Abstract
Erythrocytes are the key target in 5′-AMP induced hypometabolism. To understand how regulation of endogenous erythrocyte AMP levels modulates systemic metabolism, we generated mice deficient in both CD73 and AMPD3, the key catabolic enzymes for extracellular and intra-erythrocyte AMP, respectively. Under physiological conditions, these mice displayed enhanced capacity for physical activity accompanied by significantly higher food and oxygen consumption, compared to wild type mice. Erythrocytes from Ampd3−/− mice exhibited higher half-saturation pressure of oxygen (p50) and about 3-fold higher levels of ATP and ADP, while they maintained normal 2,3-bisphosphoglycerate (2,3-BPG), methemoglobin levels and intracellular pH. The affinity of mammalian hemoglobin for oxygen is thought to be regulated primarily by 2,3-BPG levels and pH (the Bohr effect). However, our results show that increased endogenous levels of ATP and ADP, but not AMP, directly increase the p50 value of hemoglobin. Additionally, the rise in erythrocyte p50 directly correlates with an enhanced capability of systemic metabolism.
Highlights
We have previously proposed that oxygen transport was disrupted by adenosine monophosphate (AMP)-uptake, which led us to ask whether these effects could be investigated by blocking AMP degradation in erythrocytes
We reported that AMP deaminase (AMPD) enzymatic activities were present in all tissues of Ampd3−/− mice except the erythrocytes and that Ampd3−/− mice were much more sensitive to AMP induced hypometabolism (AIHM), supporting our previous findings that erythrocytes are the cellular initiators of AIHM
The actograms revealed that wheel running activities for Ampd3−/−/Cd73−/− mice appeared largely continuous during zeitgeber time (ZT) 12–24, unlike the other genotypes, whose periods of activity were interrupted by periods of rest
Summary
We have previously proposed that oxygen transport was disrupted by AMP-uptake, which led us to ask whether these effects could be investigated by blocking AMP degradation in erythrocytes. Intracellular AMP is catabolized by two established pathways, dephosphorylation by cytosolic 5′ -nucleotidase to adenosine, or deamination to IMP by AMP deaminase (AMPD)[9]. We observed that the AIHM effect was more pronounced in the Cd73−/− mice[2] These findings led us to ask whether the loss of both CD73 and AMPD3 would lead to increased erythrocyte physiological adenine nucleotides levels, which could alter erythrocyte oxygen transport function. We observed that an increase in endogenous concentrations of adenine nucleotides, ATP, in AMPD3 deficient erythrocytes is sufficient to decrease Hb affinity for oxygen. This is reflected in corresponding increases in p50 values in Ampd3−/− erythrocytes. The lower affinity for oxygen in erythrocytes increased the delivery of oxygen to tissues, especially working muscle, allowing Ampd3−/−/Cd73−/− mice to maintain high metabolic activities over longer periods during wheel-running
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