Degenerative (non-inflammatory) myopathies

Degenerative myopathies are characterised by myofibre necrosis. Inflammatory cells may be seen in response to necrosis, but are not responsible for initiating muscle damage as they are in the inflammatory myopathies.120 _{Causes of degenerative}

myopathies include trauma, overexertion, nutritional deficiencies and toxicities.

1.4.2.1 Traumatic myopathies

Trauma to skeletal muscle can occur with impact injuries, lacerations, crush injuries, penetrating wounds and excessive stretching.121 _{Muscle damage and the development}

of a fibrotic myopathy in the iliopsoas muscle of a dog has also been reported in association with the migration and surgical removal of a grass awn.122 _{In dogs used for}

pig hunting, traumatic wounds are particularly common,123 _{and penetrating wounds}

caused by the tusks of wild boars can be associated with significant muscle damage. Traumatic myopathies frequently cause a severe but transient elevation in serum creatine kinase,50 _{and a slower elevation in aspartate aminotransferase.}67 _{If large}

regions of muscle are traumatised, as can occur with excessive pressure in crush syndrome, release of muscle contents into circulation can result in electrolyte imbalances and myoglobinaemia, leading to acute renal failure.124

21

1.4.2.2 Exertional myopathies

Muscle necrosis due to overexertion or excessive exercise has been reported in a wide range of species, and is referred to as an exertional myopathy or exertional

rhabdomyolysis.125 _{Altered blood flow to muscle and exhaustion of aerobic energy}

during overexertion leads to increased production of lactic acid and decreased delivery of oxygen and removal of cellular waste.126 _{This damages myofibres, and when severe,}

can cause widespread muscle necrosis and rhabdomyolysis. The histological

appearance of muscle in exertional myopathies and rhabdomyolysis depends on the time since the injury occurred. Within a few hours, myofibres show changes typical of acute necrosis, including hypereosinophilia and fragmentation of the sarcoplasm, with loss of cross striations, haemorrhage, and pyknotic or absent nuclei.125 _{Brown granular}

casts of myoglobin may be seen in renal tubules and are associated with tubular necrosis. In lesions of a longer duration, necrotic myofibres can be mineralised, and there is infiltration of leukocytes and proliferation of myoblasts and sarcolemmal cells.

Exertional rhabdomyolysis is most commonly reported in dogs that participate in high energy exercise, such as sled racing.127 _{In humans, genetic polymorphisms that may}

predispose to the development of exertional rhabdomyolysis have been identified,128

and in horses it has been shown that underlying muscle disorders (such as polysaccharide storage myopathy) can play a role.129 _{Specific risk factors for the}

development of exertional rhabdomyolysis have not been identified in dogs, and vitamin E and antioxidant status do not have any effect.127

1.4.2.3 Nutritional myopathies

Contraction of striated muscle generates large numbers of free radicals.127 _Antioxidant

defence mechanisms, such as vitamin E and the selenium-dependent glutathione peroxidase system, are therefore important in protecting muscle from injury induced by free radicals. If animals (particularly livestock) consume a diet deficient in selenium and/or vitamin E, or if neonatal animals are born to a deficient dam, muscle

degeneration and nutritional myopathy may result.120 _{Affected muscles often appear}

22

animals with congenital nutritional myopathy, the most severe lesions are usually seen in the heart,130, 131 _{whereas skeletal muscle lesions generally predominate in animals}

affected after three to four weeks of age.115 _{A myopathy resembling white muscle}

disease has been reported in an adult sheep dog in New Zealand, which was characterised histologically by widespread skeletal muscle necrosis with loss of

striations, swelling and fragmentation of the sarcoplasm and rare calcified fibres, with minimal interstitial cellular response.131 _{Selenium deficiency was not confirmed in this}

case, but overseas there are case reports of selenium/vitamin E responsive myocardial degeneration in dogs,132 _{and experimental feeding of selenium and vitamin E deficient}

diets to puppies causes a skeletal myopathy.133

1.4.2.4 Toxic myopathies

A wide range of plant toxins, fungal toxins and synthetic chemicals and drugs can be associated with the development of skeletal and cardiac myopathies in animals. Typically, toxic myopathies are characterised by myofibre necrosis, but some toxins also cause inflammation or interfere with mitochondrial, lysosomal or microtubular function.134 _{Plant-related myopathies are most commonly seen in grazing animals,}

although some plants, such as Ageratina altissima (white snakeroot), are capable of causing a secondary toxicity in animals or humans that eat meat or milk from poisoned animals.135 _{Determining the individual plant species implicated in a toxic myopathy}

may be difficult, and the toxic principles of many plants are unknown. A recent example of this is seasonal pasture myopathy/atypical myopathy in horses, where outbreaks were first recognised in the 1980s, but the underlying cause (hypoglycin A in box elder seeds) was only found in 2013 after extensive epidemiological and

biochemical investigations.136

Certain drugs, chemicals and medications, either on their own or in combination, can cause muscle damage.134 _{One of the most frequently recognised drug-induced}

myopathies in animals is ionophore toxicity. Ionophore antibiotics may be added to ruminant feed to promote growth and reduce the incidence of bloat, and ruminants are able to tolerate high ionophore concentrations. However, other animals

23

(particularly horses and dogs) are more sensitive to these drugs,120 _{and can develop a}

cardiac and skeletal muscle myopathy if they are exposed to ionophores. In one case report, accidental contamination of dry dog food with monensin caused anorexia, dyspnoea, severe weakness, myoglobinuria and marked increases in serum CK, AST and lactate dehydrogenase activities in a 2-year-old sheltie dog.137 _{Histological lesions}

of ionophore toxicity are characterised by multifocal monophasic muscle necrosis, and necrotic fibres are infiltrated with macrophages over time.111 _{Ultrastructurally, there is}

marked swelling and disintegration of mitochondria. Both type I and type II muscle fibres are affected, but satellite cells can survive acute toxicity and aid in muscle regeneration. Confirmation of toxicity is through laboratory analysis for specific ionophores.138

In humans, there are numerous drugs that can cause skeletal muscle myopathies, including anticholesterolaemic drugs (statins), anti-inflammatory/immunosuppressive drugs, antinucleoside analogues, dietary agents and recreational drugs (cocaine, heroin, amphetamines and alcohol).134 _{These myopathies are most commonly}

necrotising (degenerative), but can also be inflammatory or can target mitochondria, myofibrils or microtubules of muscle. Dogs are sometimes used in drug toxicity testing or as experimental models of drug-induced myopathies,139,140 _{but drug-induced}

myopathies in dogs are otherwise rare.