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Maurer, J.* ; Zhao, X.* ; Irmler, M. ; Gudiksen, A.* ; Pilmark, N.S.* ; Li, Q.* ; Goj, T.* ; Beckers, J. ; Hrabě de Angelis, M. ; Birkenfeld, A.L. ; Peter, A. ; Lehmann, R. ; Pilegaard, H.* ; Karstoft, K.* ; Xu, G.* ; Weigert, C.

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

Am. J. Physiol.-Cell Physiol. 325, C1131-C1143 (2023)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Lactate ; Metformin ; Pyruvate Dehydrogenase Complex ; Respiration ; Skeletal Muscle; Respiratory Complex I; Skeletal-muscle; Lactic-acidosis; Dehydrogenase; Phosphorylation; Inhibition; Activation; Therapy
ISSN (print) / ISBN 0363-6143
e-ISSN 1522-1563
Journal American Journal of Physiology - Cell Physiology
Quellenangaben Volume: 325, Issue: 4, Pages: C1131-C1143 Article Number: , Supplement: ,
Publisher American Physiological Society
Publishing Place 6120 Executive Blvd, Suite 600, Rockville, Md, United States
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)
Institute of Experimental Genetics (IEG)
Grants King Christian X Foundation
Research Foundation of Rigshospitalet(Denmark)
Aase and Ejnar Danielsen Foundation
Key Foundation from the National Natural Science Foundation of China
Mobility Programme of the Sino-German Center for Research Promotion
German Federal Ministry of Education and Research (BMBF)