Integrating metabolomics and phenomics with systems models of cardiac hypoxia. Prog Biophys Mol Biol

Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Progress in Biophysics and Molecular Biology (Impact Factor: 2.27). 01/2008; 96(1-3):209-25. DOI: 10.1016/j.pbiomolbio.2007.07.014
Source: PubMed


Hypoxia is the major cause of necrotic cell death in myocardial infarction. Cellular energy supply and demand under hypoxic conditions is regulated by many interacting signaling and transcriptional networks, which complicates studies on individual proteins and pathways. We apply an integrated systems approach to understand the metabolic and functional response to hypoxia in muscle cells of the fruit fly Drosophila melanogaster. In addition to its utility as a hypoxia-tolerant model organism, Drosophila also offers advantages due to its small size, fecundity, and short life cycle. These traits, along with a large library of single-gene mutations, motivated us to develop new, computer-automated technology for gathering in vivo measurements of heart function under hypoxia for a large number of mutant strains. Phenotype data can be integrated with in silico cellular networks, metabolomic data, and microarrays to form qualitative and quantitative network models for prediction and hypothesis generation. Here we present a framework for a systems approach to hypoxia in the cardiac myocyte, starting from nuclear magnetic resonance (NMR) metabolomics, a constraint-based metabolic model, and phenotypic profiles.

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    • "In fact, several metabolomics studies have been conducted using Drosophila that focused on the effect of heat tolerance on third instar larvae [6], [7] and adult flies as well as [8]–[11] hypoxia tolerance [12], pheromones [13], oxidative stress [14], longevity [15] and obesity [16] in Drosophila larvae and adults. Furthermore, metabolomics using Drosophila as model organism has been applied for the study of Listeria monocytogenes infection [17] and drug efficacy test [18]. "
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    ABSTRACT: The Drosophila melanogaster embryo has been widely utilized as a model for genetics and developmental biology due to its small size, short generation time, and large brood size. Information on embryonic metabolism during developmental progression is important for further understanding the mechanisms of Drosophila embryogenesis. Therefore, the aim of this study is to assess the changes in embryos' metabolome that occur at different stages of the Drosophila embryonic development. Time course samples of Drosophila embryos were subjected to GC/MS-based metabolome analysis for profiling of low molecular weight hydrophilic metabolites, including sugars, amino acids, and organic acids. The results showed that the metabolic profiles of Drosophila embryo varied during the course of development and there was a strong correlation between the metabolome and different embryonic stages. Using the metabolome information, we were able to establish a prediction model for developmental stages of embryos starting from their high-resolution quantitative metabolite composition. Among the important metabolites revealed from our model, we suggest that different amino acids appear to play distinct roles in different developmental stages and an appropriate balance in trehalose-glucose ratio is crucial to supply the carbohydrate source for the development of Drosophila embryo.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "Acute alititude illness occurs in nonacclimatized subjects shortly after ascent to alititudes higher than 2500 m and as early as 1 hour after exposure to hypoxia (Hackett et al., 2001). Other nonaltitude-related diseases such as ischemia-reperfusion, stroke, and myocardial infarction may also have etiologies related to acute hypoxia (Corbucci et al., 2005; Feala et al., 2008). Chronic hypoxic conditions resulting from living at high altitude lead to acclimatization processes such as increased pulmonary ventilation, enhanced oxygen transportation efficiency in the circulatory system, and subsequent improvement of physical fitness to minimize tissue damage (Wang, 2006). "
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    ABSTRACT: Aims: The metabolic variability and response to acute systematic hypoxia have been characterized by the high resolution of liquid chromatography/time-of-flight/mass spectrometry (LC-TOF/MS) in this study. Specifically, we compared the urinary metabolic profiles of six healthy sedentary men under normoxia (21% O2) with acute systematic hypoxic conditions of 12% (equivalent to about 4500 m in altitude) and 15% O2 (equivalent to about 3000 m in altitude) for 2 h in a normobaric hypoxia chamber. Results: A clear separation of dose-dependent responses was visualized by Partial Least Squares Discriminant Analysis (PLS-DA) between normoxic and hypoxic conditions. Over one thousand features were found in this study, about 10% of which showed significant change from hypoxia treatment and 26 metabolites were identified; however, there is great variability in metabolite concentrations among the 6 subjects, which reflects the diversity of human systems. Within the variability, we found that 1-methyladenosine and 5-methylthioadenosine are conspicuously upregulated; on the other hand, 3-inodoleacetic acid and L-glutamic acid were downregulated. Conclusion: The increase in purine metabolic products (uric acid, xanthine, and hypoxathine) results from hypoxia; this increase can be used as a marker for the hypoxic condition. 1-Methyladenosine was also highly upregulated from MH to SH and may be a very sensitive biomarker that reflects cellular hypoxia, due to its potential connection to HIF-1. The increase of free carnitine and acetyl carnitines, on the other hand, signals a change in the pathway of energy, or lipid, metabolism.
    Full-text · Article · Mar 2014 · High altitude medicine & biology
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    ABSTRACT: The National Heart, Lung, and Blood Institute and Office of Rare Diseases at the National Institutes of Health organized a workshop (September 14 to 15, 2006, in Bethesda, Md) to advise on new research directions needed for improved identification and treatment of rare inherited arrhythmias. These included the following: (1) Na+ channelopathies; (2) arrhythmias due to K+ channel mutations; and (3) arrhythmias due to other inherited arrhythmogenic mechanisms. Another major goal was to provide recommendations to support, enable, or facilitate research to improve future diagnosis and management of inherited arrhythmias. Classifications of electric heart diseases have proved to be exceedingly complex and in many respects contradictory. A new contemporary and rigorous classification of arrhythmogenic cardiomyopathies is proposed. This consensus report provides an important framework and overview to this increasingly heterogeneous group of primary cardiac membrane channel diseases. Of particular note, the present classification scheme recognizes the rapid evolution of molecular biology and novel therapeutic approaches in cardiology, as well as the introduction of many recently described diseases, and is unique in that it incorporates ion channelopathies as a primary cardiomyopathy in consensus with a recent American Heart Association Scientific Statement.
    Full-text · Article · Dec 2007 · Circulation
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