Cytochrome c oxidase deficiency in the muscle of patients with zidovudine myopathy is segmental and affects both mitochondrial DNA- and nuclear DNA-encoded subunits.
Zidovudine (AZT) can induce a mitochondrial disorder associated with mitochondrial (mt) DNA depletion affecting skeletal muscle, heart, and liver. Zidovudine myopathy is characterized by ragged-red fibers and partial cytochrome c oxidase (COX) deficiency. We evaluated at a single fiber level the expression of COX II (mtDNA-encoded) and COX IV (nuclear DNA-encoded) subunits in 12 HIV-infected patients with zidovudine myopathy. We also evaluated COX activity on longitudinal muscle sections in one patient. In all patients, evaluation of the expression of COX II and COX IV subunits showed focal deficiency. All fibers negative for COX II or COX IV were negative by COX histochemistry; 32-92% (median 61%) of COX-negative fibers were negative for COX II antigens, and 7-58% (median 28%) were negative for COX IV antigens. One hundred and thirty-nine of 317 COX-negative fibers 139 (43.8%) were selectively negative for COX II; 28 of 317 (8.8%) COX-negative fibers were selectively negative for COX IV. A study of longitudinal distribution of COX activity demonstrated that COX deficiency was segmental with blurred borders, as previously observed in patients with myoclonus epilepsy with ragged-red fibers. We conclude that proteins encoded by mtDNA are predominantly, but not exclusively, involved in zidovudine myopathy. Our results confirm the value of single muscle fiber evaluation in the assessment of mitochondrial abnormalities related to zidovudine.
GERMEN, Inserm E 0011, EA 2347, Faculté de Médecine, Université Paris XII, France.
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Yerroum
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Pham-Dang
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Authier
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Monnet
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Gherardi
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Chariot
D002875:Chromosomes / Q000187:drug effects* / Q000235:genetics; D030401:Cytochrome-c Oxidase Deficiency; D004272:DNA, Mitochondrial / Q000187:drug effects* / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics; D006801:Humans; D017240:Mitochondrial Myopathies / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015215:Zidovudine / Q000009:adverse effects*
D004272:DNA, Mitochondrial; D015215:Zidovudine; D003576:Electron Transport Complex IV