Zidovudine (AZT) induced alterations in mitochondrial biogenesis in rat striated muscles

Zidovudine (AZT) and didanosine (ddI), two drugs used in the treatment of A IDS, are also known to cause mitochondrial abnormalities. We investigated t he physiological relevance of the mitochondrial defects by measuring in sit u skeletal muscle performance and cytochrome c oxidase (CYTOX) enzyme activ ity in heart muscle, red high-oxidative (RG) and white low-oxidative (WG) p ortions of the gastrocnemius muscle of control (n = 17), AZT(n = 14), or dd I-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) rep lication and transcription. AZT had a pronounced effect on blood pressure a nd skeletal muscle performance, which were significantly decreased during c ontractile activity at 2 and 5 Hz, compared with control. A significant dec rease in CYTOX activity in heart and RG, but not WG muscles, was also evide nt. In the heart, this was accompanied by an apparent compensatory increase in mtTFA mRNA level that could not be attributed to enhanced transcription al activation mediated by nuclear respiratory factor I (NRF-1). In contrast with AZT, no effect of ddI was found on the extent of fatigue or muscle en zyme activity. These results indicate that AZT induces mitochondrial defect s primarily in muscles with the highest oxidative capacities (heart and RG) . The long-term effects of AZT on mitochondrial biogenesis have the potenti al to reduce muscle performance, but the effects on performance in this sho rtterm study were likely due to an inability of the AZT-treated animals to maintain blood pressure during contractile activity.