AZT DECREASES RAT MYOCARDIAL CYTOCHROME-OXIDASE ACTIVITY AND INCREASES BETA-MYOSIN HEAVY-CHAIN CONTENT

AZT a widely-utilized drug for the treatment of HIV infection, inhibit s the polymerase responsible for mitochondrial DNA replication (mtDNA) . The aim of this study was to assess myocardial alterations caused by this action. Ventricular muscle from rats treated for greater than or equal to 35 days with 1 mg/ml of AZT in their drinking water was anal ysed for cytochrome oxidase activity and the content of mRNAs for the nuclear-encoded cytochrome oxidase (COX) subunit VIc and the mitochond rial-encoded COX subunit III. In addition contractile protein expressi on was assessed by examining mRNA levels for alpha- and beta-myosin he avy chains (MHC). Changes in MHC mRNA levels were correlated with chan ges in alpha- and beta-MHC proteins and changes in myofibrillar ATPase activity. Results show that AZT caused a reduction in COX activity, C OX subunit III mRNA, and mtDNA levels. There was no decrease in the CO X subunit VIc mRNA. MHC expression was altered such that the relative content of beta-MHC protein and mRNA were increased. Accumulation of b eta-MHC was reflected in the reduction of myofibrillar ATPase activity at pCa values of 5.875 and 6.125. These data demonstrate that AZT ind uces a reorganization of cardiac gene expression indicative of changes in cardiac contractile properties. The observed decreases in mtDNA le vels along with mRNA for a mitochondrial-encoded protein and COX activ ity is consistent with the postulated mechanism whereby AZT induces a myopathy by diminishing mtDNA replication. (C) 1998 Academic Press.