Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy

Steen B Haugaard; Ove Andersen; Steen B Pedersen; Flemming Dela; Bjørn Richelsen; Jens Ole Nielsen; Sten Madsbad; Johan Iversen; Steen B Haugaard; Ove Andersen; Steen B Pedersen; Flemming Dela; Bjørn Richelsen; Jens Ole Nielsen; Sten Madsbad; Johan Iversen

doi:10.1002/jmv.20410

Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy

Steen B Haugaard, Ove Andersen, Steen B Pedersen, Flemming Dela, Bjørn Richelsen, Jens Ole Nielsen, Sten Madsbad, Johan Iversen, Steen B Haugaard, Ove Andersen, Steen B Pedersen, Flemming Dela, Bjørn Richelsen, Jens Ole Nielsen, Sten Madsbad, Johan Iversen

Department of Clinical Medicine

35 Citations (Scopus)

Abstract

The nucleoside reverse transcriptase inhibitors (NRTIs), especially stavudine, may deplete mitochondrial (mt) DNA in human tissues by inhibiting the mitochondrial polymerase gamma, a setting, which is associated with hyperlactatemia. The aim of the present study was to examine whether hyperlactatemia is associated with depletion of skeletal muscle (sm)-mtDNA and decreased oxidative capacity in HIV-infected patients on NRTI based highly active antiretroviral therapy (HAART) and whether HIV infection itself is associated with sm-mtDNA depletion. Sm-mtDNA was determined in 42 HIV-infected patients (35 patients on HAART including at least one NRTI (HIV-NRTI) and 7 patients never treated with antiretroviral drugs (NAIVE)) and 14 healthy controls. Whole body oxidative capacity (DeltaGOX) was estimated in HIV-infected patients by indirect calorimetry. Hyperlactatemia (>or=2.0 mM) was detected in six HIV-NRTI, who all used Stavudine (P < 0.01), displayed depleted sm-mtDNA (P < 0.02) and decreased DeltaGOX (P < 0.01) compared with normolactatemic HIV-NRTI (n = 29). NAIVE displayed decreased sm-mtDNA (P < 0.05), increased HIV-RNA (P < 0.01) and increased plasma TNF-alpha (P < 0.05) compared to all HIV-NRTI (n = 35), in turn displaying decreased sm-mtDNA (P < 0.01) compared to healthy controls. Thus, hyperlactatemia in HIV-NRTI may be associated with pronounced depletion of sm-mtDNA, decreased oxidative capacity and current stavudine therapy. Further, HIV may deplete sm-mtDNA of NAIVE, which in part could be mediated through an enhanced pro-inflammatory response.

Original language	English
Journal	Journal of Medical Virology
Volume	77
Issue number	1
Pages (from-to)	29-38
Number of pages	9
ISSN	0146-6615
DOIs	https://doi.org/10.1002/jmv.20410 https://doi.org/10.1002/jmv.20410
Publication status	Published - 2005

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Haugaard, S. B., Andersen, O., Pedersen, S. B., Dela, F., Richelsen, B., Nielsen, J. O., Madsbad, S., Iversen, J., Haugaard, S. B., Andersen, O., Pedersen, S. B., Dela, F., Richelsen, B., Nielsen, J. O., Madsbad, S., & Iversen, J. (2005). Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy. Journal of Medical Virology, 77(1), 29-38. https://doi.org/10.1002/jmv.20410, https://doi.org/10.1002/jmv.20410

Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy. / Haugaard, Steen B; Andersen, Ove; Pedersen, Steen B et al.

In: Journal of Medical Virology, Vol. 77, No. 1, 2005, p. 29-38.

Research output: Contribution to journal › Journal article › Research › peer-review

Haugaard, SB, Andersen, O, Pedersen, SB, Dela, F, Richelsen, B, Nielsen, JO, Madsbad, S, Iversen, J, Haugaard, SB, Andersen, O, Pedersen, SB, Dela, F, Richelsen, B, Nielsen, JO, Madsbad, S & Iversen, J 2005, 'Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy', Journal of Medical Virology, vol. 77, no. 1, pp. 29-38. https://doi.org/10.1002/jmv.20410, https://doi.org/10.1002/jmv.20410

@article{94091b605f2f11dea8de000ea68e967b,

title = "Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy",

abstract = "The nucleoside reverse transcriptase inhibitors (NRTIs), especially stavudine, may deplete mitochondrial (mt) DNA in human tissues by inhibiting the mitochondrial polymerase gamma, a setting, which is associated with hyperlactatemia. The aim of the present study was to examine whether hyperlactatemia is associated with depletion of skeletal muscle (sm)-mtDNA and decreased oxidative capacity in HIV-infected patients on NRTI based highly active antiretroviral therapy (HAART) and whether HIV infection itself is associated with sm-mtDNA depletion. Sm-mtDNA was determined in 42 HIV-infected patients (35 patients on HAART including at least one NRTI (HIV-NRTI) and 7 patients never treated with antiretroviral drugs (NAIVE)) and 14 healthy controls. Whole body oxidative capacity (DeltaGOX) was estimated in HIV-infected patients by indirect calorimetry. Hyperlactatemia (>or=2.0 mM) was detected in six HIV-NRTI, who all used Stavudine (P < 0.01), displayed depleted sm-mtDNA (P < 0.02) and decreased DeltaGOX (P < 0.01) compared with normolactatemic HIV-NRTI (n = 29). NAIVE displayed decreased sm-mtDNA (P < 0.05), increased HIV-RNA (P < 0.01) and increased plasma TNF-alpha (P < 0.05) compared to all HIV-NRTI (n = 35), in turn displaying decreased sm-mtDNA (P < 0.01) compared to healthy controls. Thus, hyperlactatemia in HIV-NRTI may be associated with pronounced depletion of sm-mtDNA, decreased oxidative capacity and current stavudine therapy. Further, HIV may deplete sm-mtDNA of NAIVE, which in part could be mediated through an enhanced pro-inflammatory response.",

author = "Haugaard, {Steen B} and Ove Andersen and Pedersen, {Steen B} and Flemming Dela and Bj{\o}rn Richelsen and Nielsen, {Jens Ole} and Sten Madsbad and Johan Iversen and Haugaard, {Steen B} and Ove Andersen and Pedersen, {Steen B} and Flemming Dela and Bj{\o}rn Richelsen and Nielsen, {Jens Ole} and Sten Madsbad and Johan Iversen",

note = "Keywords: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; DNA, Mitochondrial; Gene Deletion; HIV Infections; Humans; Lactic Acid; Middle Aged; Mitochondrial Diseases; Muscle, Skeletal; Oxidation-Reduction",

year = "2005",

doi = "10.1002/jmv.20410",

language = "English",

volume = "77",

pages = "29--38",

journal = "Journal of Medical Virology",

issn = "0146-6615",

publisher = "JohnWiley & Sons, Inc.",

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TY - JOUR

T1 - Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy

AU - Haugaard, Steen B

AU - Andersen, Ove

AU - Pedersen, Steen B

AU - Dela, Flemming

AU - Richelsen, Bjørn

AU - Nielsen, Jens Ole

AU - Madsbad, Sten

AU - Iversen, Johan

AU - Haugaard, Steen B

AU - Andersen, Ove

AU - Pedersen, Steen B

AU - Dela, Flemming

AU - Richelsen, Bjørn

AU - Nielsen, Jens Ole

AU - Madsbad, Sten

AU - Iversen, Johan

N1 - Keywords: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; DNA, Mitochondrial; Gene Deletion; HIV Infections; Humans; Lactic Acid; Middle Aged; Mitochondrial Diseases; Muscle, Skeletal; Oxidation-Reduction

PY - 2005

Y1 - 2005

N2 - The nucleoside reverse transcriptase inhibitors (NRTIs), especially stavudine, may deplete mitochondrial (mt) DNA in human tissues by inhibiting the mitochondrial polymerase gamma, a setting, which is associated with hyperlactatemia. The aim of the present study was to examine whether hyperlactatemia is associated with depletion of skeletal muscle (sm)-mtDNA and decreased oxidative capacity in HIV-infected patients on NRTI based highly active antiretroviral therapy (HAART) and whether HIV infection itself is associated with sm-mtDNA depletion. Sm-mtDNA was determined in 42 HIV-infected patients (35 patients on HAART including at least one NRTI (HIV-NRTI) and 7 patients never treated with antiretroviral drugs (NAIVE)) and 14 healthy controls. Whole body oxidative capacity (DeltaGOX) was estimated in HIV-infected patients by indirect calorimetry. Hyperlactatemia (>or=2.0 mM) was detected in six HIV-NRTI, who all used Stavudine (P < 0.01), displayed depleted sm-mtDNA (P < 0.02) and decreased DeltaGOX (P < 0.01) compared with normolactatemic HIV-NRTI (n = 29). NAIVE displayed decreased sm-mtDNA (P < 0.05), increased HIV-RNA (P < 0.01) and increased plasma TNF-alpha (P < 0.05) compared to all HIV-NRTI (n = 35), in turn displaying decreased sm-mtDNA (P < 0.01) compared to healthy controls. Thus, hyperlactatemia in HIV-NRTI may be associated with pronounced depletion of sm-mtDNA, decreased oxidative capacity and current stavudine therapy. Further, HIV may deplete sm-mtDNA of NAIVE, which in part could be mediated through an enhanced pro-inflammatory response.

AB - The nucleoside reverse transcriptase inhibitors (NRTIs), especially stavudine, may deplete mitochondrial (mt) DNA in human tissues by inhibiting the mitochondrial polymerase gamma, a setting, which is associated with hyperlactatemia. The aim of the present study was to examine whether hyperlactatemia is associated with depletion of skeletal muscle (sm)-mtDNA and decreased oxidative capacity in HIV-infected patients on NRTI based highly active antiretroviral therapy (HAART) and whether HIV infection itself is associated with sm-mtDNA depletion. Sm-mtDNA was determined in 42 HIV-infected patients (35 patients on HAART including at least one NRTI (HIV-NRTI) and 7 patients never treated with antiretroviral drugs (NAIVE)) and 14 healthy controls. Whole body oxidative capacity (DeltaGOX) was estimated in HIV-infected patients by indirect calorimetry. Hyperlactatemia (>or=2.0 mM) was detected in six HIV-NRTI, who all used Stavudine (P < 0.01), displayed depleted sm-mtDNA (P < 0.02) and decreased DeltaGOX (P < 0.01) compared with normolactatemic HIV-NRTI (n = 29). NAIVE displayed decreased sm-mtDNA (P < 0.05), increased HIV-RNA (P < 0.01) and increased plasma TNF-alpha (P < 0.05) compared to all HIV-NRTI (n = 35), in turn displaying decreased sm-mtDNA (P < 0.01) compared to healthy controls. Thus, hyperlactatemia in HIV-NRTI may be associated with pronounced depletion of sm-mtDNA, decreased oxidative capacity and current stavudine therapy. Further, HIV may deplete sm-mtDNA of NAIVE, which in part could be mediated through an enhanced pro-inflammatory response.

U2 - 10.1002/jmv.20410

DO - 10.1002/jmv.20410

M3 - Journal article

C2 - 16032748

SN - 0146-6615

VL - 77

SP - 29

EP - 38

JO - Journal of Medical Virology

JF - Journal of Medical Virology

IS - 1

ER -

Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy

Abstract

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