Objective. Zidovudine is an antiretroviral nucleoside analog reverse transcriptase inhibitor that induces mitochondrial myopathy by interfering with the replication of mitochondrial DNA (mtDNA). Because zidovudine inhibits thymidine kinases, the mechanism of mtDNA depletion may be related to an impairment of the de novo synthesis of pyrimidine nucleotides, which are required building blocks of mtDNA. This study was undertaken to determine whether mitochondrial myopathy is a class effect of antiretroviral nucleoside analogs, and whether the muscle disease can be prevented by treatment with uridine as a pyrimidine nucleotide precursor.Methods. BALB/c mice were treated with zidovudine or zalcitabine. Some of the mice were cotreated with mitocnol, a dietary supplement with high uridine bioavailability. Mice hind limb muscles were examined after 10 weeks.Results. Zidovudine induced muscle fiber thinning, myocellular fat deposition, and abnormalities of mitochondrial ultrastructure. In mice treated with zidovudine, organelles contained low mtDNA copy numbers and reduced cytochrome c oxidase activity. The expression of the mtDNA-encoded cytochrome c oxidase I subunit, but not of nucleus-encoded mitochondrial proteins, was impaired. Zidovudine also increased the levels of myocellular reactive oxygen species and blood lactate. Uridine supplementation attenuated or normalized all pathologic abnormalities and had no intrinsic effects. Zalcitabine did not elicit muscle toxicity.Conclusion. Our findings indicate that zidovudine, but not zalcitabine, induces mitochondrial myopathy, which is substantially antagonized by uridine supplementation. These results provide proof of the importance of pyrimidine pools in the pathogenesis of zidovudine myopathy. Since uridine supplementation is tolerated well by humans, this treatment strategy should be investigated in clinical trials.Zidovudine is a nucleoside analog reverse transcriptase inhibitor (NRTI) that is widely used in the antiretroviral treatment of patients infected with the human immunodeficiency virus (HIV). A major limitation of long-term use of zidovudine is the occurrence of mitochondrial myopathy. Patients taking zidovudine may also experience an elevation in serum lactate, which may even serve as a noninvasive test for the presence of myopathy (1). A decreased intramuscular copy number of mitochondrial DNA (mtDNA) probably plays an important role in the pathogenesis of myopathy (2-4), but the exact mechanism of mtDNA depletion is under debate. Some NRTIs are thought to interfere with the mitochondrial metabolism by impairing the activity of polymerase-gamma, the enzyme which replicates mtDNA. Dideoxynucleoside analogs (stavudine, didanosine, and zalcitabine) are the drugs most commonly implicated (5), with zalcitabine being the strongest inhibitor of polymerase-gamma. Zidovudine, however, is only a weak inhibitor of polymerase-gamma (5).Results of recent studies indicate that zidovudine may cause mtDNA depletion by a different mechanism, Supported by the DFG (grant WA...
