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9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV19-21 July 2007, Sydney, Australia |
URIDINE SUPPLEMENTATION WITH MITOCNOL ANTAGONIZES ZIDOVUDINE-INDUCED MITOCHONDRIAL MYOPATHY AND HYPERLACTATAEMIA IN VIVO
Antiviral Therapy 2007; 12(Suppl. 2):L26 (abstract no. P-07)
D Lebrecht1, C Deveaud2, B Beauvoit2, J Bonnet2, JB
Kirschner3 and UA Walker1,4
1Medizinische Universitätsklinik, Department of Rheumatology
and Clinical Immunology, Freiburg, Germany; 2Institut de
Biochimie et de Génétique Cellulaires, UMR 5095 CNRS-Université
Victor Ségalen Bordeaux cedex, France; 3Medizinische
Universitätsklinik, Department of Neuropediatrics and Muscle
Disorders, Freiburg, Germany; 4Basel University, Department of
Rheumatology, Basel, Switzerland
This poster abstract is also be presented as oral abstract O-23
OBJECTIVE: Zidovudine induces a mitochondrial myopathy in humans by interfering with the replication of mitochondrial DNA (mtDNA). We investigated if this form of myopathy is a class effect of antiretroviral nucleoside analogues and if muscle damage may be antagonized by uridine supplementation in vivo.
METHODS: Balb/c mice were fed with Mitocnol (340 mg/kg/day) a dietary supplement with high uridine bioavailability with or without zidovudine or zalcitabine. Skeletal muscle histology and mitochondrial functions were assessed after 12 weeks.
RESULTS: Zidovudine, unlike zalcitabine, induced a significant hyperlactataemia and mitochondrial myopathy with fiber thinning, depleted mtDNA, reduced levels of cytochrome c oxidase activity (COX) and mtDNA-encoded cytochrome c subunit I (COX I). Reactive oxygen species (malondialdehyde) were increased. Mitocnol had no side effects itself, but attenuated or fully normalized all muscle pathology (Table 1).
| Table 1. (Abstract O-23) | ||||||
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| Zidovudine | Zalcitabine | |||||
| Zidovudine | (100 mg/kg/day) | Zalcitabine | (13 mg/kg/day) | |||
| Control | Mitocnol | (100 mg/kg/day) | + Mitocnol | (13 mg/kg/day) | + Mitocnol | |
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| Muscle fibre diameter, µm | 18.2 ±1.2 | 20.2 ±0.5* | 13.3 ±1.3‡ | 17.1 ±1.2*§ | 18.2 ±1.5 | 18.5 ±1.8 |
| Fibre per 0.09 mm2 | 129 ±19 | 131 ±12 | 171 ±20‡ | 151 ±19*† | 148 ±26 | 125 ±21 |
| Oil-red O | – | – | +++ | + | – | – |
| Muscle lipids, mg lipid/mg tissue |
0.7 ±0.2 | 0.8 ±0.1 | 2.5 ±0.6‡ | 1.5 ±0.2‡§ | 0.8 ±0.1 | 0.9 ±0.2 |
| Fibre degeneration (PAS) | – | – | +++ | + | – | – |
| mtDNA copies, copies/myonucleus |
587 ±58 | 632 ±129 | 472 ±88* | 574 ±91† | 577 ±77 | 579 ±81 |
| COX activity, µmol/min/g protein |
29 ±4 | 26 ±14 | 15 ±8‡ | 23 ±7*† | 27 ±5 | 24 ±4 |
| COX/SDH-ratio % | 100 ±25 | 102 ±11 | 51 ±34* | 108 ±10 | 97 ±8 | 103 ±16 |
| COX I/COX IV-ratio (% of control) |
100 ±24 | 92 ±10 | 76 ±28* | 103 ±19† | 105 ±17 | 95 ±15 |
| Malondialdehyde, µmol/g tissue |
45 ±26 | 44 ±16 | 91 ±55* | 52 ±21† | 48 ±24 | 38 ±31 |
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| *P<0.05 versus controls; †versus no Mitocnol; ‡P<0.001 versus control; §versus no Mitocnol. | ||||||
CONCLUSION: Zidovudine, but not zalcitabine, induces a mitochondrial myopathy with thin muscle fibres and hyperlactataemia, both of which are antagonized by Mitocnol.
2007-07-24
P-07
Copyright © 2007 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Medical Editor, International Medical Press, 36 St Mary-at-Hill, London EC3R 8DU, United Kingdom.