Biochemical and mechanistic aspects into how various hypometabolic states are initiated in mammals are poorly understood. Here, we show how a state of hypometabolism is initiated by 5-AMP uptake by erythrocytes. Wild type, ecto-5-nucleotidase-deficient, and adenosine receptor-deficient mice undergo 5-AMP-induced hypometabolism in a similar fashion. Injection of 5-AMP leads to two distinct declining phases of oxygen consumption (VO 2 ). The phase I response displays a rapid and steep decline in VO 2 that is independent of body temperature (T b ) and ambient temperature (T a ). It is followed by a phase II decline that is linked to T b and moderated by T a . Altering the dosages of 5-AMP from 0.25-to 2-fold does not change the phase I response. For mice, a T a of 15°C is effective for induction of DH with the appropriate dose of 5-AMP. Erythrocyte uptake of 5-AMP leads to utilization of ATP to synthesize ADP. This is accompanied by increased glucose but decreased lactate levels, suggesting that glycolysis has slowed. Reduction in glycolysis is known to stimulate erythrocytes to increase intracellular levels of 2,3-bisphosphoglycerate, a potent allosteric inhibitor of hemoglobin's affinity for oxygen. Our studies showed that both 2,3-bisphosphoglycerate and deoxyhemoglobin levels rose following 5-AMP administration and is in parallel with the phase I decline in VO 2 . In summary, our investigations reveal that 5-AMP mediated hypometabolism is probably triggered by reduced oxygen transport by erythrocytes initiated by uptake of 5-AMP. Mammals in deep hypometabolism (DH)5 with severe hypothermia and stupor are only observed naturally during hibernation (1). During hibernation, an animal's overall metabolic rate, based on oxygen consumption, is a small fraction of its euthermic needs. The biochemical event that triggers this hypometabolism is an enigma. It is thought that non-hibernating mammals cannot undertake a similar hypometabolic process because deep hypothermia is often associated with ventricular fibrillation and cardiac arrest.However, organs from non-hibernators can withstand a considerable ischemic period in a hypometabolic state. For example, during human organ transplantation, donated organs are transported in a cold ischemic state in the complete absence of blood circulation for many h (2), yet when implanted into a recipient, the restoration of blood flow and rewarming revives full organ function. This phenomenon also illustrates the important role of oxygen transportation by erythrocytes in metabolic activity. In addition, observations that exsanguination and prolonged hypoxia can result in hypothermia further demonstrate the importance of oxygen transportation and availability as factors that can modulate the metabolic rate in mammals (3, 4).We have demonstrated that the metabolite 5Ј-AMP can induce mice to undergo transient hypometabolism with T b as low as 26°C, similar to a torpor-like state (5). The T b of animals in torpor is defined to be at or moderately below 31°C (6). Here, we demonstrate tha...
A hypometabolic state can be induced in mice by 5′-AMP administration. Previously we proposed that an underlying mechanism for this hypometabolism is linked to reduced erythrocyte oxygen transport function due to 5′-AMP uptake altering the cellular adenylate equilibrium. To test this hypothesis, we generated mice deficient in adenosine monophosphate deaminase 3 (AMPD3), the key catabolic enzyme for 5′-AMP in erythrocytes. Mice deficient in AMPD3 maintained AMPD activities in all tissues except erythrocytes. Developmentally and morphologically, the Ampd3−/− mice were indistinguishable from their wild type siblings. The levels of ATP, ADP but not 5′-AMP in erythrocytes of Ampd3−/− mice were significantly elevated. Fasting blood glucose levels of the Ampd3−/− mice were comparable to wild type siblings. In comparison to wild type mice, the Ampd3−/− mice displayed a deeper hypometabolism with a significantly delayed average arousal time in response to 5′-AMP administration. Together, these findings demonstrate a central role of AMPD3 in the regulation of 5′-AMP mediated hypometabolism and further implicate erythrocytes in this behavioral response.
No abstract
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.