Comprehensive quantification of fuel use by the failing and nonfailing human heart
Danielle Murashige,Cholsoon Jang,Michael D. Neinast,Jonathan J. Edwards,Alexis J. Cowan,Matthew C. Hyman,Joshua D. Rabinowitz,David S. Frankel,Zolt Arany +8 more
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TLDR
A comprehensive and quantitative picture of human cardiac fuel use is provided, using blood from artery, coronary sinus, and femoral vein in 110 patients with or without heart failure to quantify the uptake and release of 277 metabolites.Abstract:
The heart consumes circulating nutrients to fuel lifelong contraction, but a comprehensive mapping of human cardiac fuel use is lacking. We used metabolomics on blood from artery, coronary sinus, and femoral vein in 110 patients with or without heart failure to quantify the uptake and release of 277 metabolites, including all major nutrients, by the human heart and leg. The heart primarily consumed fatty acids and, unexpectedly, little glucose; secreted glutamine and other nitrogen-rich amino acids, indicating active protein breakdown, at a rate ~10 times that of the leg; and released intermediates of the tricarboxylic acid cycle, balancing anaplerosis from amino acid breakdown. Both heart and leg consumed ketones, glutamate, and acetate in direct proportionality to circulating levels, indicating that availability is a key driver for consumption of these substrates. The failing heart consumed more ketones and lactate and had higher rates of proteolysis. These data provide a comprehensive and quantitative picture of human cardiac fuel use.read more
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Extra-cardiac BCAA catabolism lowers blood pressure and protects from heart failure
TL;DR: In this paper , the authors used in vivo isotope infusions to show that cardiac BCAA oxidation in fact increases, rather than decreases, in heart failure, and cardiac specific activation of BCAA oxidization does not protect from heart failure even though systemic activation does.
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Defects in the Proteome and Metabolome in Human Hypertrophic Cardiomyopathy
TL;DR: In this paper , the authors conducted proteomic and targeted, quantitative metabolomic analyses on heart tissue from patients with hypertrophic cardiomyopathy (HCM) and from nonfailing control human hearts.
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Identifying functional metabolic shifts in heart failure with the integration of omics data and a heart-specific, genome-scale model.
Bonnie V. Dougherty,Kristopher D. Rawls,Glynis L. Kolling,Kalyan C. Vinnakota,Kalyan C. Vinnakota,Anders Wallqvist,Jason A. Papin +6 more
TL;DR: In this paper, the authors explore transcriptional changes in late-stage heart failure using publicly available data integrated with a model of heart metabolism, and demonstrate the utility of iCardio in interpreting heart failure gene expression data by identifying tasks inferred from differential expression (TIDEs), which represent metabolic functions associated with changes in gene expression.
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SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism
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Metabolomic and Transcriptomic Signatures of Chemogenetic Heart Failure.
Fotios Spyropoulos,Andrea Sorrentino,Jiska van der Reest,Peiran Yang,Markus Waldeck-Weiermair,Benjamin Steinhorn,Emrah Eroglu,Seyed Soheil Saeedi Saravi,Paul Yu,Marcia C. Haigis,Helen Christou,Thomas Michel +11 more
TL;DR: Evidence is provided that chemogenetic generation of oxidative stress leads to a robust heart failure model with distinct transcriptomic and metabolomic signatures and set the basis for understanding the underlining pathophysiology of chronic oxidative stress in the heart.
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Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells
Cosimo Commisso,Shawn M. Davidson,Rengin G. Soydaner-Azeloglu,Seth J. Parker,Jurre J. Kamphorst,Sean R. Hackett,Elda Grabocka,Michel Nofal,Jeffrey A. Drebin,Craig B. Thompson,Joshua D. Rabinowitz,Christian M. Metallo,Matthew G. Vander Heiden,Matthew G. Vander Heiden,Dafna Bar-Sagi +14 more
TL;DR: It is shown that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell, and its pharmacological inhibition compromises the growth of Ras- transformed pancreatic tumour xenografts.
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