What is Myosin Heavy Chain Myopathy (MYHM)?

Horses of Quarter Horse-related breeds (American Paint, Appaloosa, crosses) that have a specific genetic mutation in the gene MYH1 can develop myosin heavy chain myopathy (MYHM). MYHM presents as two overlapping clinical syndromes; immune-mediated myositis (IMM) and nonexertional rhabdomyolysis. MYH1 encodes a muscle specific protein called myosin heavy chain 1 that is found in type 2 X muscle fibers; the fastest contracting muscle fibers. In Quarter Horses, over 50% of the locomotor muscles consists of these fast contracting type 2X muscle fibers. A genetic mutation in MYH1 can cause the horse’s immune system to attack the skeletal muscle cells (fibers) that contain the mutated myosin protein. Certain triggers are needed to activate the immune-system and cause muscle disease.

What is Immune Mediated Myositis (IMM)?

Immune mediated myositis (IMM) is one of the forms of MYHM. With IMM, the immune system attacks the type 2X fibers in skeletal muscle cells along the back and rump causing a rapid loss in size and strength of the muscles (atrophy).

What causes IMM?

This immune mediated disease is caused by a loss of self-tolerance in the horse’s immune system to a protein normally present in its own muscle cells. The immune system in horses with the MYH1 mutation can be triggered to perceive type 2X muscle fibers as foreign, which initiates a process in the body that tells the white blood cells to destroy type 2X muscle fibers. Certain infectious agents or possibly vaccines are thought to “trigger” this reaction. The most common “trigger” causing IMM in the horses is Streptococcus infections. The trigger for initiating IMM is often, however, not known. Some owners report signs of IMM atrophy developing a few weeks after strangles or flu/rhino vaccinations or after giving immune stimulants.

What are the clinical signs?

• Rapid muscle loss over back (epaxial) and rump (glutial) in 1-3 days
• Depression
• Loss of appetite
• Stiffness

Are certain types of horses more susceptible to IMM than others?

Quarter Horses and Paints are the primary breeds affected by the MYH1 mutation with the incidence highest in reining and cutting horses. Horses under the age of 8 years old or over the age of 17 years old are more likely to develop IMM. Thoroughbreds, ponies, and Icelandic Horses have been diagnosed with another form of IMM that is not associated with the MYH1 mutation.

How is IMM diagnosed?

• History
  • Quarter Horse-related breeds with a recent history of respiratory disease or that have had recent exposure to horses with respiratory disease are at higher risk for developing IMM.
• Routine Diagnostics
  • Blood chemistry typically shows a chronic increase in serum creatine kinase (CK) and aspartate transaminase (AST) up to 10,000 U/L.
• Genetic Testing
  • For Quarter Horse-related breeds, a definitive diagnosis of IMM and MYHM can now be made by genetic testing through Veterinary Genetics Laboratory at the University of California, Davis. Click here for testing.
  • Myosin heavy chain myopathy is inherited as a codominant trait. This means that one copy of the MYH1 mutation (heterozygotes) is enough to make horses susceptible to developing a myosin heavy chain myopathy. Horses with two copies (homozygotes) seem to have more frequent and severe symptoms.
• Results Reported As

N/N	No copies of MYHM mutation. Horse does not have increased susceptibility for IMM or nonexertional rhabdomyolysis.
N/My	1 copy of the MYHM mutation is present. Horse may develop IMM following infection or vaccination, or nonexertional rhabdomyolysis. Horse can pass on the mutation to 50% of offspring.
My/My	2 copies of the MYHM mutation are present. Horse is at risk and may develop IMM following infection or vaccination, or nonexertional rhabdomyolysis. Horses will pass on the mutation to all offspring.

• Muscle Biopsy
  • Since genetic testing is a pain-free way to establish a diagnosis, muscle biopsy is rarely necessary to diagnose IMM. To make a diagnosis with a muscle biopsy, samples of the gluteal or epaxial muscles need to be submitted within the first few weeks of atrophy. Semimembranosus muscle is often normal. Extensive white blood cell infiltration and inflamed blood vessels, accompanied by regenerating and/or atrophied muscle fibers, are characteristic features of IMM in the first few weeks of atrophy.

What other diseses look similar to IMM?

• Equine Motor Neuron Disease or Vitamin E responsive myopathy
• Malabsorption/cachetic conditions
• Cushing’s disease in older horses
• Homozygous for type 1 PSSM
• Neurogenic muscle atrophy (trauma)

How is IMM treated?

IMM is remarkably responsive to corticosteroids. Typical therapy consists of dexamethasone (0.05 mg/kg) for 3 days, followed by prednisolone (1 mg/kg for 7 to 10 days) tapered by 100 mg/week over 1 month. We recommend bloodwork (CBC) be analyzed and antibiotic therapy recommended if a leukocytosis, hyperfibrinogenemia or lymphadenopathy is present.

Are there any management strategies that can help a horse with IMM?

Horses recovering from IMM muscle atrophy should be fed a concentrate with high quality protein balanced for vitamins and minerals. Alfalfa hay and amino acids supplements may provide building blocks for muscle development. If IMM has occurred within a month of vaccination, we recommend extending the time between necessary vaccines to at least 4-6 weeks for future vaccines to try and determine which vaccines the horse reacts to. We don’t recommend using the strangles vaccine in these horses because it appears to be a trigger for muscle atrophy or damage.

What is the prognosis for a horse with IMM?

Approximately 20% of horses heterozygous (My/N) for the MYH1 mutation develop rapid atrophy which with treatment usually resolves without long term consequences. Improvement in appetite should occur within 48 hours of steroid therapy. Muscle atrophy should stop, and muscle mass should return within 2-3 months when treated with corticosteroids. To prevent severe atrophy, call your veterinarian to begin corticosteroid therapy as soon as you notice muscle atrophy. In some cases, there may be areas in a muscle that have a permanent indentation. Without corticosteroid treatment, atrophy will eventually resolve and return of muscle mass may take a longer period of time. Horses with two copies of the MYH1 mutation (homozygotes My/My) have more severe atrophy and greater recurrence of atrophy, particularly within in the first year or two.

Homozygous horses may be euthanized due to the severity and recurrence of disease.

What is Nonexertional Rhabdomyolysis?

Some horses with the MYH1 mutation develop acute severe muscle damage that is not triggered by exercise. Rather than muscle atrophy, horses show signs of stiffness and possible swelling of muscles along their back and haunches and difficulty rising. A blood sample will reveal high levels of creatine kinase (CK) and aspartate transaminase (AST), both indicators of muscle damage.

How does the MYH1 mutation cause rhabdomyolysis?

The exact mechanism by which the MYH1 mutation causes rhabdomyolysis is not known. It may be an immune-response similar to IMM or the mutation may change the interaction of myosin with actin during muscle contractions.Fibers with the mutation appear to be more sensitive to activation by calcium. In some cases, strangles infection, especially guttural pouch infections, are present when rhabdomyolysis develops. There is similarity between the M protein of S equi and the type 2X myosin which could possibly explain this link. Horses can also develop MYHM nonexertional rhabdomyolysis when exposed to anaplasma phagocytophila.

How common is MYHM Nonexertional Rhabdomyolysis?

Nonexertional rhabdomyolysis caused by the MYH1 mutation is relatively rare but is most frequent in My/My homozygous horses.

What are the clinical signs?

• Firm, swollen and painful back and rump muscles
• Stiff gait and reluctance to move
• Difficulty rising
• Rapid heart rate
• Rapid breathing
• Fever and nasal discharge in some cases

Are certain groups of horses more susceptible?

Quarter Horse-related breeds with the MYH1 mutation are more susceptible and horses homozygous for this mutation (My/My) seem to have more severe symptoms than heterozygous horses (My/N).

How is Nonexertional Rhabdomyolysis diagnosed?

• Routine Diagnostics
  • Complete blood count is needed to determine if a concurrent infection is present. Increased white blood cells with an increase of neutrophils and fibrinogen are observed with infection.
• Blood Chemistry
  • Creatine kinase values over 50,000 U/L are common with MYHM. Diagnosis of S. equi should be confirmed by either culture or polymerase chain reaction assay (PCR).
• Genetic Testing
  • For Quarter Horse-related breeds, a definitive diagnosis of MYHM can now be made by genetic testing through Veterinary Genetics Laboratory at the University of California, Davis. Click here for testing.
• Results Reported As

N/N	No copies of the MYHM mutation. Horse does not have increased susceptibility for IMM or nonexertional rhabdomyolysis.
N/My	1 copy of the MYHM mutation is present. Horse may develop IMM following infection or vaccination, or nonexertional rhabdomyolysis. Horse can pass on the mutation to 50% of offspring.
My/My	2 copies of the MYHM mutation are present. Horse is at risk and may develop IMM following infection or vaccination, or nonexertional rhabdomyolysis. Horses will pass on the mutation to all offspring.

• Muscle Biopsy
  • A genetic test is the preferred diagnostic procedure. A muscle biopsy of the semimembranosus or semitendinosus muscle may be helpful in horses with a negative MYH1 genetic test to try and identify other causes of nonexertional rhabdomyolysis. Characteristics of rhabdomyolysis include light staining for glycogen in type 2X fibers, swelling of the muscle cells, disruption of sarcoplasm, and increased large white blood cells (macrophages).

What other diseses can look similar?

• Polysaccharide storage myopathy
• Malignant hyperthermia
• Nutritional myodegeneration
• Toxic myopathy- box elder and European sycamore maple

What is the treatment?

For S. equi infections, flushing infected guttural pouches, and antibiotics are common treatments. Corticosteroids may be prescribed for MYHM. For nonexertional rhabdomyolysis, treatment with dantrolene, given 3-4 times a day until serum CK starts to decline, may be indicated.

What is the prognosis?

The prognosis for a horse with nonexertional rhabdomyolysis is guarded as cases can be quite severe resulting in the horse having difficulty rising after lying down. Some horses will go on to develop muscle atrophy after they show nonexertional rhabdomyolysis.

How should I manage a horse with the MYHM mutation in the future?

Approximately 80% of horses heterozygous (My/N) for the MYH1 mutation do not develop signs of muscle atrophy or damage and vaccinations do not seem to be a trigger. We recommend when initially vaccinating an My/N or My/My horse, that only those vaccines that are necessary are given spaced out by 4-6 weeks using as small a number of vaccines per syringe as possible each time, e.g. just tetanus (wait 4-6 weeks), just EEE, WEE and VEE (wait 4-6 weeks), just West Nile (wait 4-6 weeks). If no muscle damage or atrophy is triggered, then it may well be safe to use these vaccines together next year. If owners notice atrophy after vaccination, then a discussion should ensue with your veterinarian of the risks or benefits for that vaccine. Owners should have quick access to prednisolone if atrophy is initiated after a vaccination, Flu/rhino vaccines are a common trigger of IMM as are S. equi vaccines which are not generally recommended for horses that have the MYHM mutation.

References

1. Valberg SJ, Schultz AE, Finno CJ, Bellone RR, Hughes SS. Prevalence of clinical signs and factors impacting expression of myosin heavy chain myopathy in Quarter Horse-related breeds with the MYH1 E321G mutation. Journal of Veterinary Internal Medicine. 2022 May;36(3):1152-9.
2. Finno CJ, Giuliana G, Perumbakkam S, Williams ZJ, Bordbari MH, Gardner KL, Burns E, Peng S, Durward-Akhurst SA, Valberg SJ. A mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses. Skeletal Muscle 2018 8:7. https://doi.org/10.1186/s1339.
3. Gianino GM, Valberg SJ, Perumbakkam S, Henry ML, Gardner K, Penedo C, Finno CJ. Prevalence of the E321G MYH1 variant for immune-mediated myositis and nonexertional rhabdomyolysis in performance subgroups of American Quarter Horses.J Vet Intern Med. 2019 Mar;33(2):897-901.
4. Valberg SJ, Henry ML, Perumbakkam S, Gardner KL, Finno CJ. An E321G MYH1 mutation is strongly associated with nonexertional rhabdomyolysis in Quarter Horses. J Vet Intern Med. 2018 Sep;32(5):1718-1725.
5. Lewis SS, Valberg SJ, Nielsen IL. 2007. Suspected immune-mediated myositis in horses. J Vet Intern Med 21:495-503.
6. Hunyadi L, Sundman EA, Kass PH, Williams DC, Aleman M. 2017. Clinical Implications and Hospital Outcome of Immune-Mediated Myositis in Horses. J Vet Intern Med 31:170-5.
7. Durward-Akhurst SA, Finno CJ, Barnes N, Shivers J, Guo LT, et al. 2016. Major Histocompatibility Complex I and II Expression and Lymphocytic Subtypes in Muscle of Horses with Immune-Mediated Myositis. J Vet Intern Med 30:1313-21.