Metabolic abnormalities in skeletal muscle of patients receiving zidovudine therapy observed by 31P in vivo magnetic resonance spectroscopy.

Abstract

Patients on long-term zidovudine (AZT) therapy experience muscle fatigue and weakness attributed to AZT-induced mitochondrial toxicity in skeletal muscle. To determine if the clinico-pathological abnormalities in these patients correspond to abnormal muscle energy metabolism, we used 31P in vivo magnetic resonance spectroscopy to follow phosphorylated metabolites during exercise. We studied 19 normal volunteers, 6 HIV-positive patients never treated with AZT, and 9 HIV-positive patients 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 mitochondria. Changes in phosphocreatine, ATP, and intracellular pH in the gastrocnemius muscle were followed during a graded steady state exercise protocol, and the recovery of phosphocreatine was followed on cessation of exercise. We found that graded steady state exercise produced a greater depletion of muscle phosphocreatine levels in the AZTtreated patients, compared to either HIV-positive patients who were not treated with AZT or normal controls. No differences in the effects of steady state exercise on muscle phosphocreatine levels were observed between the control group and the HIV-positive patients who had not been treated with AZT. The results suggest that the effect of AZT on muscle energy metabolism is significant, and similar to the effect observed in patients with known mitochondrial myopathies. Using a well-known model for control of mitochondrial metabolism, the observed differences in steady state phosphocreatine levels during exercise suggest that AZT treatment decreases the maximal work output and the maximal rate of muscle ATP synthesis. (J. Clin. Invest. 1995. 96:126-131.)

3′-Azido-3′-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: A possible mechanism of AZT hepatotoxicity

“…During the pre-highly active antiretroviral therapy (HAART) era, AZT monotherapy in AIDS patients was closely associated with myopathy, cardiomyopathy, and hepatotoxicity [1][2][3][4][5][6][7][8][9][10]. Subsequent work in HIV negative rat models treated with AZT confirmed the presence of the same type of toxicities in the rat [11,15].…”

“…AZT capitalizes on human immunodeficiency virus's (HIV) unique method of replication by inhibiting the viral reverse transcriptase, which blocks the life-cycle of HIV and effectively slows the progression of AIDS. When given in monotherapy at high doses over long periods of time, AZT is known to cause damage to many tissues, including a mitochondrial skeletal muscle myopathy, a dilated cardiomyopathy, and hepatotoxicity [1][2][3][4][5][6][7][8][9][10][11]. These conditions are related to AZT use and not to the progression of AIDS since when patients experiencing one or more of these adverse effects discontinued AZT therapy, the adverse effects would resolve [8,9].…”

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

“…A high lactate/pyruvate ratio (consistent with abnormal mitochondrial function) is seen in the blood of patients with AZT myopathy (Chariot et al, 1994). Assessment of muscle metabolism in vivo using magnetic resonance spectroscopy shows marked phosphocreatine depletion with slow recovery only in AZT-treated, HIV-positive patients (Sinnwell et al, 1995).…”

“…These changes occur after prolonged therapy (Bessen et al, 1988). Exercise decreases muscle phosphocreatine (detected by 31 P nuclear magnetic resonance) in AZT-treated patients (Sinnwell et al, 1995). Abnormal mitochondrial respiratory function is found.…”

“…The accessory subunit provides tighter DNA binding of the complex, thus allowing highly processive DNA synthesis . Dalakas et al, 1990Arnaudo et al, 1991Chattha et al, 1993d'Amati et al, 1992Freiman et al, 1993Herskowitz et al, 1992Jolliet and Widmann, 1990 Kohler and Lewis, 1998Lewis and Dalakas, 1995Lewis et al, 2000Lipshultz et al, 2000Sinnwell et al, 1995 Decreased mtDNA in vitro. Decreased mtDNA, mtRNA, mitochondrial polypeptides, and mitochondrial ultrastructural damage in vivo.…”