Exertional rhabdomyolysis (ER) has been recognized in horses for more than 100 years as a syndrome of muscle pain and cramping associated with exercise. Recently it has been recognized that this syndrome has numerous possible causes. Sporadic forms of ER are due to over-training and muscle strain, dietary deficiencies of electrolytes, vitamin E and selenium or exercise in conjunction with herpes or influenza virus infections. Chronic forms are due to specific inherited abnormalities such as polysaccharide storage myopathy (PSSM) in Quarter Horses, Warmbloods and Draft breeds or recurrent exertional rhabdomyolysis (RER) in Thoroughbreds, Standardbreds and Arabians. PSSM, a glycogen storage disorder, can effectively be managed by providing regular daily exercise and a high fiber diet with minimal starch and sugar and provision of a fat supplement. RER appears to be a disorder of intracellular calcium regulation that is triggered by excitement. Changing management to provide horses with a calm environment and training schedule and substitution of fat for grains in high caloric rations are helpful means to manage this condition.
Exertional rhabdomyolysis continues to be a performance-limiting or career-ending disorder for many equine athletes. In the last 15 years, research advances have provided greater insight into this syndrome. Of greatest importance is the realization that exertional rhabdomyolysis comprises several myopathies that, despite similarities in clinical presentation, differ considerably in regards to pathogenesis (cellular events, reactions, and other pathologic mechanisms occurring in the development of disease). In addition, new knowledge regarding effective management of horses with exertional rhabdomyolysis, particularly with regard to diet, have significantly reduced the severity ER in many horses.
Clinical Signs of ER: Clinical signs of exertional rhabdomyolysis usually occur shortly after the beginning of exercise. The most common sign is firm and painful muscles over the lumbar (loin) and sacral (croup) regions of the topline, including the large gluteal muscles. Excessive sweating, quick, shallow breathing, rapid heart rate, and muscle tremors are also noticed. In extreme cases, horses may be reluctant or refuse to move and may produce discolored urine due to the release of myoglobin from damaged muscle tissue. Episodes of ER vary from subclinical to severe in which massive muscle necrosis and renal failure from myoglobinuria occurs.
Diagnosis of Exertional Rhabdomyolysis: In order to confirm a diagnosis of ER blood samples should be obtained to determine that serum creatine kinase (CK) and aspartate transaminase (AST) activity are elevated. When muscle cells are damaged, CK and AST are released into the bloodstream within hours. AST activity may be heightened in asymptomatic horses with chronic exertional rhabdomyolysis.
Muscle biopsies are helpful in distinguishing various forms of chronic tying-up. Biopsies taken at our veterinary hospital are from the middle gluteal muscle using a 6 mm modified Bergstrom biopsy needle and frozen immediately. Biopsies shipped by referring veterinarians to our laboratory are of the semimembranosus/ semitendinosus muscles performed by an open surgical technique. Muscle biopsies are stained with a battery of histochemical and tinctorial stains and examined under the microscope to look for specific types of exertional rhabodmyolysis.
Classification: Exertional rhabdomyolysis can be subdivided into one of two distinct forms—sporadic and chronic. Horses that experience a single episode or infrequent episodes of muscle necrosis with exercise are categorized as having sporadic exertional rhabdomyolysis, whereas horses that have repeated episodes of exertional rhabdomyolysis accompanied by increased muscle enzyme activity, even with mild exertion, are classified as having chronic exertional rhabdomyolysis.
Sporadic Exertional Rhabdomyolysis
Sporadic exertional rhabdomyolysis occurs most commonly in horses that are exercised in excess of their level of conditioning. This happens frequently when a training program is accelerated too abruptly, particularly after an idle period of a few days, weeks, or months. Endurance competitions held on hot, humid days may elicit sporadic exertional rhabdomyolysis in susceptible horses because of high body temperatures, loss of fluid and electrolytes in sweat, and depletion of muscle energy stores. These metabolic imbalances can lead to muscle dysfunction and damage. In some instances, horses seem more prone to exertional rhabdomyolysis following respiratory infections. Therefore, horses should not be exercised if they have a fever, cough, nasal discharge, or other signs of respiratory compromise.
Nutritional Management of Sporadic Exertional Rhabdomyolysis:
A well-designed exercise program and a nutritionally balanced diet with appropriate caloric intake and adequate vitamins and minerals are the core elements of treating exertional rhabdomyolysis. In some cases, deficiencies of vitamins, minerals or electrolytes may cause sings of muscle pain and stiffness in horses. Suggested deficiencies include:
Vitamin E and selenium. Adequate amounts of vitamin E and selenium prevent the detrimental interaction of peroxides with lipid membranes of the muscle cell. Most horses with chronic rhabdomyolysis have adequate or more than adequate concentrations of vitamin E and selenium, and further supplementation has not been found to have protective effects on muscle integrity in exercising horses. Many feeds, particularly those designed for horses with rhabdomyolysis, provide adequate selenium supplementation and caution should be taken not to provide excessive selenium in the diet. Likewise, sufficient vitamin E is provided in most diets by green grasses, well-cured hay, and rice bran.
Electrolytes and minerals. Horses performing in hot weather often develop electrolyte imbalances, particularly if exercise continues for several hours. Free-choice access to loose salt or a salt block should be provided to these horses, or alternatively, one to four ounces of salt can be added to the feed daily. Extreme climatic conditions may necessitate the use of commercial electrolyte mixtures containing a 2:1:4 ratio of sodium:potassium:chloride. Fresh water should be available to horses at all times, especially if they are being supplemented with electrolytes.
Dietary imbalances of electrolytes, particularly deficiencies of sodium, potassium, and calcium, have been implicated in exertional rhabdomyolysis. Correction of imbalances may be crucial in the management of some exertional rhabdomyolysis cases.
Chromium. Supplementation with oral chromium (5 mg/day) has been suggested to calm horses and improve their responses to exercise possibly by affecting glucose and glycogen metabolism, possibly by potentiating the action of insulin. The purported calming effect of chromium may be beneficial in horses with recurrent exertional rhabdomyolysis because it appears that stress is a critical precipitator of this disorder. However, because PSSM horses display abnormal sensitivity to insulin, chromium supplementation may be counterproductive in these animals.
Chronic Exertional Rhabdomyolysis
Chronic exertional rhabdomyolysis arises frequently from heritable myopathies such as polysaccharide storage myopathy (PSSM) or recurrent exertional rhabdomyolysis (RER). Other causes of chronic exertional rhabdomyolysis are probable; however, their etiopathologies remain unknown.
Part II: Management of Recurrent Exertional Rhabdomyolysis
Recurrent Exertional Rhabdomyolysis (RER)
Recurrent exertional rhabdomyolysis commonly afflicts Thoroughbreds and likely Standardbreds and Arabians. During a racing season, 5-10 % of Thoroughbreds often exhibit signs of RER and of those 2 and 3 year-old horses with RER, up to 15% may not be able to train sufficiently to race at all that season. Interestingly, if horses that experience RER can race, there is no difference between their performances and those of matched control horses. In one investigation of heritability, a farm had 18 horses tie-up repeatedly over three years. Fourteen of the broodmares on this farm were bred to a particular stallion; all of the offspring experienced tying-up. When the same mares were bred to another stallion, only two of the offspring tied-up. On a different farm, one mare prone to tying-up produced six offspring with the disorder. A breeding trial conducted at the University of Minnesota as well as pedigree studies from a variety of farms now suggest that susceptibility to RER is inherited as an autosomal dominant trait.
The most severely affected horses are nervous young (two-year-old) fillies in race training at tracks. The sex predilection for females, however, is not obvious in older horses with RER. Episodes of RER occur most often when horses are restrained during exercise, and incidences of RER may become more frequent as level of fitness increases. Clinical expression of RER is often stress-induced, and horses with RER are typically described as having nervous or very nervous temperaments. Older horses with RER may have muscle stiffness and soreness but only show overt evidence of tying-up after Steeplechase or cross-country phases of a 3-day event.
A specific cause for RER in Thoroughbreds has recently been identified. It appears that the mechanism by which muscle contraction is regulated can be disrupted by excitement and exercise in some susceptible horses. This discovery was based on the observation that intercostal muscle biopsies from RER horses readily develop contractures when exposed to agents (halothane and caffeine) that increase intramuscular calcium release. The threshold for developing a contracture is much lower for RER horses compared to normal horses similar to a muscle disease in people and swine called malignant hyperthermia. Every time a muscle contracts, calcium is released from muscle storage sites and then taken back up into storage sites for muscle relaxation. The altered contraction and relaxation of muscle suggests that abnormal intracellular calcium regulation is the cause of this form of RER. These intramuscular calcium concentrations are extremely small compared to the amount of calcium in the rest of the body and are completely independent of dietary calcium concentrations.
Diet manipulation is becoming the method of choice in controlling RER, particularly in equine athletes that are closely monitored for pharmacological substances. A well-designed exercise program and a nutritionally balanced diet with appropriate caloric intake and adequate vitamins and minerals are the core elements of treating RER.
Effect of Modulation of Dietary Fat and Starch: Increasing dietary fat supplementation and decreasing dietary starch have resulted in beneficial effects to horses with RER, however, the mechanism for this is not clearly understood. Fat supplementation is only beneficial to RER horses when total dietary caloric intake is high. The beneficial effects of fat supplementation in RER horses may be due to the exclusion of dietary starch rather than specific protective effects of high dietary fat. Given the close relationship between nervousness and tying-up in horses with RER, assuaging anxiety and excitability by reducing dietary starch and increasing dietary fat may decrease predisposition to RER by making these horses calmer prior to exercise.
Controlled and field studies have shown that feeding 2 to 5 pounds of rice bran or rice bran-based products (Re-Leve by Hallway Feeds, Lexington, KY) to both PSSM and RER horses has resulted in significant improvement in disease.
Recommended Diets for Horses with RER: As with any horse, feeding forage at a rate of 1.5-2% of body weight is a fundamental part of the diet. RER horses seem to benefit from fat supplementation only when they require high caloric intakes. Once caloric needs are assessed, a diet should be designed with an appropriate amount of fat and starch. Thoroughbred horses with frequent episodes of rhabdomyolysis are usually being fed 5-15 pounds of sweet feed per day. The incidence of subclinical rhabdomyolysis is low in Thoroughbreds being fed a moderate caloric intake whether it is in the form of sweet feed or rice bran. However, when calories are increased by the addition of more sweet feed, the incidence of subclinical and clinical rhabdomyolysis is much greater. One way to lower serum CK after exercise when a high caloric intake is required is to feed a low-starch, high-fat ration. For RER horses, the recommendation is to feed no greater than 20% of daily DE as nonstructural carbohydrate and to supply 20-25% of daily DE from fat. The diet should contain no more than five pounds of sweet feed, 600 ml of vegetable oil, and five pounds of rice bran per day. For horses undergoing intense exercise, the combination of sweet feed and oil or sweet feed and rice bran does not achieve an adequate DE without feeding amounts of cereal grains that have been shown to elicit rhabdomyolysis in susceptible horses.
A specialized diet, Re-Leve, (www.Re-Leve.com) has been designed for intensely exercised horses with chronic exertional rhabdomyolysis. Re-Leve contains 13% fat by weight (rice bran and corn oil) or 20% DE as fat and only 9% DE as starch. This type of high-energy diet for RER horses might be provided through a combination of other commercially available grains, several fat supplements, and highly fermentable fiber sources (soy hulls, beet pulp). Other commercially available concentrates contain moderate amounts of fat (6-10%) and have lower NSC values (17–30 % by weight). However, they cannot be fed in the quantities necessary to achieve the calories required to sustain intense exercise in RER horses without exceeding recommended NSC limits for these horses. They should therefore be combined with a fat supplement.
All supplemental feeds should be reduced in amount on days when energy requirements are not as high, particularly if the horse is at risk of weight gain. Other management strategies may help to decrease the intensity of the postprandial glycemic response, and include feeding small meals, providing at least 1.5-2.0% body weight per day in forage, and feeding a forage source either two hours before or concurrently with any grain. Avoiding high starch supplements such as molasses is also important.
Surprisingly, recent studies in RER horses show that significant reductions or normalization of post-exercise serum CK activity occurs within a week of commencing a diet providing 20% DE as fat and 9% DE as starch. This low serum CK activity compared to the high CK activity observed in the same horses on an isocaloric diet where 40% DE was starch was not the result of any measurable change in muscle glycogen or metabolism during exercise. Potentially, the rapid response to decreasing starch and increasing fat was a result of neurohormonal changes that resulted in a calmer demeanor, lower pre-exercise heart rates, and a decreased incidence of stress-induced rhabdomyolysis. Avoiding prolonged stall rest in fit Thoroughbreds with RER is also important since post-exercise CK activity is higher following two days of rest compared to values taken later in the week when performing consecutive days of the same amount of submaximal exercise. It is quite possible that exercise exerts beneficial effects on horses with chronic exertional rhabdomyolysis that are separate from the impact of reduction in dietary starch and/or fat supplementation. Failure to implement an appropriate exercise routine will likely lead to failure to control rhabdomyolysis.
Additional management strategies for chronic exertional rhabdomyolysis. RER horses are often very fit when they develop rhabdomyolysis and require only a few days off before commencing a reduced amount of training. Stall confinement should be kept to less than 24 hours if possible. Since RER appears to be a stress-related disorder, management strategies to reduce stress and excitability in these horses are important. These include turn-out, exercising or feeding these horses before other horses, providing compatible equine company, and the judicious use of low-dose tranquilizers during training. Anecdotal reports of increased nervousness have been received when selenium is supplemented at higher than the recommended levels. Feeds designed for RER should be evaluated for their selenium concentrations and should not be supplemented in addition if adequate levels are provided in the feed.
Dantrolene (4mg/kg PO) given 1 hour before exercise to horses that are not fed their morning feed is effective in preventing RER. However, little absorption of dantrolene occurs in horses that have been on full feed at the time of administration. Dantrolene is used to prevent malignant hyperthermia in humans and swine by decreasing the release of calcium from the calcium release channel. Phenytoin (1.4-2.7 mg/kg PO BID), has also been advocated as a treatment for horses with RER (Beech 1988). Therapeutic levels vary, so oral doses are adjusted by monitoring serum levels to achieve 8 ug/ml and not exceed 12 ug/ml. Phenytoin acts on a number of ion channels within muscle and nerves including sodium and calcium channels. Unfortunately long-term treatment with dantrolene or phenytoin is expensive.
Part III: Management of Polysaccharide Storage Myopathy (PSSM)
Polysaccharide Storage Myopathy (PSSM)
Polysaccharide storage myopathy affects primarily Quarter Horses and horses with Quarter Horse bloodlines such as Paints and Appaloosa. In addition, Warmbloods as well as Morgans have been diagnosed with this disorder. Horses with PSSM typically have calm dispositions and are in good body condition. A change in exercise routine often triggers an episode of rhabdomyolysis. This change need not be profound; something as subtle and seemingly harmless as unaccustomed stall confinement may provoke an episode. Signs of PSSM include sweating, stretching out as if posturing to urinate, muscle fasciculations, and rolling or pawing following exercise. Severe cases may display stiffness and hesitance to move within minutes of starting exercise, and extreme cases may result in the horse being unable to stand and in discomfort even when lying down. Serum creatine kinase (CK) activity may be persistently elevated despite an extended period of rest.
The muscle biopsy is very useful for identifying PSSM. PSSM is a glycogen storage disorder characterized by the accumulation of glycogen and abnormal polysaccharide complexes in 1-40% of skeletal muscle fibers. Muscle glycogen concentrations in affected horses are 1.5 to 4 times greater than in normal horses. In humans, glycogen storage diseases commonly result from impaired utilization and breakdown of glycogen by tissues. No limitations in the ability of skeletal muscle to metabolize glycogen have been identified in PSSM horses and in fact, PSSM horses have higher glycogen utilization rates than healthy horses during anaerobic exercise. As such the metabolic defect responsible for marked glycogen accumulation appears to involve abnormal regulation of glycogen synthesis rather than a defect in utilization. We have found that horses with PSSM clear glucose from the bloodstream after an IV bolus, or oral meal much faster than normal horses. It appears they do this because of increased insulin sensitivity. When insulin is given to PSSM horses it causes a profound drop in blood sugar, which lasts for twice as long relative to normal horses. Thus it appears that one of the abnormalities in PSSM is that when fed a starch meal, these horses, store a higher proportion of the absorbed glucose in their muscle compared to normal horses. The mechanism of glucose transport into muscles of PSSM does not appear to be regulated in the same fashion as healthy horses. Why this in itself causes muscle cells to become damaged with exercise is not clear at this time. Accumulation of polysaccaride occurs gradually over time and may not be apparent until 2 yrs of age even though rhabdomyolysis may occur in young foals. Breeding trials support an autosomal dominant mode of inheritance for PSSM. Although the specific cause of PSSM in horses remains unknown, it can naively be seen as the opposite of type 2 Diabetes.
A glycogen storage disorder with similar histological characteristics occurs in draft breeds. Belgian and Percheron horses appear to have about a 25% prevalence of EPSM in the population. This syndrome is referred to as equine polysaccharide storage myopathy (EPSM). While similarities exist between PSSM and EPSM, draft horses with EPSM often exhibit signs not indicative of PSSM, including normal serum creatine kinase, difficulty backing and holding up limbs, a shivers-like gait, and loss of muscle mass. Some drafts afflicted with EPSM also show recumbency and weakness with only slight increases in serum CK and AST, and this combination of signs is not seen in Quarter horses with PSSM.
Prevention of Rhabdomyolysis with PSSM
Training: Horses with PSSM will not improve if the only change made is the addition of dietary fat. Prevention of further episodes of rhabdomyolysis requires a very gradual increase in the amount of daily exercise horses experience. Minimizing stress, providing regular routines and daily exercise are highly beneficial. Turn-out each day with other horses in as large an area as possible will keep the horse active and is in my experience the single most important thing that can benefit these horses. If there has been a recent severe episode of tying-up I recommend turning the horse out for 2 weeks on the diet recommended below. After switching your horse’s diet for 2 weeks, horses can begin longing once a day for 5 minutes at a walk and trot. Gradually increase the time by 2 minutes a day. If the horse seems stiff, stand the horse still for 1 minute and see if the stiffness persists when walking. If stiffness is present, stop there, if not continue after a 2 minutes walk. When the horse can do 15 minutes provide a 5-minute break at a walk and gradually increase walking and trotting after this. Once the horse has reached 30 minutes of trotting on a lunge-line (with a break at 15 min) then I would begin to ride for 20 to 30 minutes and gradually increase the length and intensity of exercise. It should take at least 3 weeks before the horse is ridden. Keeping horses with PSSM fit increases oxidative metabolism, increases glycogen utilization and this seems the best prevention against further episodes of tying-up.
Dietary management of PSSM: As with any horse, feeding forage at a rate of 1.5-2% of body weight is a fundamental part of the diet. Once caloric needs are assessed, a diet should be designed with an appropriate amount of fat and starch. The amount of fat supplied to horses with PSSM is controversial. If PSSM horses are exercised regularly, many respond to low-calorie, low-starch diets that are only lightly supplemented with fat. Although recommended in the lay-press, not all horses with exertional rhabdomyolysis require diets in which 25% of daily caloric intake is supplied by fat. In fact, such a diet is not always appropriate, is difficult to achieve in the face of high-calorie requirements, and may result in problems with weight gain and unpalatable diets.
Fat Sources: Animal- and vegetable-based fats are the major sources of fat available for equine consumption. Examples of vegetable oils used for supplementation include corn, soy, peanut, coconut, safflower, linseed, flaxseed, and canola. Corn and soy oils are the most palatable. Vegetable oils are highly digestible (90-100%) and energy dense. While it can be messy to dole out, unpalatable to some horses, prone to rancidity in warm weather, and difficult to feed in large amounts, oil is an effective way to boost daily energy intake and may be the most economical way of providing fat to horses that do not require large amounts of supplementation. Horses receiving large amounts of oil may need vitamin E supplementation. Animal fat varies in digestibility (75-90%). Because animal fat is more saturated, it tends to be solid at room temperature and would need to be melted before being top-dressed on feed. Most horses find animal-based fats less palatable than vegetable-based fats. Rice bran contains about 20% fat as well as a considerable amount of vitamin E. Products containing rice bran are readily accepted by most horses. Commercial rice bran products are usually in powder or pellet form and are considerably more stable than animal fat and vegetable oils. Many rice bran-based products are balanced for calcium and phosphorus or are concurrently fed with a mineral supplement to offset the naturally high phosphorus content. Recently commercial diets have been developed for horses with exertional rhabdomyolysis. To be effective these diets need to be low in starch as well as high in fat.
Recommended diets for PSSM horses: In Quarter Horse-related breeds, PSSM can usually be managed with grass hay or mixed hay and a fat supplement that is balanced for vitamins and minerals. Starch should be decreased to less than 10% of daily digestible energy (DE) intake by eliminating grain and molasses. Rice bran can be gradually introduced into the diet as powder or as a pelleted feed. Some horses that will not eat powder will consume pelleted forms of rice bran (Re-Leve, Hallway Feeds, Lexington, KY). It is important for owners to understand that if horses eat the rice bran at a slower rate than sweet feed this can be beneficial as it reduces rapid absorption of starch. Depending on the caloric requirements of the horse, 1-5 pounds of rice bran can be fed but must be combined with a reduction in dietary starch to less than 10% of DE. Interestingly, rice bran oil is now being used as a means to manage human beings with type I and type II diabetes as it significantly lowers daily blood glucose concentrations (measured as glycosylated hemoglobin). Horse with severe forms of PSSM respond with lower serum CK activity when fed ReLeve compared to other rice bran products, likely due to the lower starch content of ReLeve compared to rice bran.
An alternative source of fat is corn oil added to alfalfa pellets. An upper limit of 600 ml of oil per day is recommended, and additional vitamin E should be added to the diet. It is not possible to achieve the high caloric requirements for intense exercise using oil supplementation of alfalfa pellets, sweet feed, or rice bran without exceeding recommended maximum amounts of these products. To achieve the appropriate caloric intake for PSSM horses performing intense exercise, high fat, low-starch pelleted feeds designed for PSSM horses in intense exercise are recommended (Table 1). Supplying fat at 6-10% by weight (or 15-20% of DE) of the entire ration to PSSM Quarter Horses (unless a higher energy intake is required for exercise) is likely quite sufficient for managing PSSM and further benefit from more fat has not been demonstrated in controlled trials. Note, however, that none of these diets will result in clinical improvement of muscle stiffness and exercise tolerance without gradually increasing the amount of daily exercise and maximizing access to turnout.
Expectations of fat supplementation. The time required for improvement in signs of exertional rhabdomyolysis is controversial. It has been suggested that a minimum of four months of supplementation is required and that relapses are associated primarily with disruption of supplementation. However, in the author’s experience clinical improvement with PSSM is more dependent on the amount of daily exercise and turnout than on the length or amount of dietary fat supplementation. For example, when serum CK was monitored daily post-exercise, levels were almost within the normal range after four weeks of daily exercise, without fat supplementation. In addition, when PSSM horses were turned out 24 hours a day on grass, post-exercise serum CK was normal compared to high activities during the same exercise test with stall-kept horses on a hay diet. Thus, it seems that consistent fat supplementation without implementing a structured daily exercise regime in PSSM horses is highly likely to result in failure and confinement, while consuming high levels of fat is likely to lead to obesity.
Contributed By: Stephanie Valberg, DVM, PhD, Associate Professor, University of Minnesota, College of Veterinary Medicine (AAEP)