Rhabdomyolysis. Necrotic myofibers.
Rhabdomyolysis (literally dissolution
of striated muscle) is myonecrosis
on a massive scale with leakage
of myofiber contents, including
myoglobin, CK, and other proteins
into the circulation. Myonecrosis
is caused by two basic mechanisms,
mechanical physical injury
and energy depletion. Failure
of ATP-powered pumps allows influx
of calcium into the myofiber.
Calcium activates proteases and
phospolipases, leading to disintegration
of plasma membrane, contractile
filaments, and other myofiber
The causes of rhabdomyolysis are listed in the table below.
|Excessive exertion, including status epilepticus, and alcohol withdrawal|
|Muscle ischemia, including compartment syndromes|
|Inherited metabolic disorders
affecting energy metabolism.
LPIN1 mutations. LPIN1 is expressed in muscle and adipose tissue and is important in triglyceride synthesis. Mutations of LPIN1 cause autosomal recessive acute recurrent myoglobinuria (ARARM).
RYR1 mutations. The ryanodine receptor 1 (RYR1) is a calcium channel that releases calcium ions from the sarcoplasmic reticulum into the transverse tubular system(T-tubule). This stimulates muscle contraction. RYR1 mutations cause central core and multiminicore myopathy and malignant hyperthermia.
|Muscle viral and bacterial infections, especially influenza and enteroviruses|
|Electrolyte imbalance and other severe metabolic derangements|
|Toxins (alcohol, heroin, cocaine)|
|Drugs, especially lipid-lowering agents|
Clinically, rhabdomyolysis is characterized by weakness, myalgia, and muscle swelling, and biochemically by elevation of CK, which is proportionate to the extent of myonecrosis. Muscle regenerates rapidly following myonecrosis. The most important complication of severe rhabdomyolysis is renal failure. When plasma myoglobin exceeds 0.5-1.5 mg/dl, it leaks into the urine and when its urine concentration rises above 100 mg/dl, it gives urine a red-brown color (myoglobinuria) and precipitates in distal tubules in the form of casts. Myoglobinuria is used synonymously with rhabdomyolysis. A large proportion of acute renal failure cases and associated deaths are caused by rhabdomyolysis. Myoglobin causes intrarenal vasoconstriction, tubular injury, and tubular obstruction by casts.
The lipid lowering agents statins, which are the most frequently prescribed drugs today, cause a range of neuromuscular adverse effects, which include myalgia, elevated CK, rhabdomyolysis, immune-mediated myopathy, mitochondrial myopathy, and peripheral neuropathy. Furthermore, statins can unmask or precipitate symptoms of other myopathies. The muscle biopsy in statin-related neuromuscular disorders may show myonecrosis, inflammatory myopathy, mitochondrial abnormalities, or denervation atrophy.
While statins are the most
frequent cause of drug-induced
neuromuscular adverse effects,
numerous other agents, partially
listed in the table below, can
cause muscle disease by a variety
|DRUGS, AGENTS||MUSCLE DISEASE, PATHOLOGY|
|Alcohol, drugs of abuse, statins, emetine, hypokalemia, ε-aminocaproic acid||Myonecrosis|
|d-penicillamine, phenytoin, α-interferon, L-tryptophan||Inflammatory myopathy|
|AZT, cyclosporin, statins||Mitochondrial myopathy|
|IV corticosteroids and neuromuscular blockade agents||Myosin loss, critical illness myopathy|
|Corticosteroids||Type 2 fiber atrophy|
|Antimalarials, amiodarone, perhexilene||Vacuolar myopathy (lysosomal)|
|Cochicine, vinristine||Vacuolar myopathy (sarcoplasmic reticulum)|
- Bosch X, Poch E, Grau JM. Rhabdomyolysis and Acute Kidney Injury. N Engl J Med 2009;361:62-72 PubMed
- Mastaglia, F. Iatrogenic myopathies. Curr Opin Neurol 2010, 23:445–9. PubMed
- Lanner JT. Ryanodine receptor physiology and its role in disease. Adv Exp Med Biol. 2012;740:217-34. PubMed
- Michot C, Hubert L, Romero NB, et al. Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia. J Inherit Metab Dis. 2012 Nov;35:1119-28. PubMed
Updated: January, 2013