Metabolite profiling of 5′-AMP induced hypometabolism

Abstract

We have previously demonstrated that 5′-adenosine monophosphate (5′-AMP) can be used to induce deep hypometabolism in mice and other non-hibernating mammals. This reversible 5′-AMP induced hypometabolism (AIHM) allows mice to maintain a body temperature about 1 °C above the ambient temperature for several hours before spontaneous reversal to euthermia. Our biochemical and gene expression studies suggested that the molecular processes involved in AIHM behavior most likely occur at the metabolic interconversion level, rather than the gene or protein expression level. To understand the metabolic processes involved in AIHM behavior, we conducted a non-targeted comparative metabolomics investigation at multiple stages of AIHM in the plasma, liver and brain of animals that underwent AIHM. Dozens of metabolites representing many important metabolic pathways were detected and measured using a metabolite profiling platform combining both liquid-chromatography–mass spectrometry and gas-chromatography–mass spectrometry. Our findings indicate that there is a widespread suppression of energy generating metabolic pathways but lipid metabolism appears to be minimally altered. Regulation of carbohydrate metabolites appears to be the major way the animal utilizes energy in AIHM and during the following recovery process. The 5′-AMP administered has largely been catabolized by the time the animals have entered AIHM. During AIHM, the urea cycle appears to be functional, helping to avoid ammonia toxicity. Of all tissues studied, brain’s metabolite flux is the least affected by AIHM.