Zidovudine [AZT] myotoxicity: Quantitative separation of AZT effects on proliferation and differentiation of muscle cells in vitro. Lack of myotoxicity potentiation by retrovirus

We compared quantitatively the myotoxicity of 3'-azido-2', 3'-dideoxythymid ine (AZT) against uninfected and ts1 retrovirus infected mouse skeletal mus cle (ATCC CRL 1772) cells at different stages of maturation in vitro. The A ZT half inhibitory concentration (IC50) for myoblast proliferation was dete rmined for uninfected myoblasts and parallel cultures infected with ts1 vir us. The AZT IC50d for muscle cell differentiation was determined in culture s where myoblasts were grown to confluence and then changed to the fusion m edium to which AZT was added at increasing concentrations. Creatine kinase activity was used as a marker of muscle cell differentiation and was determ ined in homogenates after 7 days. Total cellular mitochondrial DNA was anal yzed by Southern blotting. The estimated AZT IC50 for muscle cell prolifera tion (2-5 mu M) was significantly less than the AZT IC50 for muscle cell di fferentiation (100 mu M). infection with ts1 retrovirus did not significant ly shift the IC50 for either proliferation or differentiation of muscle cel ls. Toxic concentrations of AZT did not cause selective depletion of mitoch ondrial DNA. The myotoxic effects of AZT on myoblast proliferation and musc le cell differentiation in vitro were quantitatively different and were not changed by productive ts I retrovirus infection of muscle cells. These res ults suggest that AZT may impair muscle fiber regeneration in the course of retrovirus associated myopathy. The mechanism of AZT myotoxicity was not e xplained by alterations in total mitochondrial DNA content. (C) 1999 Intox Press, Inc.