7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 13–16 November 2005, Dublin, Ireland

Muscle mitochondrial DNA and RNA copy number/cell are reduced in treatment-naïve HIV-infected people, regardless of glucose in/tolerance

D Reeds¹, WT Cade¹, A Becker¹, S Mohammed¹, WG Powderly¹, MP de Baar², E de Rooij² and KE Yarasheski^1
1Washington University School of Medicine, St. Louis, MO, USA; ²Primagen, Amsterdam, The Netherlands

Antiviral Therapy 2005; Supplement 3:L14 (abstract no. 20)

BACKGROUND: Mitochondrial DNA (mtDNA) depletion may be a mediator of metabolic syndromes in HIV-infected people treated with highly active antiretroviral therapy (HAART). Skeletal muscle is mt-rich and the primary site for glucose disposal.

HYPOTHESIS: Muscle mtDNA depletion is associated with HIV-metabolic syndromes.

METHODS: We quantified muscle mtDNA and mtRNA copy number per cell in vastus lateralis muscle samples (10mg) obtained after an overnight fast from 13 HIV-infected subjects with impaired glucose tolerance (HIV+IGT), 10 HIV+ with normal glucose tolerance (HIV+NGT), 12 HIV-seronegative controls (CTRL), and correlated these with parameters of glucose lipid, and amino acid metabolism measured during a hyperinsulinaemic– euglycaemic clamp, NRTI use and serum markers of inflammation.

RESULTS: In comparison with CTRL, muscle mtRNA and mtDNA copies/cell were lower (P<0.05) in HIV+NGT (–40 and –23%) and HIV+IGT (–38 and –29%), but not different between HIV+NGT and HIV+IGT. In comparison with CTRL, muscle mtRNA and mtDNA copies/cell were lower in treatment-naïve subjects and those on AZT- 3TC- or d4T-ddI-based regimens, but similar among these HIV-infected participants. Non-parametric bivariate correlations suggested that muscle mtRNA copies/cell was modestly associated with the duration of HIV-infection (r=–0.34, P=0.016), serum C-reactive protein levels (r=–0.40, P=0.007), and mildly associated with glucose disposal parameters (carbohydrate oxidation; r=0.20, P=0.09, and insulin sensitivity; r=0.23, P=0.06). For mtDNA, non-parametric bivariate correlations were modest for serum triglycerides (r=–0.36, P=0.003), total cholesterol (r=–0.34, P=0.004), and serum IL-6 levels (r=–0.36, P=0.01), and mild for glucose disposal rate measured at high insulin levels (570–660 pM; r=0.23, P=0.06).

CONCLUSIONS: Lower mtDNA and mtRNA levels predict a reduced capacity of muscle mt to synthesize proteins, regardless of glucose in/tolerance status. Although not definitive in this cross-sectional study, the mediator(s) of muscle mtDNA and mtRNA depletion appear more related to HIV-associated factors and less related to metabolic syndromes or HAART components.

Acknowledgements: Supported by the NIH and Primagen.

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2005-11-13
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