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GNPS - Cardiomyocyte-specific NAMPT Knockout Mice: Metabolomics of Heart Ventricle Tissues at 2-weeks Post-Deletion

ABSTRACT: Metabolomics from heart ventricular tissues of wild-type (WT) and cardiomyocyte-specific conditional NAMPT knockout (cNKO) mice untreated or treated with nicotinamide riboside (cNKO-NR), harvested at 2-weeks post-NAMPT deletion (post-tamoxifen). For untargeted metabolomic running, mass spectrometer was operated in both negative (NEG, 70 to 1000 m/z) and positive (POS, 50 to 117.9 m/z) ion mode with the HILIC 25-minute method for the detection of metabolites. For targeted metabolomic running, mass spectrometer was operated in two positive-mode scans (SCAN1 at 118.5 to 800 m/z and SCAN2 at 70 to 117.5 m/z) with the HILIC 20-minute method for the detection of NAD derivatives.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Joseph A. Baur

PROVIDER: MSV000095445 | GNPS | Fri Jul 26 06:35:00 BST 2024

REPOSITORIES: GNPS

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Project description:Compelling evidence suggests that mitochondrial dysfunction contributes to the pathogenesis of heart failure, including defects in the substrate oxidation, and the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS). However, whether such changes occur early in the development of heart failure, and are potentially involved in the pathologic events that lead to cardiac dysfunction is unknown. To address this question, we conducted transcriptomic/metabolomics profiling in hearts of mice with two progressive stages of pressure overload-induced cardiac hypetrophy: i) cardiac hypertrophy with preserved ventricular function achieved via transverse aortic constriction for 4 weeks (TAC) and ii) decompensated cardiac hypertrophy or heart failure (HF) caused by combining 4 wk TAC with a small apical myocardial infarction. Transcriptomic analyses revealed, as shown previously, downregulated expression of genes involved in mitochondrial fatty acid oxidation in both TAC and HF hearts compared to sham-operated control hearts. Surprisingly, however, there were very few changes in expression of genes involved in other mitochondrial energy transduction pathways, ETC, or OXPHOS. Metabolomic analyses demonstrated significant alterations in pathway metabolite levels in HF (but not in TAC), including elevations in acylcarnitines, a subset of amino acids, and the lactate/pyruvate ratio. In contrast, the majority of organic acids were lower than controls. This metabolite profile suggests “bottlenecks” in the carbon substrate input to the TCA cycle. This transcriptomic/metabolomic profile was markedly different from that of mice PGC-1a/b deficiency in which a global downregulation of genes involved in mitochondrial ETC and OXPHOS was noted. In addition, the transcriptomic/metabolomic signatures of HF differed markedly from that of the exercise-trained mouse heart. We conclude that in contrast to current dogma, alterations in mitochondrial metabolism that occur early in the development of heart failure reflect largely post-transcriptional mechanisms resulting in impedance to substrate flux into the TCA cycle, reflected by alterations in the metabolome. Microarray gene expression profiling was performed with bi-ventricle RNA isolated from (1) 3 month-old female C57Bl6/J mice with transverse aortic constriction (CH), vs sham-operated control (Sham-CH), (2) 3 month-old female C57Bl6/J mice with heart failure (HF), vs. sham-operated control (Sham-HF); (3) 2 month-old female C57Bl6/J mice with voluntary wheel training for 2 months (Run), vs. Sedentary control (Sed). Five biological replicates are included for each group.

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GNPS - Cardiomyocyte-specific NAMPT Knockout Mice: Metabolomics of Heart Ventricle Tissues at 2-weeks Post-Deletion

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