built up on a wealth of new knowledge of equine exercise physiology, muscle histochemistry, and genetics. Many clinician scientists past and present have provided the building blocks that have led to the discovery of specific muscle disorders in horses, the most perplexing of which has been exertional rhabdomyolysis, also called tying-up. Horses with tying-up develop a shortened, stiff stride, anxiety, pain, and eventually inability to move forward with light exercise. In this review, I hope to pay tribute to these contributions, to provide insight into the advances in equine exercise physiology, muscle biopsy, and genomics that led to the discovery of equine muscle disorders, as well as provide an overview of the current state of knowledge of exertional rhabdomyolysis in horses.

History of Exertional Rhabdomyolysis

The dogmas of the quiet past are inadequate to the stormy present. The occasion is piled high with difficulty, and we must rise with the occasion. As our case is new, so we must think anew and act anew.
—Abraham Lincoln

Exertional rhabdomyolysis (ER) in horses is a centuries-old condition that is well described in the literature of the 19^th century. In 1883, the clinical signs of ER, or as it was then termed “azoturia,” were described as “sweating and trembling, scarcely able to turn in the stall, the muscles of the back and loins in a state of spasm, tail quite stiff.”¹ Azoturia was known to develop in “animals rather handsome, well-shaped, and good thrivers, than others differently constituted.”¹ It occurred most often in the fall and winter in horses fed legumes or corn. Further, veterinarians had already recognized that “azoturia does not, or very rarely, attacks horses roaming at large in the fields, whether young or old; also that in all cases it is more apt to occur under conditions succeeding a period of rather smart or active work that followed enforced idleness.”¹

The variety of terms used for this condition over centuries is as diverse as its proposed etiologies. Initially “hysteria,” “lumbago,” and “black water” were applied.² In 1883, the coffee-colored urine found with severe ER was believed to be due to excessive nitrogenous waste and thus the term azoturia was used.¹ Veterinarians readily admitted, however, that “in our day azoturia is freely spoken of as something new or strange, but it has apparently been well-enough recognized by many who have preceded us.”¹ “Holiday disease” or “Monday morning disease” described the common occurrence of ER after a day or more of rest.^3,4 Lay terms “set fast, cording up, and tying-up” well describe the tightening of muscles during episodes. “Paralytic hemaglobinuria” was coined in the late 19^th century, based on finding heme pigment in the urine, and this term was replaced with “paralytic myoglobinuria” when myoglobin was identified in urine.^2,4 ER is now the most commonly used term that describes the degeneration of striated skeletal muscle with exercise.

The development of ER was a common and catastrophic occurrence during the 19th century and early part of the 20th century before cars replaced draft and carriage horses as a means of transportation. Mortality rates as high as 50% were reported in some clinics.^2,4 Although it was an important disease, little was really known about its etiology, and speculation abounded. In 1917, Steffin stated that “No one disease [ER] in the horse has been subject to so many theories, theoretical treatments and hypothetical suggestions as this one.”⁵ Most early theories were based on observation. A kidney disease was initially believed to cause ER because of the “black water” passed by horses and pain palpable in the loins over the kidney.⁶ The higher incidence in horses rested, fed a full ration, and then exercised led to a popular theory of nutritional intoxication. “A disturbance or perversion of function, not very well understood, produced by a superabundant supply of a particular nutritive material, leads to the exaltation and ultimate loss of function of particular parts of the voluntary muscular system and the extensive disturbance of the nervous system.”¹ Others proposed a streptococcal infection as the basis for ER and thought that cold predisposed horses to the disease.

In the early 20^th century, elegant scientific studies by Birger Carlström definitively established that azoturia was a muscular disease with myoglobinuria arising from damaged muscle.^2,4 Further, Carlström was able to reproduce ER in draft-type horses by feeding 3 kg of molasses during a period of rest before exercise. Muscle biopsy samples obtained during an acute episode of ER had muscle glycogen concentrations that were twice normal and muscle lactate concentrations up to 3 times normal. As a result of these well-designed studies, Carlström’s theory that a period of rest on a high grain diet brought about a lactic acidosis with exercise that coagulated muscle tissue was pervasively held to be true for all breeds of horses for 60 years. His observations were astute precursors to the discovery of polysaccharide storage myopathy in horses.

As lighter breeds of horses increased in popularity in the mid 20^th century, confusion abounded as to whether the milder clinical signs of “tying-up” in lighter breeds of horses had a similar basis as azoturia in draft-type horses. Robertson reported in 1886 that “when developed in lighter animals, and those employed for fast work, the same general causes seem to be in operation which we have already indicated as observed in agricultural horses.¹ However, a higher incidence was noted in mares than geldings and as a rule, “the female is more susceptible of nervous excitement than the male.” Debate ensued among practitioners as to whether these were one or two conditions, and opinions often varied based on the type of clinical practice. In 1917, Steffin recognized that the development of ER varied with circumstances, localities, environment, feeding customs, breeds, and individuals.⁵ Meginnis in 1957 further substantiated the view that tying-up and azoturia were different muscle disorders, noting from his practice that there were four significant differences between ER in light versus draft breeds: (1) seasonality (none in racehorses), (2) history (fit racehorses worked daily unaffected by a change in ration), (3) handling (racehorses were less severely affected if walked during an attack, and (4) mortality (much lower in light breeds).⁷ Many others, however, disagreed and thought that lighter breeds had a milder form of the same disease, azoturia, that afflicted heavier breeds.^3,8,9 One point most authors agreed on was that “until the physiologic chemists can determine the changed chemistry in the metabolism of the normal and ‘tying-up’ horses, prevention and treatment will be merely guesswork.”⁷  [...]