Exertional rhabdomyolysis

What it is

Exertional rhabdomyolysis (tying-up, azoturia, "Monday morning disease") is the breakdown of skeletal muscle fibres associated with exercise. As the fibres rupture they release creatine kinase (CK), aspartate aminotransferase (AST) and myoglobin into the blood; myoglobin is excreted in the urine and can damage the kidneys. Two broad groups are distinguished:

• Sporadic rhabdomyolysis: an isolated episode in a horse with normal muscle, caused by exercise beyond its fitness, exhaustion in endurance rides, heat, electrolyte imbalances or, possibly, vitamin E and selenium deficiency.
• Chronic or recurrent rhabdomyolysis, due to an underlying myopathy:
  • Recurrent exertional rhabdomyolysis (RER) of Thoroughbreds, Standardbreds and Arabians: attributed to abnormal regulation of intracellular calcium in muscle. Episodes occur mainly in nervous horses on high-grain diets after days of rest.
  • Type 1 polysaccharide storage myopathy (PSSM1): caused by a dominantly inherited gain-of-function mutation of the GYS1 gene (glycogen synthase), which makes muscle accumulate glycogen and an abnormal polysaccharide.
  • Type 2 PSSM (PSSM2): diagnosed by biopsy when there is abnormal glycogen accumulation without the GYS1 mutation. It probably groups several different disorders, including the myofibrillar myopathy of Arabians and warmbloods, and its cause is unknown.

Who it affects

• The sporadic form, any horse, especially on returning to work after rest or in endurance rides.
• RER, Thoroughbreds and Standardbreds, more often young females and nervous horses, and Arabian endurance horses.
• PSSM1, Quarter Horses and related breeds, European and North American draught horses and, less often, other breeds.
• PSSM2, Quarter Horses and warmbloods, and myofibrillar myopathy, Arabians and warmbloods.

Anatomy involved

• Gluteus medius muscle: in the horse it is a huge muscle mass that forms the croup and extends into the lumbar region; it is one of the muscles that become hardest and most painful during an episode, and the usual site for needle biopsy.
• Epaxial muscles: the longissimus and the other muscles of the back and loins contract and become painful, giving the horse a hunched posture and a short, stiff stride.
• Semimembranosus and semitendinosus muscles: the muscles of the caudal thigh are also affected and are the preferred site of surgical biopsy to diagnose PSSM.
• The kidneys can suffer tubular necrosis from myoglobin and dehydration.

Clinical signs

During or shortly after exercise the horse becomes stiff, shortens its stride, refuses to move and sweats excessively; the muscles of the croup and back are hard and painful on palpation. There may be tachycardia, tachypnoea, muscle tremors and colic-like signs. Urine is red or brown from myoglobin in moderate or severe cases. In the most severe cases the horse becomes recumbent and may develop acute kidney injury. In PSSM the signs may be subtler: exercise intolerance, lack of energy, muscle stiffness or atrophy, sometimes without clear increases in CK.

Diagnosis

• Muscle enzymes: CK rises within hours and returns to normal within days; AST rises more slowly and stays elevated longer. A high CK 4–6 hours after a short, light exercise test indicates an underlying myopathy in horses without signs at rest.
• Urine: dipstick positive for blood without red cells in the sediment (myoglobinuria); urea and creatinine to assess the kidney.
• GYS1 genetic test on blood or hair for PSSM1, the test of choice in affected breeds.
• Muscle biopsy (semimembranosus or semitendinosus, or needle biopsy of the gluteus medius) for PSSM2, myofibrillar myopathy and other myopathies. Commercial genetic tests for PSSM2 are not validated (see Key studies).
• Differential diagnosis: colic, laminitis, aortoiliac thrombosis, atypical myopathy (Acer poisoning) and other causes of stiffness or dark urine.

Treatment and prevention

• Acute episode: stop exercise and do not force the horse to walk (if it must be moved, use a trailer) and control pain. Intravenous or oral fluid therapy if there is myoglobinuria or dehydration, to protect the kidney. Non-steroidal anti-inflammatory drugs and acepromazine only once the horse is well hydrated. Dantrolene reduces muscle contraction.
• Prevention in RER: daily exercise with no full rest days, turnout, reducing stress and excitement, replacing part of the grain with fat and fibre and, in some horses, dantrolene before exercise.
• Prevention in PSSM: daily turnout and regular, progressive exercise, a diet low in starch and sugar, with fat as an energy source if needed, and adequate vitamin E and selenium.
• The evidence for diet and dantrolene comes from crossover studies with very few horses.
• The horse is a food-producing animal in many countries and drug use is subject to national regulations and withdrawal periods. In the EU, the equine identification document (passport) states whether the horse is excluded from slaughter for human consumption, and this decides which medicines may be given.

Key studies

• MacLeay et al. (1999), study of the records of 984 Thoroughbreds at a Midwestern US racetrack during one season, with a case-control study of management (59 cases and 47 controls). Exertional rhabdomyolysis affected 4.9% of horses, mainly 2-year-old females. Nervous horses were 5.4 times more likely to be affected and those with some lameness 4.2 times more likely. Episodes were associated with rest days before galloping and with more than 4.5 kg of grain a day. Management data come from retrospective questionnaires.
• Isgren et al. (2010), case-control study in 683 Standardbred trotters from 22 yards in the UK. The annual incidence of exertional rhabdomyolysis was 6.4 per 100 horses. Females (OR 7.1; 95% CI 2.1–23.4) and nervous horses (OR 7.9; 95% CI 2.3–27.0) were at higher risk. Susceptible horses won more races than controls, and none of the 36 genotyped carried the GYS1 mutation. Confidence intervals are wide because of the small number of cases.
• Norton et al. (2016), genomic study of 491 Thoroughbred and 196 Standardbred racehorses. The heritability of RER was estimated at about 0.34–0.46 in Thoroughbreds and 0.39–0.49 in Standardbreds, depending on the model. It indicates a moderate genetic basis, although it does not identify the causal mutation.
• McCue et al. (2008), study of 831 horses of 36 breeds with PSSM diagnosed by biopsy. The GYS1 mutation was found in 17 breeds, and was present in 87% of draught horses and 72% of Quarter Horses with PSSM, but in only 18% of warmbloods and 24% of other light breeds. This difference led to the definition of PSSM2. Cases come from a single reference laboratory.
• Valberg et al. (2021), cross-sectional study of the variants tested by commercial genetic tests for PSSM2 and myofibrillar myopathy, in warmblood and Arabian horses with a biopsy diagnosis and breed-matched controls (182 horses) and in 205 public genomes. No variant was associated with the histological diagnosis, and the sensitivity of all of them was below 0.33; the variants were also present in ancient domestic horses. The authors advise against using them for diagnosis, pre-purchase examination or breeding selection. The lead author runs a muscle biopsy laboratory, although she declares no financial interest in it.