Home Equine Neuromuscular Diagnostic Laboratory Resources Recurrent Exertional Rhabdomyolysis (RER)

Recurrent Exertional Rhabdomyolysis (RER)

Tying-up is a term used to describe horses that develop firm hard muscles following exercise because of muscle damage. Horses sweat profusely, breathe rapidly and become stiff with reluctance to move. A diagnosis of tying-up is based on a blood sample that measures the presence of muscle proteins such as creatine kinase (CK) and aspartate aminotransferase (AST) in the blood. For many owners this is a very frustrating condition. It often occurs in the most talented horses at a time when they are showing promise in race training or moving up a training level in 3 Day Eventing. An update of our research findings generated to date includes the following.

What is Recurrent Exertional Rhabdomyolysis (RER) or Tying-Up?

Recurrent exertional rhabdomyolysis (RER) is an intermittent form of tying-up in horses that appears to involve an abnormality in intracellular calcium regulation as the possible cause. At present, there is no specific diagnostic test for RER. The diagnosis is based on observations such as a history of repeated episodes of tying-up in fit horses that are on a well-balanced diet and reasonable training regime and demonstrated elevations in serum CK activity with exercise. Muscle biopsies of horses with RER may not have any visible abnormalities or may be characterized by the presence of centrally located nuclei in muscle biopsies without evidence of abnormal polysaccharide. Horses with RER often develop tying-up when they are overly excited.

There are a number of different mechanisms by which owners can manage horses with RER in order to reduce episodes of tying-up. Any management program should be established by discussing your horse’s individual case with your veterinarian.

How common is tying-up in Thoroughbred racehorses?

From our study of 1000 horses at Canterbury Park in Shakopee, MN during one racing season.

5% of Thoroughbreds tied-up that season
33% of trainers had a horse with tying-up in training
The distribution was no more than three tying-up horses/trainer
15% of the two- and three-year-olds that tied up were unable to race that season
No difference in race performance between tying-up horses that raced versus matched normal control horses

Why do some horses tie-up when trained under the same circumstances as others?

Horses have evolved a unique mechanism for handling intracellular calcium flux which likely enhances their athletic ability. The amount of calcium inside a muscle cell is thousands of times lower than that in the bloodstream and is not related to dietary calcium. Intracellular calcium flux is the trigger for muscle contraction. These equine adaptations include a high sensitivity to the flight or fight response which, when stressed, can increase the release of calcium from their storage sights in skeletal muscle (sarcoplasmic reticulum). Horses also have a large amount of a protein calsequestrin in the intracellular storage sites that allows them to store more calcium in these sites. Finally, horses have a change (truncation) in their sarcolipin gene which leaves the calcium pump in the storage sites functioning at its maximum. These adaptations probably enhance the speed and strength of muscle contraction in horses but it seems to put them on a fine edge where excessive release of calcium from these storage sites can tip them over into a bout of tying up. Under stressful conditions or with overwork, horses can have a single bout of rhabdomyolysis called sporadic tying up.

Some horses, however, develop chronic episodes of tying up and one form of this is RER. RER appears to be a complex disease, meaning there are likely several genetic and environmental factors that affect its expression. No specific gene has been identified as the cause of tying-up. For horses with an individual susceptibility to RER, certain specific factors make these horses more likely to have episodes. Such factors may include young age, female gender, nervous temperament, high level of fitness, limited daily turn-out, irregular exercise schedules, high stress environment, pain from lameness, holding back the horse’s speed when exercising, and excitement during exercise. Unless horses are exposed to these stressful factors, the disease may not be apparent.

How is RER in horses best diagnosed?

The most reliable means for diagnosing RER is a combination of history, clinical findings, and serum CK and AST activities. In chronic, difficult to manage cases, a muscle biopsy may be necessary for diagnostics. Muscle cells from RER horses can have characteristics that can be visualized with certain histological stains.

Is there a genetic test for RER?

There are no scientifically validated tests for recurrent exertional rhabdomyolysis (RER). A genetic test for Px encoding CACNA2D3 has been suggested to be a risk factor for RER, however, there are no published peer-reviewed publications validating this association. Our research indicates that this gene is not expressed in skeletal muscle of horses whether they have RER or are healthy. If a gene is not expressed it is not producing the CACNA2D3 protein and therefore is very unlikely to have an impact on muscle function. Currently, we do not recommend this genetic test because we have not found this gene to be expressed in the skeletal muscle of either normal or RER horses.

What factors predispose horses to tying-up?

At the University of Minnesota we asked Thoroughbred racehorse trainers to fill out questionnaires on tying-up. Sixty horses with tying-up and 30 matched normal controls were included in the analysis. Results of predisposing factors included;

Age: 2-year-olds tie-up more frequently than 3-year-olds, and 3-year-olds tie-up more frequently than 4-year-olds or older horses.
Gender: 65% were fillies
Temperament: 48% of tie-up horses were characterized as nervous, versus 24% of the normal controls
Lameness: Lameness was more common in tie-up horses
Diet: Most horses that tied up were fed >10lbs of grain/sweet feed/day
Exercise Intensity: Racehorses tied-up most often with gallop training, and not when breezing or racing.
Other Data: Three-day-event horses tie-up after the steeplechase, prior to cross-country phase. Racing Standardbreds tie-up after 15 minutes of jogging.

What is the underlying defect in the muscle that causes some Thoroughbred horses to repeatedly tie-up?

Our research suggests that horses susceptible to RER have enhanced muscle cell storage of calcium in intracellular sites called the sarcoplasmic reticulum. When motor nerves cause the muscle cell membrane to activate, calcium is released from the sarcoplasmic reticulum, which allows muscle contraction to occur and stimulates energy metabolism. We believe that under conditions of chronic high stress, excessive release of calcium occurs from the sarcoplasmic reticulum during exercise. This excessive release causes persistent muscle contracture, interruption of energy metabolism and loss of mitochondrial (cellular energy centers) and disrupted myofiber integrity. The abnormality in intramuscular calcium regulation may be due to the effect of stress on regulatory mechanisms combined with individual genetic characteristics.

How do I manage a Thoroughbred horse that is predisposed to tying-up?

Management that avoids the stressful triggering factors is important:

Place the horse in stall near a quiet area of the barn.
Time of training (first rather than last).
Turn-out is very advantageous, the more time in exercise, movement and socialization the better.
Avoid training regimes like holding back at a gallop or intervals that excite the horse.
After consulting your veterinarian, tranquilize before exercise to prevent excitement.
Treatment of lameness.
Avoid stall rest or lay-up if possible, provide calm exercise if rested the previous day.
If necessary, medications that affect intracellular calcium regulation, such as dantrolene 2- 4 mg/kg given orally 1 hour before exercise may help. Consult your veterinarian with regard to this medication.

How do I feed a horse that ties-up?

During successful collaboration with Dr. Joe Pagan at Kentucky Equine Research, we have completed several diet and training studies and developed the following recommendations.

Nutritional Requirements

Nutrient requirements will vary depending on the horse’s size, breed, discipline, and level of activity. Digestible energy (DE) requirements will vary from maintenance to twice maintenance. RER occurs most frequently in Thoroughbred and Standardbred racehorses that have high DE requirements of 30-35 Mcal DE/day.

Forage

Thoroughbred horses do not appear to show the same significant increase in serum insulin concentrations in response to consuming hay with an nonstructural carbohydrate content (NSC) of 17% as seen in Quarter Horses. This fact, combined with the high caloric requirements of racehorses, suggests it is not as important to select hay with very low NSC content in RER Thoroughbreds as it is in PSSM horses.

Energy Sources

Substitution of fat for NSC in an energy-dense ration significantly reduces muscle damage in exercising RER horses. A controlled trial using a specialized feed developed for RER showed that NSC should provide no greater than 20%, and fat should provide between 20% and 25% of daily DE intake for optimal management of RER horses requiring high DE intakes (>30 Mcal DE/day). Low-NSC, high-fat diets in RER horses may decrease muscle damage by assuaging anxiety and excitability, which have been linked to developing rhabdomyolysis in susceptible horses. High-fat, low-NSC diets fed to fit RER horses produced lower glucose, insulin, and cortisol responses along with a calmer demeanor and lower pre-exercise heart rates.

Concentrates

Racehorses in full training typically consume 6-7 kg/day of concentrate. Racehorse concentrates for RER horses should contain 12-18% NSC and 10-13% fat. To maintain high energy densities, the concentrate should also contain sources of highly digestible fiber such as beet pulp or soy hulls. While a calm demeanor is desired during training, some racehorse trainers feeding low-NSC, high-fat feeds have found it beneficial to supplement with a titrated amount of grain three days prior to a race to potentially boost liver glycogen and increase a horse’s energy during the race. Studies in RER horses show that significant reductions or normalization of post-exercise serum CK activity occurs within a week of commencing a low-starch, high-fat diet. Days of no training and standing in a stall are discouraged because post-exercise CK activity is higher after two days of rest compared with values taken when performing consecutive days of the same amount of submaximal exercise. Concentrate intakes <3kg/day may not provide adequate amounts of protein, minerals, or vitamins thus a balancer pellet may be a better choice for these horses.

How can I learn more about RER?

Dr. Valberg and others working in the Neuromuscular Diagnostic Laboratory have published numerous general interest and scientific articles on RER, including the ones listed below.

Peer-Reviewed Publications:

Valberg, Stephanie J., Deborah Velez-Irizarry, Zoë J. Williams, Marisa L. Henry, Hailey Iglewski, Keely Herrick, and Clara Fenger. “Enriched Pathways of Calcium Regulation, Cellular/Oxidative Stress, Inflammation, and Cell Proliferation Characterize Gluteal Muscle of Standardbred Horses between Episodes of Recurrent Exertional Rhabdomyolysis.” Genes 13, no. 10 (2022): 1853
Aldrich, Kennedy, Deborah Velez-Irizarry, Clara Fenger, Melissa Schott, and Stephanie J. Valberg. “Pathways of calcium regulation, electron transport, and mitochondrial protein translation are molecular signatures of susceptibility to recurrent exertional rhabdomyolysis in Thoroughbred racehorses.” Plos one 16, no. 2 (2021): e0244556.
Henry, M., C. Fenger, J. Pagan, L. Sordillo, J. Gandy, and S. Valberg. “24 Antioxidant, reactive oxygen species, and Coenzyme Q10 concentrations and expression of electron transfer proteins in thoroughbreds with recurrent exertional rhabdomyolysis.” Journal of Equine Veterinary Science 100 (2021): 103487.
Autry, Joseph M., Christine B. Karim, Mariana Cocco, Samuel F. Carlson, David D. Thomas, and Stephanie J. Valberg. “Purification of sarcoplasmic reticulum vesicles from horse gluteal muscle.” Analytical biochemistry 610 (2020): 113965.
Autry, Joseph M., Bengt Svensson, Samuel F. Carlson, Zhenhui Chen, Razvan L. Cornea, David D. Thomas, and Stephanie J. Valberg. “Sarcoplasmic reticulum from horse gluteal muscle is poised for enhanced calcium transport.” Veterinary sciences 8, no. 12 (2021): 289.
Valberg, Stephanie J. “Muscle conditions affecting sport horses.” Veterinary Clinics: Equine Practice 34, no. 2 (2018): 253-276.
Valberg SJ, Soave K, Williams ZJ, Perumbakkam S, Schott M, Finno CJ, Gardner KL, Petersen JL, Fenger F, Autry JM, Thomas DD. Coding sequences of sarcoplasmic reticulum calcium ATPase regulatory peptides and expression of calcium regulatory genes in recurrent exertional rhabdomyolysis. J Vet Intern Med. 2019;33(2): 933-941 doi: 10.1111/jvim.15425.
Valberg SJ. Muscling in on the cause of tying up. The Milne Lecture Proceedings of the American Assoc Equine Practitioners 2012.
Valberg SJ. Exertional Rhabdomyolysis. In-Depth Muscle Disorders. 52nd Proc American Assoc Equine Pract 2006;365-372.
Finno CJ, McKenzie EC, Valberg SJ and Pagan JD. Effect of fitness on glucose, insulin and cortisol responses to diets varying in starch and fat content in horses with recurrent exertional rhabdomyolysis. J Equine Vet J. 2010 Nov;42 Suppl 38:323-8
McKenzie EC; Garrett R, Payton, M, Riehl J, Firshman AM, Valberg SJ. Effect of feed restriction on plasma dantrolene concentrations in horses. Equine Vet J. 2010 Nov;42 Suppl 38:613-7
Dranchak PK, Valberg SJ, Gary W. Onan GW, Gallant EM, Binns MM, Swinburne JE and James R. Mickelson JR. Exclusion of Linkage of Recurrent Exertional Rhabdomyolysis in Thoroughbred Horses to the RYR1, CACNA1S and ATP2A1 Genes. Am J Vet Res 2006;67(8):1395-1400.
Dranchak PK, Valberg SJ, Onan GW, Gallant EM, MacLeay JM, McKenzie EC, De La Corte FD, Ekenstedt K, Mickelson JR. Inheritance of recurrent exertional rhabdomyolysis in thoroughbreds. J Am Vet Med Assoc. 2005 Sep 1;227(5):762-7.
McKenzie EC, Valberg SJ, Godden SM and Finno CJ. The effect of oral dantrolene sodium on post-exercise serum creatine kinase activity in thoroughbred horses with recurrent exertional rhabdomyolysis. Am J Vet Res 2004;65(1):74-9.
McKenzie EC, Valberg SJ, Godden S, Pagan JD, MacLeay JM, Geor RJ, Carlson GP. Effect of dietary starch, fat and bicarbonate content on exercise responses and serum creatine kinase activity in equine recurrent exertional rhabdomyolysis J Vet Int Med 2003;17:693-701.
Lentz LR, Valberg SJ, Herold L, Onan GW, Mickelson JR and Gallant EM. Myoplasmic calcium regulation in myotubes from horses with recurrent exertional rhabdomyolysis Am J Vet Res 2002;63:1724-1731.
McKenzie EC, Valberg SJ. Pagan JD, Carlson GP, MacLeay JM and DeLaCorte FD. Electrolyte balance in Thoroughbred horses with recurrent exertional rhabdomyolysis consuming diets with varying Dietary Cation-Anion Balance. Am J Vet Res 2002;63:1053-1060.
McKenzie EC, Valberg SJ, and Pagan JD A review of dietary fat supplementation in horses with exertional rhabdomyolysis. Proceedings Am Assoc Equine Pract 2002 pp381-386.
Ward TL, Valberg SJ, Roghair TJ, Gallant EM and Mickelson JR. Skeletal muscle membrane activities in thoroughbred horses with exertional rhabdomyolysis. Am J Vet Res 2000;61:242-247.
MacLeay JM, Valberg SJ, Pagan J, Billstrom JA, and Roberts J. Effect of diet and exercise intensity on serum CK activity in Thoroughbreds with recurrent exertional rhabdomyolysis. Am J Vet Res 2000;61:1390-1395.
Mlekoday JA, Mickelson JR, Valberg SJ, Horton JH, Gallant EM and Thompson LV. Calcium sensitivity of force production and myofibrillar ATPase activity in muscles from Thoroughbred horses with recurrent exertional rhabdomyolysis. Am J Vet Res 2001;62:1647-1652.
MacLeay JM, Valberg SJ, Geyer CJ., Sorum SA and Sorum MD. Heritable basis for recurrent exertional rhabdomyolysis in thoroughbred racehorses. Am J Vet Res 1999;60:250-256.
Valberg SJ, Mickelson JR, Gallant EM, MacLeay JM, Lentz L and De La Corte FD. Exertional rhabdomyolysis in Quarter Horses and Thoroughbreds; one syndrome, multiple etiologies. International Conference on Equine Exercise Physiology 5, Equine Vet J Suppl. 1999;30: 533-538.
MacLeay JM, Valberg SJ, Pagan J, Billstrom JA, Roberts J, Kaese H, McGinnity J. Effect of diet on recurrent exertional rhabdomyolysis in thoroughbred. International Conference on Equine Exercise Physiology 5, Equine Vet J Suppl. 1999;30:458-462.
Lentz LR, Valberg SJ, Balog E, Mickelson JR and Gallant EM. Abnormal regulation of contraction in equine recurrent exertional rhabdomyolysis. Am J Vet Res 1999:60:992-999.
MacLeay JM, Sorum SA, Valberg SJ, Marsh W and Sorum M. Epidemiological factors influencing exertional rhabdomyolysis in Thoroughbred racehorses. Am J Vet Res 1999;60(12) 1562-1566.
Valberg S, Jonsson L, Holmgren N and Lindholm A. Muscle histopathology and plasma aspartateaminotransferase, creatine kinase and myoglobin changes with exercise in horses with recurrent exertional rhabdomyolysis. Equine Vet J 1993, 25:11-16.
Valberg S, Lindholm A and Hagendal J. Blood chemistry and skeletal muscle metabolic responses to exercise in horses with recurrent exertional rhabdomyolysis. Equine Vet J 1993, 25:17-22.
Holmgren N and Valberg S. Measurement of serum myoglobin concentrations in horses by immunodiffusion. Am J Vet Res 1992, 53:957-960.
Fritz KL, McCue ME, Valberg SJ, Rendahl AK, Mickelson JR. Genetic mapping of recurrent exertional rhabdomyolysis in a population of North American Thoroughbreds. Anim Genet. 2012 Dec;43(6):730-8.
McKenzie EM, Valberg SJ, Pagan J. Nutritional management of exertional rhabdomyolysis. In: ed. NE Robinson. Current Therapy in Equine Veterinary Medicine 5. Saunders St Louis MO 2003, pp727-734.