Jan Peetz

• The heart is reported to show a net consumption of lactate. This may contribute up to 15% to the total body lactate disposal. In this work, the consumption of lactate was shown for the first time on the single cell level with the new FRET-based lactate sensor Laconic. Research published until today, almost exclusively reports the monocarboxylate transporter 1 (MCT1) as the transporter responsible for myocardial lactate uptake. As this membrane transporter transports lactate together with H+ in a stoichiometry of 1:1, lactate transport is coupled to pH regulation. Consequently, interactions of MCT1 and acid/base regulating proteins (carbonic anhydrases (CAs and sodium bicarbonate co-transporters (NBCs)) are described in the oocyte expression system, skeletal muscle and cancer cells. In this work it is shown that activity of extracellular CA increases lactate uptake into mouse cardiomyocytes by 27% and lactate induced JA/B by 42.8% to 46.2%. This effect is most likely mediated via NBC/CA interaction because inhibition of extracellular CA reduces HCO3-- dependent acid extruding JA/B by 53.3% to 78.4%. This may link lactate uptake to cellular respiration. When lactate was applied in medium gassed with 100% N2, lactate induced acidification was 12.6% faster than in medium gassed with 100% O2. Thus, CO2 produced on the pathway transferring redox energy from substrates like glucose and lactate to ADP and phosphate via oxidative phosphorylation, may support further lactate uptake. The findings of this work suggest an auto regulation of lactate uptake via CO2 release in ventricular mouse cardiomyocytes.