Zidovudine (AZT) induced alterations in mitochondrial biogenesis in rat striated muscles.
Zidovudine (AZT) and didanosine (ddI), two drugs used in the treatment of AIDS, are also known to cause mitochondrial abnormalities. We investigated the physiological relevance of the mitochondrial defects by measuring in situ skeletal muscle performance and cytochrome c oxidase (CYTOX) enzyme activity in heart muscle, red highoxidative (RG) and white low-oxidative (WG) portions of the gastrocnemius muscle of control (n = 17), AZT-(n = 14), or ddI-treated (n = 11) rats for 28 days. We also evaluated the hypothesis that AZT treatment could alter the expression of the mitochondrial transcription factor A (mtTFA), a key molecule involved in mitochondrial DNA (mtDNA) replication and transcription. AZT had a pronounced effect on blood pressure and skeletal muscle performance, which were significantly decreased during contractile activity at 2 and 5 Hz, compared with control. A significant decrease in CYTOX activity in heart and RG, but not WG muscles, was also evident. In the heart, this was accompanied by an apparent compensatory increase in mtTFA mRNA level that could not be attributed to enhanced transcriptional activation mediated by nuclear respiratory factor 1 (NRF-1). In contrast with AZT, no effect of ddI was found on the extent of fatigue or muscle enzyme activity. These results indicate that AZT induces mitochondrial defects primarily in muscles with the highest oxidative capacities (heart and RG). The long-term effects of AZT on mitochondrial biogenesis have the potential to reduce muscle performance, but the effects on performance in this short-term study were likely due to an inability of the AZT-treated animals to maintain blood pressure during contractile activity.
Freyssenet
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Department of Biology, York University, Toronto, Canada.
DiCarlo
M
M
Escobar
P
P
Grey
J
J
Schneider
J
J
Hood
D A
DA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D016049:Didanosine / Q000633:toxicity; D003576:Electron Transport Complex IV / Q000378:metabolism; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D051265:NF-E2-Related Factor 1; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins; D015215:Zidovudine / Q000633:toxicity*
D004268:DNA-Binding Proteins; D051265:NF-E2-Related Factor 1; C495632:Nfe2l1 protein, rat; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D012333:RNA, Messenger; D015534:Trans-Activators; C097078:XL-MTTFA protein, Xenopus; D029867:Xenopus Proteins; D015215:Zidovudine; D003576:Electron Transport Complex IV; D016049:Didanosine