METABOLIC ABNORMALITIES IN SKELETAL-MUSCLE OF PATIENTS RECEIVING ZIDOVUDINE THERAPY OBSERVED BY P-31 IN-VIVO MAGNETIC-RESONANCE SPECTROSCOPY

Patients on long-term zidovudine (AZT) therapy experience muscle fatig ue and weakness attributed to AZT-induced mitochondrial toxicity in sk eletal muscle. To determine if the clinico-pathological abnormalities in these patients correspond to abnormal muscle energy metabolism, we used P-31 in vivo magnetic resonance spectroscopy to follow phosphoryl ated metabolites during exercise. We studied 19 normal volunteers, 6 H IV-positive patients never treated with AZT, and 9 HIV-positive patien ts who had been treated with AZT for a mean period of 33 mo (range 12- 48 mo) and had muscle biopsy-proven AZT-myopathy with abnormal mitocho ndria. Changes in phosphocreatine, ATP, and intracellular pH in the ga strocnemius muscle were followed during a graded steady state exercise protocol, and the recovery of phosphocreatine was followed on cessati on of exercise. We found that graded steady state exercise produced a greater depletion of muscle phosphocreatine levels in the AZT-treated patients, compared to either HIV-positive patients who were not treate d with AZT or normal controls. No differences in the effects of steady state exercise on muscle phosphocreatine levels mere observed between the control group and the HIV-positive patients who had not been trea ted with AZT. The results suggest that the effect of AZT on muscle ene rgy metabolism is significant, and similar to the effect observed in p atients with known mitochondrial myopathies. Using a well-known model for control of mitochondrial metabolism, the observed differences in s teady state phosphocreatine levels during exercise suggest that AZT tr eatment decreases the maximal work output and the maximal rate of musc le ATP synthesis.