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Skeletal muscle mitochondrial dysfunction in contemporary antiretroviral therapy: a single cell analysis

Hunt, Matthew; Mcniff, Megan M; Vincent, Amy E; Sabin, Caroline; Winston, Alan; Payne, Brendan AI; (2022) Skeletal muscle mitochondrial dysfunction in contemporary antiretroviral therapy: a single cell analysis. AIDS , 36 (14) pp. 1927-1934. 10.1097/QAD.0000000000003334. Green open access

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Abstract

OBJECTIVE: To quantify mitochondrial function in skeletal muscle of people treated with contemporary antiretroviral therapy. DESIGN: Cross-sectional observational study. METHODS: Quantitative multiplex immunofluorescence was performed to determine mitochondrial mass and respiratory chain complex abundance in individual myofibres from tibialis anterior biopsies. Individual myofibres were captured by laser microdissection and mitochondrial DNA (mtDNA) content and large-scale deletions were measured by real-time PCR. RESULTS: Forty five antiretroviral therapy (ART) treated people with HIV (PWH, mean age 58 years, mean duration of ART 125 months) were compared with 15 HIV negative age-matched controls. Mitochondrial complex I (CI) deficiency was observed at higher proportional levels in PWH than negative controls (P = 0.008). Myofibre mitochondrial mass did not differ by HIV status.No ART class was significantly associated with mitochondrial deficiency, including prior exposure to historical NRTIs (nucleoside analogue reverse transcriptase inhibitors) associated with systemic mitochondrial toxicity.To exclude an effect of untreated HIV, we also studied skeletal muscle from 13 ART-naïve PWH (mean age 37). These showed negligible CI defects, as well as comparable myofibre mitochondrial mass to ART-treated PWH.Most CI-deficient myofibres contained mtDNA deletions. No mtDNA depletion was detected. CONCLUSION: Here, we show that PWH treated with contemporary ART have mitochondrial dysfunction in skeletal muscle, exceeding that expected due to age alone. Surprisingly, this was not mediated by prior exposure to mitochondrially toxic NRTIs, suggesting novel mechanisms of mitochondrial dysfunction in contemporary ART-treated PWH. These findings are relevant for better understanding successful ageing in PWH.

Type: Article
Title: Skeletal muscle mitochondrial dysfunction in contemporary antiretroviral therapy: a single cell analysis
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1097/QAD.0000000000003334
Publisher version: https://doi.org/10.1097/QAD.0000000000003334
Language: English
Additional information: This research was funded in part, by the Wellcome Trust [109975/Z/15/Z, 203105/Z/16/Z, 215888/Z/19/Z, authors BP and AV]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute for Global Health > Infection and Population Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute for Global Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10153376
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