Zidovudine-induced experimental myopathy: dual mechanism of mitochondrial damage.
Myopathy often complicates Zidovudine (AZT) treatment in patients with acquired 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 AZT does not cause in skeletal muscle true dystrophic lesions, but rather mitochondrial alterations confined to the fast fibers. In the same animal models, the biochemical analysis confirmed that mitochondria are the target of AZT toxicity in muscles. The effects of AZT on mitochondria energy transducing mechanisms were investigated in isolated mitochondria both in vivo and in vitro. Membrane potential abnormalities, due to a partial impairment of the respiratory chain capability observed in muscle mitochondria from AZT-treated rats, closely resemble those of control mitochondria in the presence of externally added AZT. mtDNA deletion analysis by PCR amplification and Southern blot analysis did not show any relevant deletion, while mtDNA depletion analysis demonstrated a significant decrease in mtDNA in AZT-treated rats. The present findings show that AZT causes damage to mitochondria by two mechanisms: a short-term mechanism that affects directly the respiratory chain, and a long-term mechanism that alters the mitochondrial DNA thus impairing the mitochondrial protein synthesis. In addition, the ultrastructural observations indicate that the fiber types are differently affected upon AZT treatment, which poses a number of questions as to the pathogenesis of this myopathy.
Masini
A
A
Dipartimento di Scienze Biomediche, Università di Modena, Italy.
Scotti
C
C
Calligaro
A
A
Cazzalini
O
O
Stivala
L A
LA
Bianchi
L
L
Giovannini
F
F
Ceccarelli
D
D
Muscatello
U
U
Tomasi
A
A
Vannini
V
V
D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects*; D004272:DNA, Mitochondrial / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D017240:Mitochondrial Myopathies / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015215:Zidovudine / Q000009:adverse effects*
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D015215:Zidovudine