Beyond a highly probable hereditary factor, there does not seem to be a single cause that triggers ER in horses. Exercise is seen in every case, but exercise is always accompanied by another factor. It is likely that several factors must act together in order to cause an ER attack.

Other possible factors include:

- The overfeeding of non-structural carbohydrates (grain and pellets, for example)

- Poor conditioning or fitness, sudden increase of workload

- The work of a horse after a period of rest, if the concentrate ration was not reduced

- Electrolyte or mineral imbalances, especially seen with potassium

- A deficiency in selenium or vitamin E

- Imbalance of hormones, including the reproductive hormones in nervous fillies and mares and thyroid hormones in horses with hypothyroidism

- Wet, cold, or windy weather conditions

The more factors that are present, the greater the likelihood that the horse will develop ER. However, the most common cause of ER is an imbalance between the animal's diet and his workload, especially when he has a high-grain diet.

ER occurs when there is an inadequate flow of blood to the muscles of an exercising horse. The muscle cells, lacking in oxygen, begin to function anaerobically to produce the needed ATP. The anaerobic work creates a buildup of waste products, acid, and heat. This subsequently alters the cell by preventing the cell's enzymes from functioning and the myofilaments from efficiently contracting. The cell membranes may then be damaged if the horse is forced to continue work, which allows muscle enzymes and myoglobin to leak into the bloodstream.

The body builds up a store of glycogen from converted carbohydrates in muscle cells. Glycogen, a fuel used by muscles for energy, is depleted during work and restocked when a horse rests. Oxygen-carrying blood metabolizes glycogen, but the blood can not flow fast enough to metabolise the excess stored glycogen. The glycogen that is not metabolized aerobically (by the oxygenated blood) must then be metabolized anaerobically, which then creates the cell waste products and heat, and ER has begun. A horse on a high-grain diet with little work collects more glycogen in its muscles than it can use efficiently when exercise begins, which is why horses on a high-grain diet are more likely to develop ER.

Proper conditioning can help prevent ER, as it promotes the growth of capillaries in muscles and the number of enzymes used for energy production in muscle cells. However, improvement in these areas can take several weeks. Thus, ER is more common in horses that are only worked sporadically or lightly, and in horses just beginning an exercise regimen.

A common misconception is that ER is caused by the buildup of lactic acid. Lactate is "not" a waste product for a cell, but a fuel, used when the cell's oxygen supply is insufficient. Lactate does not damage a cell, but is rather a byproduct of the true cause of cell damage: inadequate blood supply and altered cell function. Lactate naturally builds up in an exercising horse without harming the muscle cells, and is metabolized within an hour afterward.

The pain is caused by the inadequate blood flow to the muscle tissue, the inflammation from the resulting cell damage, and the release of cell contents. Muscle spasms, caused by the lack of blood to the muscle tissue, are also painful.

For mild to moderate cases of ER, the prognosis is excellent, with the horse successfully returning to its former level of competition. However, if the vet's recommendations for preventing ER are not followed, ER may likely recur.

Horses who experience a severe case of ER (the muscle degeneration is significant) are less likely to return to their previous level of competition, as fibrosis may have occurred, which would result in loss of muscle function. The prognosis is guarded for these horses.

There is an increased risk that statin (cholesterol-reducing drugs) will cause myopathy (muscle weakness) in individuals with MADD.

Anesthesia has the potential to cause malignant hyperthermia, an uncontrolled increase in body temperature, and permanent muscle damage in patients with MADD. Individuals with MADD are advised to notify their anesthesiologist about their condition prior to surgery.

In most cases where myopathy is present with MADD, a second muscle disease is present and symptoms are worse than either disease in isolation.

Recurrent rhabdomyolysis may result from intrinsic muscle enzyme deficiencies, which are usually inherited and often appear during childhood. Many structural muscle diseases feature episodes of rhabdomyolysis that are triggered by exercise, general anesthesia or any of the other causes of rhabdomyolysis listed above. Inherited muscle disorders and infections together cause the majority of rhabdomyolysis in children.

The following hereditary disorders of the muscle energy supply may cause recurrent and usually exertional rhabdomyolysis:

- Glycolysis and glycogenolysis defects: McArdle's disease, phosphofructokinase deficiency, glycogen storage diseases VIII, IX, X and XI

- Lipid metabolism defects: carnitine palmitoyltransferase I and II deficiency, deficiency of subtypes of acyl CoA dehydrogenase (LCAD, SCAD, MCAD, VLCAD, 3-hydroxyacyl-coenzyme A dehydrogenase deficiency), thiolase deficiency

- Mitochondrial myopathies: deficiency of succinate dehydrogenase, cytochrome c oxidase and coenzyme Q10

- Others: glucose-6-phosphate dehydrogenase deficiency, myoadenylate deaminase deficiency and muscular dystrophies

The exact number of cases of rhabdomyolysis is difficult to establish, because different definitions have been used. In 1995, hospitals in the U.S. reported 26,000 cases of rhabdomyolysis. Up to 85% of people with major traumatic injuries will experience some degree of rhabdomyolysis. Of those with rhabdomyolysis, 10–50% develop acute kidney injury. The risk is higher in people with a history of illicit drug use, alcohol misuse or trauma when compared to muscle diseases, and it is particularly high if multiple contributing factors occur together. Rhabdomyolysis accounts for 7–10% of all cases of acute kidney injury in the U.S.

Crush injuries are common in major disasters, especially in earthquakes. The aftermath of the 1988 Spitak earthquake prompted the establishment, in 1995, of the Renal Disaster Relief Task Force, a working group of the International Society of Nephrology (a worldwide body of kidney experts). Its volunteer doctors and nurses assisted for the first time in the 1999 İzmit earthquake in Turkey, where 17,480 people died, 5392 were hospitalized and 477 received dialysis, with positive results. Treatment units are generally established outside the immediate disaster area, as aftershocks could potentially injure or kill staff and make equipment unusable.

Acute exertional rhabdomyolysis happens in 2% to 40% of people going through basic training for the United States military. In 2012, the United States military reported 402 cases.

PSSM is most prevalent in American Quarter Horses and their related breeds (Paint horse, Appaloosa, Appendix Quarter Horse), Draft horse breeds (especially Belgian Draft and Percherons), and Warmblood breeds. The Belgian Draft been shown to have a 36% prevalence of PSSM. Other breeds that have been diagnosed with PSSM include the Arabian, Lipizzaner, Morgan, Mustang, Peruvian Paso, Rocky Mountain Horse, Standardbred, Tennessee Walking Horse, Thoroughbred, and National Show Horse. It has been suggested that the GSY1 mutation provided some benefit to hard working animals with poor-quality diets, and is now damaging members of those "thrifty" breeds that are managed with moderate to low levels of work and diets high in non-structural carbohydrates.

PSSM Type 1 (homozygous or heterozygous for the GSY1 mutation) is more common in Quarter Horses and their related breeds, and draft breeds, while PSSM Type 2 (negative for the GSY1 mutation) is more commonly seen in other breeds, including warmbloods. There is no sex predilection to the disease.

It is important for MADD patients to maintain strength and fitness without exercising or working to exhaustion. Learning this balance may be more difficult than normally, as muscle pain and fatigue may be perceived differently from normal individuals.

Symptomatic relief from the effects of MADD may sometimes be achieved by administering ribose orally at a dose of approximately 10 grams per 100 pounds (0.2 g/kg) of body weight per day, and exercise modulation as appropriate. Taken hourly, ribose provides a direct but limited source of energy for the cells. Patients with myoadenylate deaminase deficiency do not retain ribose during heavy exercise, so supplementation may be required to rebuild levels of ATP.

Creatine monohydrate could also be helpful for AMPD patients, as it provides an alternative source of energy for anaerobic muscle tissue and was found to be helpful in the treatment of other, unrelated muscular myopathies.

Some affected animals may remain subclinical, others may have mild signs that do not impede athletic performance, while some horses will have clinical signs that prevent any forced exercise. Rarely, horses will die from acute episodes of rhabdomyolysis. The reason for such variability of phenotype is not fully understood. Temperament, gender, and body type have no effect on degree of clinical signs. However, environmental factors such as diet and exercise, whether the horse is heterozygous or homozygous for the mutated GSY1 allele, and the presence of modifying genes all play a role. Additionally, some affected horses may have PSSM Type 2, which will produce different cellular changes and subsequently different phenotypic effects.

One such modifying genes is RYR1, which is responsible for calcium regulation in muscle cells. RYR1 mutation causes malignant hyperthermia, a rare but potentially fatal disorder usually associated with anesthesia. While RYR1 mutation is rare in horses, including the general Quarter Horse population, it is much more common in Quarter Horses with GSY1 mutation. Horses with both mutations are more likely to have a severe PSSM phenotype, including higher levels of blood creatine kinase (CK), more severe exercise intolerance, more severe episodes of rhabdomyolysis (more frequent muscle fasciculations, more frequent episodes that are not associated with exercise, acute death), and poor response to PSSM treatment.

Additionally, defects in both GSY1 and the SCNA4 gene, responsible for Hyperkalemic Periodic Paralysis (HYPP) in Quarter Horses and related breeds, has been found in 14% of Halter horses. A combination of both of these genes can cause severe rhabdomyolysis should the horse become recumbent due to an HYPP attack.

Due to the risk of crush syndrome, current recommendation to lay first-aiders (in the UK) is to not release victims of crush injury who have been trapped for more than 15 minutes. Treatment consists of not releasing the tourniquet and fluid overloading the patient with added Dextran 4000 iu and slow release of pressure. If pressure is released during first aid then fluid is restricted and an input-output chart for the patient is maintained, and proteins are decreased in the diet.

The Australian Resuscitation Council recommended in March 2001 that first-aiders in Australia, where safe to do so, release the crushing pressure as soon as possible, avoid using a tourniquet and continually monitor the vital signs of the patient. St John Ambulance Australia First Responders are trained in the same manner.

In dairy breeds, the disease may occur in calves between birth and 4 months of age. In rustic breeds or beef cattle, heifers and young steers up to 12 months of age can be affected. In calves, muscles in upper portion of the front legs and the hind legs are degraded, causing the animal to have a stiff gait and it may have difficulty standing. The disease may also present in the form of respiratory distress.

Trauma, vascular problems, malignant hyperthermia, certain drugs and other situations can destroy or damage the muscle, releasing myoglobin to the circulation and thus to the kidneys. Under ideal situations myoglobin will be filtered and excreted with the urine, but if too much myoglobin is released into the circulation or in case of renal problems, it can occlude the renal filtration system leading to acute tubular necrosis and acute renal insufficiency.

Other causes of myoglobinuria include:

- McArdle's disease

- Phosphofructokinase deficiency

- Carnitine palmitoyltransferase II deficiency

- Malignant hyperthermia

- Polymyositis

- Lactate dehydrogenase deficiency

- Thermal or electrical burn

Seigo Minami, a Japanese physician, first reported the crush syndrome in 1923. He studied the pathology of three soldiers who died in World War I from insufficiency of the kidney. The renal changes were due to methemoglobin infarction, resulting from the destruction of muscles, which is also seen in persons who are buried alive. The progressive acute renal failure is because of acute tubular necrosis.

The syndrome was later described by British physician Eric Bywaters in patients during the 1941 London Blitz. It is a reperfusion injury that appears after the release of the crushing pressure. The mechanism is believed to be the release into the bloodstream of muscle breakdown products—notably myoglobin, potassium and phosphorus—that are the products of rhabdomyolysis (the breakdown of skeletal muscle damaged by ischemic conditions).

The specific action on the kidneys is not understood completely, but may be due partly to nephrotoxic metabolites of myoglobin.

The most devastating systemic effects can occur when the crushing pressure is suddenly released, without proper preparation of the patient, causing reperfusion syndrome. In addition to tissue directly suffering the crush mechanism, down stream tissue is subject to Ischemia-reperfusion injuries of the appendicular musculoskeletal system. Without proper preparation, the patient, with pain control, may be cheerful before extrication, but die shortly thereafter. This sudden decompensation is called the "smiling death."

These systemic effects are caused by a traumatic rhabdomyolysis. As muscle cells die, they absorb sodium, water and calcium; the rhabdomyolysis releases potassium, myoglobin, phosphate, thromboplastin, creatine and creatine kinase.

Compartment syndrome can be secondary to crush syndrome. Monitor for the classic 5 Ps: pain, pallor, parasthesias, pain with passive movement, and pulselessness.

Supervised exercise programs have been shown in small studies to improve exercise capacity by several measures.

Oral sucrose treatment (for example a sports drink with 75 grams of sucrose in 660 ml.) taken 30 minutes prior to exercise has been shown to help improve exercise tolerance including a lower heart rate and lower perceived level of exertion compared with placebo.

In lambs, the disease typically occurs between 3 to 8 weeks of age, but may occur in older lambs as well. Progressive paralysis occurs, which is evident through the following symptoms: arched back, difficulty moving and an open shouldered stance. Cardiac failure may occur in two forms: sudden heart failure or gradual cardiac failure characterized by lung anemia that causes death due to suffocation.

Ewes may be given an injection of vitamin E/selenium prior to lambing to prevent deficiencies in lambs. In areas, such as Ontario, where lambs are highly susceptible to the condition, management practices should include vitamin E/selenium injections.

Some horse organizations have instituted rules to attempt to eliminate this widespread disease. The American Quarter Horse Association (AQHA) mandates testing for foals descended from Impressive if both of the foal's parents were not homozygous negative (N/N) for the gene, and, since 2007, has not registered foals homozygous (H/H) for the gene. Since 2007, the Appaloosa Horse Club (ApHC) has required foals descended from Impressive to be tested, so that the results may be recorded on its certificate. The American Paint Horse Association (APHA) mandated that, after 2017, stallions must be tested for HYPP so that mare owners may make an informed decision before choosing a stallion for breeding to their mare.

Whilst diet has long been known to be linked to laminitis, there is emerging evidence that breed and body condition also play a role. Levels of hormones, particularly adiponectin, and serum insulin are also implicated, opening up new possibilities for developing early prognostic tests and risk assessments.

PPID shares similarities to Equine Metabolic Syndrome, which also causes regional adiposity, laminitis, and insulin resistance. Treatment and management may differ between the two endocrinopathies, making differentiation important. However, it is important to keep in mind that horses with EMS may develop PPID, therefore both diseases may occur simultaneously.

Hospitalization and IV hydration should be the first step in any patient suspected of having myoglobinuria or rhabdomyolysis. The goal is to induce a brisk diuresis to prevent myoglobin precipitation and deposition, which can cause acute kidney injury. Mannitol can be added to assist with diuresis. Adding sodium bicarbonate to the IV fluids will cause alkalinzation of the urine, believed to reduce the breakdown of myoglobin into its nephrotoxic metabolites, thus preventing renal damage. Often, IV normal saline is all that is needed to induce diuresis and alkalinize the urine.

Prognosis is poor if this condition is not aggressively treated. In the 1970s, mortality was greater than 80%; with the current management, however, mortality is now less than 5%.

The mechanism remains unclear and is the subject of much research. Three conditions are thought to cause secondary laminitis:

- Sepsis/endotoxemia or generalized inflammation

- Endocrinopathy

- Trauma: concussion or excessive weight-bearing

- Inflammation

Inflammatory events that are associated with laminitis include sepsis, endotoxemia, retained placenta, carbohydrate overload (excessive grain or pasture), enterocolitis, pleuropneumonia, and contact with black walnut shavings. In these cases, there is an increase in blood flow to the hoof, bringing in damaging substances and inflammatory cells into the hoof.

- Endocrinopathy

Endocrinopathy is usually the result of improper insulin regulation, and is most commonly seen with pituitary pars intermedia dysfunction (also called equine Cushing's syndrome) and equine metabolic syndrome (EMS), as well as obesity and glucocorticoid administration. In cases of EMS, most episodes occur in the spring when the grass is lush.

- Trauma

Mechanical laminitis starts when the hoof wall is pulled away from the bone or lost, as a result of external influences. Mechanical laminitis can occur when a horse habitually paws, is ridden or driven on hard surfaces ("road founder"), or in cases of excessive weight-bearing due to compensation for the opposing limb, a process called "support limb laminitis". Support limb laminitis is most common in horses suffering from severe injury to one limb, such as fracture, resulting in a non-weight bearing state that forces them to take excessive load on the opposing limb. This causes decreased blood flow to the cells, decreasing oxygen and nutrient delivery, and thus altering their metabolism which results in laminitis.

Those working in industry, in the military, or as first responders may be required to wear personal protective equipment (PPE) against hazards such as chemical agents, gases, fire, small arms and even Improvised Explosive Devices (IEDs). PPE includes a range of hazmat suits, firefighting turnout gear, body armor and bomb suits, among others. Depending on design, the wearer may be encapsulated in a microclimate, due to an increase in thermal resistance and decrease in vapor permeability. As physical work is performed, the body’s natural thermoregulation (i.e., sweating) becomes ineffective. This is compounded by increased work rates, high ambient temperature and humidity levels, and direct exposure to the sun. The net effect is that desired protection from some environmental threats inadvertently increases the threat of heat stress.

The effect of PPE on hyperthermia has been noted in fighting the 2014 Ebola virus epidemic in Western Africa. Doctors and healthcare workers were only able to work 40 minutes at a stretch in their protective suits, fearing heat strokes.

In 1994, researchers at the University of Pittsburgh, with a grant from horse organizations, isolated the genetic mutation responsible for the problem and developed a blood test for it. Using this test, horses may be identified as:

- H/H, meaning they have the mutation and it is homozygous. These horses always pass on the disease.

- N/H, meaning they have the mutation and it is heterozygous. These horses are affected to a lesser degree and pass on the disease 50% of the time.

- N/N, meaning they do not have the mutation and cannot pass it on, even if they are descendants of Impressive.

In the case of the horse Impressive, the muscles were always contracting which was equivalent to a constant work-out. Thus the development of an "impressive" musculature.

Situational heat stroke occurs in the absence of exertion. It mostly affects the young and elderly. In the elderly in particular, it can be precipitated by medications that reduce vasodilation and sweating, such as anticholinergic drugs, antihistamines, and diuretics. In this situation, the body's tolerance for high environmental temperature may be insufficient, even at rest.

Heat waves are often followed by a rise in the death rate, and these 'classical hyperthermia' deaths typically involve the elderly and infirm. This is partly because thermoregulation involves cardiovascular, respiratory and renal systems which may be inadequate for the additional stress because of the existing burden of aging and disease, further compromised by medications. During the July 1995 heat wave in Chicago, there were at least 700 heat-related deaths. The strongest risk factors were being confined to bed, and living alone, while the risk was reduced for those with working air conditioners and those with access to transportation. Even then, reported deaths may be underestimates as diagnosis can be misclassified as stroke or heart attack.

Malignant hyperthermia (MH) is a type of severe reaction that occurs to particular medications used during general anesthesia, among those who are susceptible. Symptoms include muscle rigidity, high fever, and a fast heart rate. Complications can include rhabdomyolysis and high blood potassium. Most people who are susceptible are generally otherwise normal when not exposed.

The cause of MH is the use of certain volatile anesthetic agents or succinylcholine in those who are susceptible. Susceptibility can occur due to at least six genetic mutations, with the most common one being of the RYR1 gene. Susceptibility is often inherited from a person's parents in an autosomal dominant manner. The condition may also occur as a new mutation or be associated with a number of inherited muscle diseases, such as central core disease.

In susceptible individuals, the medications induce the release of stored calcium ions within muscle cells. The resulting increase in calcium concentrations within the cells cause the muscle fibers to contract. This generates excessive heat and results in metabolic acidosis. Diagnosis is based on symptoms in the appropriate situation. Family members may be tested to see if they are susceptible by muscle biopsy or genetic testing.

Treatment is with dantrolene and rapid cooling along with other supportive measures. The avoidance of potential triggers is recommended in susceptible people. The condition affects one in 5,000 to 50,000 cases where people are given anesthetic gases. Males are more often affected than females. The risk of death with proper treatment is about 5% while without it is around 75%. While cases that appear similar to MH have been documented since the early 20th century, the condition was only formally recognized in 1960.

There are two autosomal recessive forms of this disease, childhood-onset and adult-onset. The gene for myophosphorylase, PYGM (the muscle-type of the glycogen phosphorylase gene), is located on chromosome 11q13. According to the most recent publications, 95 different mutations have been reported. The forms of the mutations may vary between ethnic groups. For example, the R49X (Arg49Stop) mutation is most common in North America and western Europe, and the Y84X mutation is most common among central Europeans.

The exact method of protein disruption has been elucidated in certain mutations. For example, R138W is known to disrupt to pyridoxal phosphate binding site. In 2006, another mutation (c.13_14delCT) was discovered which may contribute to increased symptoms in addition to the common Arg50Stop mutation.