Uridine supplementation antagonizes zidovudine‐induced mitochondrial myopathy and hyperlactatemia in mice

Abstract

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...

Zidovudine Induces Downregulation of Mitochondrial Deoxynucleoside Kinases: Implications for Mitochondrial Toxicity of Antiviral Nucleoside Analogs

“…Uridine supplementation during antiviral therapy has been shown to reduce peripheral neuropathy and encephalopathy in AIDS patients and in animal models, but the mechanism of this protective effect is not known (23,39). After uptake in cells, uridine can be metabolized to various nucleoside and nucleotide intermediates, e.g., uridine, cytidine, deoxycytidine, and thymidine nucleotides such as UTP, CTP, dCTP, and dTTP.…”

“…dN, deoxynucleoside; dNMP, deoxynucleoside monophosphate; AZTMP, AZT monophosphate; AZTTP, AZT triphosphate; pol-␥, polymerase ␥. levels may explain in part the uridine effects observed in HIV patients and in animal models in connection with antiviral treatment with nucleoside analogs (23,39,40).…”

High-dose clevudine impairs mitochondrial function and glucose-stimulated insulin secretion in INS-1E cells

“…In addition to defects in insulin secretion, decreased sensitivity in insulin target cells can also participate in diabetogenesis in patients receiving clevudine who might have a high susceptibility to mitochondrial toxicity. Interestingly, several reports have shown that NRTI induces intramitochondrial pyrimidine deficiency which may aggravate mtDNA depletion and mitochondrial dysfunction [35,36]. They also discovered that uridine supplementation attenuates steatohepatitis or mitochondrial myopathy induced by NRTI.…”

Muscle-fiber transdifferentiation in an experimental model of respiratory chain myopathy

“…Muscle capillaries are lost in dermatomyositis [1], systemic sclerosis [2-4], and chronic obstructive pulmonary disease (COPD) [5], and qualitative or quantitative defects of respiratory chain components are found in the mitochondrial myopathies [6,7]. Ultrastructural changes in mitochondria and respiratory-chain dysfunction can also be induced by medications (statins [8], zidovudine, and other antiretroviral nucleoside analogues [9], and potentially, alcohol [10]). The physiological explanations for muscle fatigue and the adjustments of muscle metabolism to such respiratory compromise have, however, been only poorly addressed.…”