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.
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- "Similarly, 5 0 -adenosine monophosphate (5 0 -AMP)-activated protein kinase, a well-known sensor and regulator of cellular energy status, is implicated in IPC leading to cardioprotection (Young 2008), while at the same time administration of 5 0 -AMP induces a deep and reversible hypometabolic state in non-hibernating mammals (Zhang et al. 2006; Daniels et al. 2010). In contrast to torpor however, the metabolic phenotype of 5 0 - AMP-induced hypometabolism is characterized by minimal alterations in lipid metabolism, with regulation of carbohydrate metabolites playing important roles both during the hypometabolic state and during the following recovery process (Zhao et al. 2014). IPC can protect tissue from further ischemiareperfusion injury, but it is when myocardial tissue receives chronically reduced coronary blood flow that it enters the well-recognized state of impaired resting contractile function and reduced energy consumption of the heart known as myocardial hibernation (Camici et al. 2008). "
ABSTRACT: Supply and demand relationships govern survival of animals in the wild and are also key determinants of clinical outcomes in critically ill patients. Most animals' survival strategies focus on the supply side of the equation by pursuing territory and resources, but hibernators are able to anticipate declining availability of nutrients by reducing their energetic needs through the seasonal use of torpor, a reversible state of suppressed metabolic demand and decreased body temperature. Similarly, in clinical medicine the majority of therapeutic interventions to care for critically ill or trauma patients remain focused on elevating physiologic supply above critical thresholds by increasing the main determinants of delivery of oxygen to the tissues (cardiac output, perfusion pressure, hemoglobin concentrations, and oxygen saturation), as well as increasing nutritional support, maintaining euthermia, and other general supportive measures. Techniques, such as induced hypothermia and preconditioning, aimed at diminishing a patient's physiologic requirements as a short-term strategy to match reduced supply and to stabilize their condition, are few and underutilized in clinical settings. Consequently, comparative approaches to understand the mechanistic adaptations that suppress metabolic demand and alter metabolic use of fuel as well as the application of concepts gleaned from studies of hibernation, to the care of critically ill and injured patients could create novel opportunities to improve outcomes in intensive care and perioperative medicine.Integrative and Comparative Biology 05/2014; 54(3). DOI:10.1093/icb/icu047 · 2.93 Impact Factor
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ABSTRACT: Gene mutations that produce misprocessed proteins are linked to many human disorders. Interestingly, some misprocessed proteins retained their biological function when stabilized by low temperature treatment of cultured cells in vitro. Here we investigate whether low temperature treatment in vivo can rescue misfolded proteins by applying 5'-AMP mediated whole body cooling to a Cystic Fibrosis (CF) mouse model carrying a mutant cystic fibrosis transmembrane conductance regulator (CFTR) with a deletion of the phenylalanine residue in position 508 (ΔF508-CFTR). Low temperature treatment of cultured cells was previously shown to be able to alleviate the processing defect of ΔF508-CFTR, enhancing its plasma membrane localization and its function in mediating chloride ion transport. Here, we report that whole body cooling enhanced the retention of ΔF508-CFTR in intestinal epithelial cells. Functional analysis based on β-adrenergic dependent salivary secretion and post-natal mortality rate revealed a moderate but significant improvement in treated compared with untreated CF mice. Our findings demonstrate that temperature sensitive processing of mutant proteins can be responsive to low temperature treatment in vivo.Journal of Biomedical Science 12/2015; 22(1):72. DOI:10.1186/s12929-015-0178-3 · 2.76 Impact Factor