Effect of L-Carnitine on AZT-Induced Mitochondrial Toxicity: Studies on Human Muscle Cultures

Abstract

M itochondrial myopathy in zidovudine-treated patients was initially reported in 1990 by Dalakas.¹ Zidovudine (AZT) is one of the nucleotide analogs, the antiretroviral drugs, provided to patients infected with human immunodeficiency virus (HIV) to control the amount of virus present in those individuals and avoid the full development of the disease (AIDS).2 The first treatment consisted of a high dose of AZT for prolonged periods; in some of the HIV-patients treated with this regimen, it was observed that AZT caused a myopathic disease that was called “AZT myopathy.”^1,3,4,5 Muscle biopsy studies from those patients revealed that this myopathy was histo- logically characterized by an increased number of a unique type of muscle fiber described as ragged red fibers.^1,6 When the muscle biopsies were studied by electron microscopy, a proliferation of mitochondria with enlarged size and abnormal cristae was observed.^1,6,7 Molecular analysis has also determined a severe reduction of the mitochondrial DNA in the muscle of HIV patients treated with AZT.⁶ We and others have reported on the mechanism by which AZT damages the muscle.^8–11 Our studies were performed in vitro, using human muscle cultures,^8,12,13 and in vivo, using rats treated with daily intraperitoneal injections of AZT.⁸ In an effort toward preventing this disease, our laboratory has also found that L-carnitine (3-hydroxy-4-me- thyl-ammoniobutanoate) in our model systems prevents and improves the pathological alterations caused by AZT.^12,13