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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Physiological Society
2023
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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. |
format | Online Article Text |
id | pubmed-10635655 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Physiological Society |
record_format | MEDLINE/PubMed |
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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