Zidovudine-induced experimental myopathy: dual mechanism of mitochondrial damage

Myopathy often complicates Zidovudine (AZT) treatment in patients with acqu ired immunodeficiency syndrome (AIDS). The pathogenesis of the myopathy is controversial, since clinical phenomena intrinsic to AIDS may interfere per se with the onset of the myopathy. In the present work we investigated the in vivo effect of AZT in an animal model species (rat) not susceptible to HIV infection. Histochemical and electron microscopic analyses demonstrated that, under the experimental conditions used, the in vivo treatment with A ZT does not cause in skeletal muscle true dystrophic lesions, but rather mi tochondrial alterations confined to the fast fibers, In the same animal mod els. the biochemical analysis confirmed that mitochondria are the target of AZT toxicity in muscles. The effects of AZT on mitochondria energy transdu cing mechanisms were investigated in isolated mitochondria both in vivo and in vitro. Membrane potential abnormalities, due to a pal tial impairment o f the respiratory chain capability observed in muscle mitochondria from AZT -treated rats, closely resemble those of control mitochondria in the presen ce of externally added AZT. mtDNA deletion analysis by PCR amplification an d Southern blot analysis did not show any relevant deletion, while mtDNA de pletion analysis demonstrated a significant decrease in mtDNA in AZT-treate d rats. The present findings show that AZT causes damage to mitochondria by two mechanisms: a short-term mechanism that affects directly the respirato ry chain, and a long-term mechanism that alters the mitochondrial DNA thus impairing the mitochondrial protein synthesis, In addition, the ultrastruct ural observations indicate that the fiber types are differently affected up on AZT treatment, which poses a number of questions as to the pathogenesis of this myopathy. (C) 1999 Elsevier Science B.V. All rights reserved.