1. What is Recurrent Exertional Rhabdomyolysis (RER) or Tying-up?
  2. How common is tying-up in Thoroughbred racehorses?
  3. Why do some horses tie-up when trained under the same circumstances as others?
  4. How is RER in horses best diagnosed?
  5. Is there a genetic test for RER?
  6. What factors predispose horses to tying-up?
  7. What is the underlying defect in the muscle that is causing some thoroughbred horses to tie-up recurrently?
  8. How can we best manage a thoroughbred horse that is predisposed to tying-up?
  9. How do I feed a horse that ties up?
  10. How can I learn more about RER in horses?

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

1. What is Recurrent Exertional Rhabdomyolysis (RER) or Tying-up?

Recurrent exertional rhabdomyolysis (RER) is an intermittent form of tying up in horses that past research points to an abnormality in intracellular calcium regulation as the possible cause. At present there is no specific diagnostic test for RER. The diagnosis is best made based on several observations: history of repeated episodes of tying-up in fit horses that are on a well-balanced diet and reasonable training regime; demonstrated elevations in serum CK activity with exercise; and 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 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.

2. How common is tying-up in Thoroughbred racehorses?

We studied 1000 horses at Canterbury Park in Shakopee, MN during the 1995 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 control horses was seen.

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

Researchers at the University of Minnesota investigated the possibility that some forms of tying-up might be inherited. One farm had 18 horses tie-up repeatedly over three years. Pairing 14 of the broodmares on this farm to one of their stallions produced 100% offspring that tied up. When the same mares were bred to another stallion, only two offspring tied-up. The dams of these two offspring had previously produced other offspring that tied-up. On another farm, one mare that tied-up produced six offspring that tied-up. It would appear from these and other families we investigated, that horses may inherit a predisposition to tie-up; but unless they are exposed to stressful factors the disease may not be apparent.

Researchers at the MSU are working to identify the genetic susceptibility to tying-up. If you would be interested in having a muscle biopsy submitted from your horses with RER please contact Dr. Stephanie Valberg valbergs@cvm.msu.edu.

4. How is RER in horses best diagnosed?

The most reliable means for diagnosing RER is a combination of history, clinical findings, blood protein measurement, and a muscle biopsy. Muscle cells from RER horses have characteristics that can be visualized with certain stains.

5. Is there a genetic test for RER?

There are no scientifically validated tests for type 2 PSSM, recurrent exertional rhabdomyoloysis (RER) or myofibrillar myopathy.  In the horse’s best interest, decisions about treating, selling, breeding or euthanizing horses should not be made based on a genetic test that has not been scientifically validated.

If a company offers genetic testing for a disease without identifying the gene and the genetic mutation for which they are testing, there are no means through which the test can be scientifically validated. A valid test for a genetic variant with a true impact on disease should be made public, will stand up to the process of scientific validation and will benefit the breed. Genetic testing should be performed at licensed laboratories. Ask a company if they are licensed to perform the genetic tests that they offer.

What does scientifically validated mean?  It means the following steps have been taken:

  1. The clinical signs of the disease have been carefully established in a group of disease horses and confirmed to be absent in a second control group.
  2. A variant in genetic sequence has been identified that passes statistical tests showing it is significantly associated with the presence of disease in the carefully classified horses. 
  3. This association between the variant and disease is confirmed in a separate population of disease affected and healthy horses to ensure the accuracy of the association.
  4. The variant is shown to change the function of the protein the gene produces or at the very least carefully modeled to show how it alters molecular biology to create the specific muscle disease.
  5. Most importantly, a careful peer review is done by scientists leading to a publication in a scientific journal that names the gene and describes the genetic mutation. Peer-review and publication allows the results to be evaluated and re-evaluated by other scientists; true, disease-causing variants will stand up to this scrutiny.

6. What factors predispose horses to tying-up?

Researchers from the University of Minnesota asked thoroughbred racehorse trainers to fill out questionnaires on Tying-up. 60 horses with tying-up and 30 matched controls are included in the following analysis.

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

7. What is the underlying defect in the muscle that causes some thoroughbred horses to tie-up recurrently?

Researchers at the University of Minnesota developed a technique in which a small intact piece of intercostal muscle from between two ribs is removed. How the muscle sample responds to electrical stimulation (simulated exercise) and to chemicals that create contracture in human muscle diseases that resemble tying-up was then evaluated.

Muscle samples from young thoroughbreds that tied-up reacted very differently than samples from normal thoroughbreds during this test. Horses that tie-up had muscle samples that were much more sensitive to contractions induced by halothane, caffeine, and potassium. The contracture reaction indicated a possible problem with the way calcium is regulated inside the muscle cell. When we test other forms of tying-up, such as that in PSSM Quarter Horses, we do not get this abnormal reaction.

8. How can we best manage a thoroughbred horse that is predisposed to tying-up?

Management that avoids the stressful triggering factors is important:

  • Position the stall in a quiet area of the barn
  • Time of training (first rather than last)
  • Turn-out (if available a big advantage, the more time to blow off steam and move about the better)
  • Avoid training regimes like holding back at a gallop or intervals that excite the horse
  • Tranquilize before exercise to prevent excitement, after consulting your veterinarian
  • Attention to and treatment of lameness
  • Avoid stall rest or lay-up if possible, providing calm exercise if rested the day before
  • If necessary, give medications that affect intracellular calcium regulation, such as dantrolene 2- 4mg/kg orally 1 hour before exercise

9. How do I feed a horse that ties up?

We have performed several diet and training studies together with Dr. Joe Pagan at Kentucky Equine Research.

Forage: A high-quality grass or oat hay should form the basis of the diet. If alfalfa hay must be fed, a mixture (half alfalfa and half oat hay) may be the best option. Vitamin and mineral supplements containing Vitamin E and selenium are beneficial; however, some feeds (including some recommended below) contain enough selenium and other vitamins and minerals and do not require additional supplements. Check with the feed company if there are any questions. We have found that these dietary changes can have a beneficial calming effect on horses.

1) Complete Feeds: these feeds do not require additional protein/vitamin/mineral supplements and are to be fed along with hay. No additional grain or mineral/vitamin mix should be added.

Re-Leve®** by Hallway Feeds (www.Re-leve.com, Phone 1-800 753-4255) was developed with University of Minnesota researchers, has been proven to be effective for RER and is good for finicky eaters. Starch content is low (9.0% by weight) and fat content high (12.5% by weight). Additional selenium should not be fed. Feed 6- 12 lbs for thin horses or horses in moderate to heavy work. If you have concerns about the horse’s energy level on this diet, it may be appropriate once all episodes of tying-up are gone, to add grain to the diet gradually to find the amount the horse can tolerate without developing tying-up.

**a portion of the proceeds from the sale of Re-Leve® are directed to Dr. Valberg

Other Complete feeds may be available in your area that can be fed with grass hay: Please consult your local nutrition company for advice and use the table provided below. In general, the starch/sugar content of the feed should not be greater than 15-20% by weight and the fat should be greater than 10% by weight.

Examples are: Ultium® by Purina in the USA:10-14 lbs per day. www.purinamills.com. or 800-227-8941, XTN® at 5-8 lbs per day combined with Empower® at 3 lbs/day by Nuterna. www.nutrenaworld.com.

2) Blending of individual feeds: Fat supplements, combined with additional protein/vitamin/mineral mixes, and a fiber base can be custom blended. If these feeds contain more than five lbs of grain per day, or the equivalent amount of starch, they often induce tying-up in susceptible horses. Consult with the manufacturer’s nutritionists to formulate the correct blend for a horse with RER that is specific to breed and level of use, using the requirements in Table 1. These blends can use solid fat supplements or liquid oils. Liquid vegetable oil can be gradually added at 1-2 cups per day to a fiber base such as hay cubes or alfalfa pellets or ration balancers. Add 600 U of vitamin E/cup of oil per day.

Electrolyte balance: Ensure that salt is always available. If horses will not use a salt block, add 1-3 tablespoon of loose iodized table salt in the feed, particularly in hot weather. If the horse is sweating a great deal, an additional tablespoon of lite salt (containing potassium chloride) can be added.

Remember to weigh the feeds using a scale and not use volume to determine actual weight.

Table 1. Nutritional requirements for an average sized horse (500 kg /1100 lbs) for RER at varying levels of exertion*. Note NSC refers to the soluble sugar + starch. Fructans in forage are not considered in this calculation, as they are not considered likely to affect the glycemic index.

Maintenance

Light Exercise

Moderate Exercise

Intense Exercise

Digestible Energy (DE) (Mcal/day)

16.4

20.5

24.6

32.8

% DE as NSC

<20%

<20%

<20%

<20%

% DE as fat

15%

15%

15%-20%

20-25%

Forage % bodyweight

1.5- 2 %

1.5- 2 %

1.5- 2 %

1.5- 2 %

Protein (g/day)

697

767

836

906

Calcium (g/day)

30

33

36

39

Phosphorus (g/day)

20

22

24

26

Sodium (g/day)

22.5

33.5

33.8

41.3

Chloride (g/day)

33.8

50.3

50.6

62

Potassium (g/day)

52.5

78.3

78.8

96.4

Selenium (mg/day)

1.88

2.2

2.81

3.13

Vitamin E (IU/day)

375

700

900

1000

*Daily requirements derived from multiple research studies (%NSC and ?t) and Kentucky Equine Research recommendations.


10. 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 S and Cardinet III, GH. The glyco(geno)lytic capacity of skeletal muscle in horses with recurrent rhabdomyolysis. In: Equine Exercise Physiology 3 ed. SGB Persson, A Lindholm and LB Jeffcott. ICEEP Publications, Davis CA 1991, pp 429-434.
  • Holmgren N and Valberg S . Measurement of serum myoglobin concentrations in horses by immunodiffusion. Am J Vet Res 1992, 53:957-960.
  • Valberg S , Jonsson L, Holmgren N and Lindholm A. Muscle histopathology and plasma aspartate aminotransferase, 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.
  • Valberg SJ , Jones JH, Smith BL and Somerville B. Skeletal muscle limitations to performance. Equine Veterinary J 1995;Suppl. 18:736-740.
  • Perkins G, Valberg SJ , Madigan JE, Carlson GP, and Jones SL. Fluid, electrolyte and renal abnormalities associated with acute rhabdomyolysis in four neonatal foals. J Vet Int Med 1998;12:173-177.
  • 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.
  • 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.
  • 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.
  • McKenzie EC, Valberg SJ, Godden SM, Pagan JD, Carlson GP, MacLeay JM and DeLaCorte FD. Comparison of volumetric urine collection vs single sample urine collection in horses consuming diets varying in cation-anion balance. Am J Vet Res 2003;64:284-291.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • Valberg SJ. Muscling in on the cause of tying up. The Milne Lecture Proceedings of the American Assoc Equine Practitioners 2012.

Book Chapters

  • Valberg S . Musculoskeletal evaluation of the performance horse: evaluation of muscle. In: Current Therapy in Equine Medicine 3. ed. E Robinson. WB Saunders Co., Philadelphia PA 1992: pp 799-802.
  • Snow DH and Valberg SJ , Muscle-Anatomy: Adaptations to exercise and training. In: eds. Rose RJ and Hodgson DH. The Athletic Horse: Principles and Practice of Equine Sports Medicine. Saunders, New York. 1994 pp 145-179.
  • Valberg SJ and Hodgson DR, Diseases of Muscle. In: ed. Smith BP. Large Animal Internal Medicine . Mosby Publishing , St Louis MO. 1996 pp 1489-1518.
  • Valberg SJ and Wilson WD. Exercise intolerance and poor performance in horses. In: ed. Smith BP. Large Animal Internal Medicine . Mosby Publishing, St Louis MO. 1996 pp 92-97.
  • Valberg SJ . Muscular causes of exercise intolerance in the horse. In: ed. Gaughan E. Veterinary Clinics of North America 1996, vol 12(3), pp 495-517.
  • MacLeay JM and Valberg SJ . Skeletal muscle structure and function in the horse. In: ed. Thompson K. Nutrition Manual for Veterinarians . AAEP and Purina Mills Publication 1997. pp11-18.
  • MacLeay and Valberg SJ. Muscle secrets. In; Equine Medical Secrets . Ed C Savage. Saunders 1999 pp169-180.
  • Valberg SJ and Hodgson DR, Diseases of Muscle. In: ed. Smith BP. Large Animal Internal Medicine . Mosby Publishing , St Louis MO 2002 pp 1266-1291.
  • Valberg SJ and Wilson WD. Exercise intolerance and poor performance in horses. In: ed. Smith BP. Large Animal Internal Medicine . Mosby Publishing, St Louis MO. 2002 pp 81-86.
  • Valberg SJ and Hodgson DR, Diseases of Muscle In: ed BP Smith . Field Guide to Large Animal Internal Medicine . Mosby Publishing, St Louis MO 2002 pp 368-378.
  • Valberg SJ and Dyson S. In: ed Ross M and Dyson S. Diagnosis And Management Of Lameness In The Horse . Saunders St Louis MO 2003, pp 723-743.
  • 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.