Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes

Metformin-induced glycolysis and lactate production can lead to acidosis as a life-threatening side effect, but slight increases in blood lactate levels in a physiological range were also reported in metformin-treated patients. However, how metformin increases systemic lactate concentrations is only...

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Autores principales: Maurer, Jennifer, Zhao, Xinjie, Irmler, Martin, Gudiksen, Anders, Pilmark, Nanna S., Li, Qi, Goj, Thomas, Beckers, Johannes, Hrabě de Angelis, Martin, Birkenfeld, Andreas L., Peter, Andreas, Lehmann, Rainer, Pilegaard, Henriette, Karstoft, Kristian, Xu, Guowang, Weigert, Cora
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Physiological Society 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635655/
https://www.ncbi.nlm.nih.gov/pubmed/37694284
http://dx.doi.org/10.1152/ajpcell.00186.2023
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author Maurer, Jennifer
Zhao, Xinjie
Irmler, Martin
Gudiksen, Anders
Pilmark, Nanna S.
Li, Qi
Goj, Thomas
Beckers, Johannes
Hrabě de Angelis, Martin
Birkenfeld, Andreas L.
Peter, Andreas
Lehmann, Rainer
Pilegaard, Henriette
Karstoft, Kristian
Xu, Guowang
Weigert, Cora
author_facet Maurer, Jennifer
Zhao, Xinjie
Irmler, Martin
Gudiksen, Anders
Pilmark, Nanna S.
Li, Qi
Goj, Thomas
Beckers, Johannes
Hrabě de Angelis, Martin
Birkenfeld, Andreas L.
Peter, Andreas
Lehmann, Rainer
Pilegaard, Henriette
Karstoft, Kristian
Xu, Guowang
Weigert, Cora
author_sort Maurer, Jennifer
collection PubMed
description Metformin-induced glycolysis and lactate production can lead to acidosis as a life-threatening side effect, but slight increases in blood lactate levels in a physiological range were also reported in metformin-treated patients. However, how metformin increases systemic lactate concentrations is only partly understood. Because human skeletal muscle has a high capacity to produce lactate, the aim was to elucidate the dose-dependent regulation of metformin-induced lactate production and the potential contribution of skeletal muscle to blood lactate levels under metformin treatment. This was examined by using metformin treatment (16–776 μM) of primary human myotubes and by 17 days of metformin treatment in humans. As from 78 µM, metformin induced lactate production and secretion and glucose consumption. Investigating the cellular redox state by mitochondrial respirometry, we found metformin to inhibit the respiratory chain complex I (776 µM, P < 0.01) along with decreasing the [NAD(+)]:[NADH] ratio (776 µM, P < 0.001). RNA sequencing and phospho-immunoblot data indicate inhibition of pyruvate oxidation mediated through phosphorylation of the pyruvate dehydrogenase (PDH) complex (39 µM, P < 0.01). On the other hand, in human skeletal muscle, phosphorylation of PDH was not altered by metformin. Nonetheless, blood lactate levels were increased under metformin treatment (P < 0.05). In conclusion, the findings suggest that metformin-induced inhibition of pyruvate oxidation combined with altered cellular redox state shifts the equilibrium of the lactate dehydrogenase (LDH) reaction leading to a dose-dependent lactate production in primary human myotubes. NEW & NOTEWORTHY Metformin shifts the equilibrium of lactate dehydrogenase (LDH) reaction by low dose-induced phosphorylation of pyruvate dehydrogenase (PDH) resulting in inhibition of pyruvate oxidation and high dose-induced increase in NADH, which explains the dose-dependent lactate production of differentiated human skeletal muscle cells.
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spelling pubmed-106356552023-11-15 Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes Maurer, Jennifer Zhao, Xinjie Irmler, Martin Gudiksen, Anders Pilmark, Nanna S. Li, Qi Goj, Thomas Beckers, Johannes Hrabě de Angelis, Martin Birkenfeld, Andreas L. Peter, Andreas Lehmann, Rainer Pilegaard, Henriette Karstoft, Kristian Xu, Guowang Weigert, Cora Am J Physiol Cell Physiol Research Article Metformin-induced glycolysis and lactate production can lead to acidosis as a life-threatening side effect, but slight increases in blood lactate levels in a physiological range were also reported in metformin-treated patients. However, how metformin increases systemic lactate concentrations is only partly understood. Because human skeletal muscle has a high capacity to produce lactate, the aim was to elucidate the dose-dependent regulation of metformin-induced lactate production and the potential contribution of skeletal muscle to blood lactate levels under metformin treatment. This was examined by using metformin treatment (16–776 μM) of primary human myotubes and by 17 days of metformin treatment in humans. As from 78 µM, metformin induced lactate production and secretion and glucose consumption. Investigating the cellular redox state by mitochondrial respirometry, we found metformin to inhibit the respiratory chain complex I (776 µM, P < 0.01) along with decreasing the [NAD(+)]:[NADH] ratio (776 µM, P < 0.001). RNA sequencing and phospho-immunoblot data indicate inhibition of pyruvate oxidation mediated through phosphorylation of the pyruvate dehydrogenase (PDH) complex (39 µM, P < 0.01). On the other hand, in human skeletal muscle, phosphorylation of PDH was not altered by metformin. Nonetheless, blood lactate levels were increased under metformin treatment (P < 0.05). In conclusion, the findings suggest that metformin-induced inhibition of pyruvate oxidation combined with altered cellular redox state shifts the equilibrium of the lactate dehydrogenase (LDH) reaction leading to a dose-dependent lactate production in primary human myotubes. NEW & NOTEWORTHY Metformin shifts the equilibrium of lactate dehydrogenase (LDH) reaction by low dose-induced phosphorylation of pyruvate dehydrogenase (PDH) resulting in inhibition of pyruvate oxidation and high dose-induced increase in NADH, which explains the dose-dependent lactate production of differentiated human skeletal muscle cells. American Physiological Society 2023-10-01 2023-09-11 /pmc/articles/PMC10635655/ /pubmed/37694284 http://dx.doi.org/10.1152/ajpcell.00186.2023 Text en The Authors. https://creativecommons.org/licenses/by/4.0/Licensed under Creative Commons Attribution CC-BY 4.0 (https://creativecommons.org/licenses/by/4.0/) . Published by the American Physiological Society.
spellingShingle Research Article
Maurer, Jennifer
Zhao, Xinjie
Irmler, Martin
Gudiksen, Anders
Pilmark, Nanna S.
Li, Qi
Goj, Thomas
Beckers, Johannes
Hrabě de Angelis, Martin
Birkenfeld, Andreas L.
Peter, Andreas
Lehmann, Rainer
Pilegaard, Henriette
Karstoft, Kristian
Xu, Guowang
Weigert, Cora
Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes
title Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes
title_full Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes
title_fullStr Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes
title_full_unstemmed Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes
title_short Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes
title_sort redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635655/
https://www.ncbi.nlm.nih.gov/pubmed/37694284
http://dx.doi.org/10.1152/ajpcell.00186.2023
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