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

Metformin-induced lactate production can lead to lactate acidosis as life-threatening side effect, whereas lactate in a physiological range might also be involved in the therapeutic effect. How metformin increases systemic lactate concentrations is only partly understood. Since human skeletal muscle has a high capacity to produce lactate, we aim to elucidate the potential contribution of skeletal muscle and the dose-dependent regulation of metformin-induced lactate production in primary human myotubes after 48 h of metformin treatment (16-776 μM). At 78 µM, metformin induced lactate production 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 a decreased [NAD+]:[NADH] ratio (776 µM, p<0.001). RNA sequencing and phospho-immunoblot data indicate inhibition of pyruvate oxidation mediated through phosphorylation of PDH complex (39 µM, p<0.01). In vivo in human skeletal muscle, we found pyruvate metabolism altered by exercise and not by metformin. Nonetheless, blood lactate levels in the pre-exercise condition are increased under metformin treatment (p<0.05). Metformin-induced inhibition of pyruvate oxidation combined with altered cellular redox state, both shift the equilibrium of the LDH reaction leading to enhanced lactate production of human myotubes. Primary human myoblasts treated with 16 – 776 µM metformin for 48 h.