Background:  Mitochondrial DNA (mtDNA) depletion has been proposed as an important factor leading to peripheral lipoatrophy in HIV-patients receiving ART. The extent to which mtDNA depletion occurs in other organs and tissue in humans has not been evaluated, and animal models for lipoatrophy have not yet been established.

Methods:  Groups of mice were treated with stavudine (d4T), zidovudine (AZT), or vehicle (5 to 20 mice per group) for as long as 15 weeks with daily human doses adjusted for murine body surface area. To better parallel the pharmacokinetics in humans, drugs were administered via oral gavage. MtDNA contend was determined by real-time polymerase chain reaction (RT-PCR) in liver, muscle, heart, brain, and fat tissue. Adiponectin and leptin were measured by ELISA in the serum.

Results:  Over a period of 15 weeks, mice receiving d4T or AZT gained less weight (d4T from 25.3±0.17 g to 29.1±0.2 g; AZT from 25.8±0.2 g to 30.2±0.2 g) than control animals (from 26.1±0.2 g to 34.8±0.2 g), while no differences in food and water intake were detected. Post mortem examination revealed that mice on AZT treatment, but particularly animals receiving d4T, had less of peripheral as well as central fat. Similarly, d4T-treated animals had lower serum adiponectin levels than control mice (2.62±0.1 µg/mL vs 3.05±0.1 µg/mL, p <0.05) and lower serum leptin concentrations (222.5±72.5 mg/mL vs 621.8±166 mg/mL). Analysis of mtDNA content revealed depletion of mtDNA in organs including the brain (–20%) and fat tissue (–27%), but the most profound and significant depletions were evident in muscle (–56%), liver (–64%), and heart (–45%).

Conclusions:  This is the first study to show fat loss and hypoadiponectinema in mice after treatment with thymidine-analogs. Long-term treatment of mice with d4T led to mtDNA depletion that was not restricted to fat tissue. These data indicate that mtDNA depletion is an unspecific event during treatment with thymidine-analogs. If indeed mtDNA depletion is a major contributor to mitochondrial dysfunction, potential long-term toxicities in various organs must be considered.