Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes
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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.
In: American Journal of Physiology: Cell Physiology, Vol. 325, No. 4, 2023, p. C1131-C1143.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes
AU - Maurer, Jennifer
AU - Zhao, Xinjie
AU - Irmler, Martin
AU - Gudiksen, Anders
AU - Pilmark, Nanna S.
AU - Li, Qi
AU - Goj, Thomas
AU - Beckers, Johannes
AU - Hrabě De Angelis, Martin
AU - Birkenfeld, Andreas L.
AU - Peter, Andreas
AU - Lehmann, Rainer
AU - Pilegaard, Henriette
AU - Karstoft, Kristian
AU - Xu, Guowang
AU - Weigert, Cora
PY - 2023
Y1 - 2023
N2 - Metformin-induced glycolysis and lactate production can lead to acidosis as a life-threatening side effect, but slight increases inblood lactate levels in a physiological range were also reported in metformin-treated patients. However, how metforminincreases systemic lactate concentrations is only partly understood. Because human skeletal muscle has a high capacity to pro-duce lactate, the aim was to elucidate the dose-dependent regulation of metformin-induced lactate production and the potentialcontribution of skeletal muscle to blood lactate levels under metformin treatment. This was examined by using metformin treat-ment (16–776μM) of primary human myotubes and by 17 days of metformin treatment in humans. As from 78lM, metformininduced lactate production and secretion and glucose consumption. Investigating the cellular redox state by mitochondrial respir-ometry, we found metformin to inhibit the respiratory chain complex I (776lM,P<0.01) along with decreasing the [NADþ]:[NADH] ratio (776lM,P<0.001). RNA sequencing and phospho-immunoblot data indicate inhibition of pyruvate oxidation medi-ated through phosphorylation of the pyruvate dehydrogenase (PDH) complex (39lM,P<0.01). On the other hand, in humanskeletal muscle, phosphorylation of PDH was not altered by metformin. Nonetheless, blood lactate levels were increased undermetformin treatment (P<0.05). In conclusion, thefindings suggest that metformin-induced inhibition of pyruvate oxidation com-bined with altered cellular redox state shifts the equilibrium of the lactate dehydrogenase (LDH) reaction leading to a dose-de-pendent lactate production in primary human myotubes.
AB - Metformin-induced glycolysis and lactate production can lead to acidosis as a life-threatening side effect, but slight increases inblood lactate levels in a physiological range were also reported in metformin-treated patients. However, how metforminincreases systemic lactate concentrations is only partly understood. Because human skeletal muscle has a high capacity to pro-duce lactate, the aim was to elucidate the dose-dependent regulation of metformin-induced lactate production and the potentialcontribution of skeletal muscle to blood lactate levels under metformin treatment. This was examined by using metformin treat-ment (16–776μM) of primary human myotubes and by 17 days of metformin treatment in humans. As from 78lM, metformininduced lactate production and secretion and glucose consumption. Investigating the cellular redox state by mitochondrial respir-ometry, we found metformin to inhibit the respiratory chain complex I (776lM,P<0.01) along with decreasing the [NADþ]:[NADH] ratio (776lM,P<0.001). RNA sequencing and phospho-immunoblot data indicate inhibition of pyruvate oxidation medi-ated through phosphorylation of the pyruvate dehydrogenase (PDH) complex (39lM,P<0.01). On the other hand, in humanskeletal muscle, phosphorylation of PDH was not altered by metformin. Nonetheless, blood lactate levels were increased undermetformin treatment (P<0.05). In conclusion, thefindings suggest that metformin-induced inhibition of pyruvate oxidation com-bined with altered cellular redox state shifts the equilibrium of the lactate dehydrogenase (LDH) reaction leading to a dose-de-pendent lactate production in primary human myotubes.
U2 - 10.1152/ajpcell.00186.2023
DO - 10.1152/ajpcell.00186.2023
M3 - Journal article
C2 - 37694284
VL - 325
SP - C1131-C1143
JO - American Journal of Physiology: Cell Physiology
JF - American Journal of Physiology: Cell Physiology
SN - 0363-6143
IS - 4
ER -
ID: 372326478