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Skeletal muscle mitochondria from AZT-treated rats have a diminished response to chronic electrical stimulation
1Department of Physiology and Biophysics, University of Illinois at Chicago 60612, USA.
Abstract:
Inhibition of DNA polymerase gamma-function mediated by 3'-azido-3'-deoxythymidine (AZT) has been proposed to cause a myopathy by reducing mitochondrial DNA (mtDNA) replication. Repeated bouts of exercise stimulate an increase in mtDNA replication, mitochondrial content, and mitochondrial volume fraction. Therefore, adaptation of rat skeletal muscle [tibialis anterior (TA)] mitochondria exposed to AZT (1 mg/ml for 35 days) and then to electrical stimulation for 8 h/day (7, 14, 21 days) with continued AZT treatment was examined. Fourteen and 21 days of stimulation increased TA cytochrome oxidase (CO) activity, mtDNA, and CO subunit III and VIc mRNA levels in both groups. The TA CO activity and CO III mRNA increases after 14 and 21 days of stimulation were diminished in AZT-treated rats. TA glyceraldehyde-3-phosphate dehydrogenase was reduced in normal rats after chronic stimulation but was unchanged in AZT-treated rats. Chronic stimulation increased the mitochondrial volume fraction by 80 and 40% in normal and AZT-treated rats, respectively. These results indicate diminution, but not complete inhibition, of mitochondrial adaptation by AZT-treated skeletal muscle in response to stimulation.
Insights
3'-azido-3'-deoxythymidine (AZT) partially inhibits skeletal muscle mitochondrial adaptation to exercise. While exercise normally boosts mitochondrial DNA replication and content, AZT treatment reduced these adaptations in rat tibialis anterior muscle.
Area of Science:
- Exercise physiology
- Mitochondrial biology
- Pharmacology
Background:
- 3'-azido-3'-deoxythymidine (AZT) is known to inhibit DNA polymerase gamma, potentially impairing mitochondrial DNA (mtDNA) replication and causing myopathy.
- Exercise is a potent stimulus for mitochondrial biogenesis, increasing mtDNA replication, mitochondrial content, and volume fraction in skeletal muscle.
Purpose of the Study:
- To investigate the effects of AZT on the adaptive response of rat skeletal muscle mitochondria to chronic electrical stimulation.
- To determine if AZT treatment diminishes exercise-induced mitochondrial adaptations.
Main Methods:
- Rats were treated with AZT (1 mg/ml) for 35 days.
- Tibialis anterior (TA) muscles were subjected to electrical stimulation for 8 h/day over 7, 14, and 21 days, with continued AZT treatment.
- Mitochondrial adaptation markers including cytochrome oxidase (CO) activity, mtDNA levels, CO subunit mRNA, and mitochondrial volume fraction were assessed.
Main Results:
- Fourteen and 21 days of stimulation increased TA cytochrome oxidase (CO) activity, mtDNA, and CO subunit III and VIc mRNA levels in both normal and AZT-treated rats.
- However, the increases in TA CO activity and CO III mRNA were diminished in AZT-treated rats compared to normal rats.
- Chronic stimulation increased mitochondrial volume fraction by 80% in normal rats and 40% in AZT-treated rats, indicating a reduced adaptive capacity in the presence of AZT.
Conclusions:
- AZT treatment partially inhibits mitochondrial adaptation in skeletal muscle in response to chronic electrical stimulation.
- The findings suggest that AZT's impact on mitochondrial function does not completely abolish exercise-induced adaptations but significantly diminishes their extent.