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. 2014 Nov;7(6):1022-31.
doi: 10.1161/CIRCHEARTFAILURE.114.001469. Epub 2014 Sep 18.

Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach

Ling Lai  1 , Teresa C Leone  1 , Mark P Keller  1 , Ola J Martin  1 , Aimee T Broman  1 , Jessica Nigro  1 , Kapil Kapoor  1 , Timothy R Koves  1 , Robert Stevens  1 , Olga R Ilkayeva  1 , Rick B Vega  1 , Alan D Attie  1 , Deborah M Muoio  1 , Daniel P Kelly  2
Affiliations

Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach

Ling Lai et al. Circ Heart Fail. 2014 Nov.

Abstract

Background: An unbiased systems approach was used to define energy metabolic events that occur during the pathological cardiac remodeling en route to heart failure (HF).

Methods and results: Combined myocardial transcriptomic and metabolomic profiling were conducted in a well-defined mouse model of HF that allows comparative assessment of compensated and decompensated (HF) forms of cardiac hypertrophy because of pressure overload. The pressure overload data sets were also compared with the myocardial transcriptome and metabolome for an adaptive (physiological) form of cardiac hypertrophy because of endurance exercise training. Comparative analysis of the data sets led to the following conclusions: (1) expression of most genes involved in mitochondrial energy transduction were not significantly changed in the hypertrophied or failing heart, with the notable exception of a progressive downregulation of transcripts encoding proteins and enzymes involved in myocyte fatty acid transport and oxidation during the development of HF; (2) tissue metabolite profiles were more broadly regulated than corresponding metabolic gene regulatory changes, suggesting significant regulation at the post-transcriptional level; (3) metabolomic signatures distinguished pathological and physiological forms of cardiac hypertrophy and served as robust markers for the onset of HF; and (4) the pattern of metabolite derangements in the failing heart suggests bottlenecks of carbon substrate flux into the Krebs cycle.

Conclusions: Mitochondrial energy metabolic derangements that occur during the early development of pressure overload-induced HF involve both transcriptional and post-transcriptional events. A subset of the myocardial metabolomic profile robustly distinguished pathological and physiological cardiac remodeling.

Keywords: energy metabolism; heart failure; metabolomics; mitochondria; transcriptome profiling.

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Figures

Figure 1
Figure 1. Myocardial transcriptional profiles for compensated (CH) and decompensated (HF) pathologic cardiac hypertrophy exhibit significant concordance
(A) Venn diagram showing differentially expressed (DE) genes in CH (left, n=5) or HF groups (right, n=5) compared to corresponding sham-operated controls (n=5 per group). The overlapping region (red) represents DE genes in both groups. (B) Scatter plot showing genes exhibiting DE ≥ 0.950 in either CH (green circles), HF (blue circles), or both (red circles) groups compared to corresponding controls. The log10-transformed fold change of genes in CH is shown on the x-axis, and corresponding fold change for HF is shown on the y-axis, plotted on a linear scale.
Figure 2
Figure 2. Altered expression of genes involved in fatty acid catabolic pathways in HF
Pathway map showing cardiac genes significantly (DE ≥ 0.950) upregulated (pink) or downregulated (green) compared to controls. Pathways involved in lipid utilization are shown including FAO (A), mitochondrial L-carnitine shuttle (B), and triglyceride degradation (C) as identified by IPA (see Supplemental Methods). The ovals in the map represent enzyme complexes with components of each gene/enzyme displayed individually as denoted by the arrows. The intensity of the color within the symbols and ovals denotes the degree of regulation.
Figure 3
Figure 3. Altered expression of genes involved in amino acid degradation in HF
Pathway map showing myocardial genes significantly (DE ≥ 0.950) upregulated (pink) or downregulated (green) compared to controls in valine, leucine, and isoleucine degradation pathways identified by IPA.
Figure 4
Figure 4. Accumulation of acylcarnitine esters in myocardial samples from the HF group
Levels of free carnitine (C0) and acylcarnitine species isolated from the bi-ventricle of CH (n=6) and HF (n=6) hearts and corresponding sham-operated controls are indicated by the labels on the x-axis. Acyl chain lengths are denoted by the numbers. Acylcarnitine species that represent monohydroxylated (OH) or dicarboxylic acid (DC) species are also shown. Note that the OH and DC carnitine species are isobaric and, thus, were not separated in this analysis. Bars represent mean ± S.E. *p< 0.05 compared with corresponded sham-operated controls (n=6).
Figure 5
Figure 5. Altered myocardial organic acid and amino acid levels in HF samples
Metabolite profiles showing (A) lactate and pyruvate, (B) organic acid intermediates within the TCA cycle and (C) amino acids determined in samples isolated from the bi-ventricle of CH (n=6), HF (n=6) and corresponding control hearts. Bars represent mean ± S.E. *p< 0.05 compared with corresponding sham-operated control.
Figure 6
Figure 6. Reduced expression of genes involved in fatty acid uptake and oxidation in HF
(A) Results of quantitative RT-PCR analysis of RNA extracted from hearts of CH (n=7), HF (n=7) and corresponding sham-operated controls (n=5-7) for the transcripts as labeled. Bars represent mean ± S.E. normalized (=1.0) to each sham control. *p < 0.05 compared to corresponding sham-operated control. (B) Mean (± S.E.) mitochondrial respiration rates of permeabilized cardiac muscle fiber strips prepared from HF mice (n=11) and sham-operated controls (n=5-8) using palmitoylcarnitine/malate (top) or pyruvate/malate (bottom) as substrate. Basal, state III (ADP-stimulated), and post-oligomycinrates are shown. Respiratory control ratio (RC) = state III/state IV. *p < 0.05 compared to Sham (HF).
Figure 7
Figure 7. Metabolomic profile of exercise-trained mouse heart
Levels of (A) free carnitine (C0), acetylcarnitine (C2), and other acylcarnitine species, and (B) organic acids isolated from the bi-ventricle of PH hearts (Run). Bars represent mean ± S.E. *p< 0.05 compared with age-, gender- (female), and strain (C57BL/6J)-matched sedentary controls (n=6 per group).
Figure 8
Figure 8. Comparative analysis of transcriptomic and metabolomic profiles representing mitochondrial energy metabolic pathways for CH, HF, and PH hearts
(A) A heat map containing gene expression array datasets representing the level of expression of genes in fatty acid utilization, TCA cycle, and ETC/OXPHOS pathways defined by IPA for CH, HF, PH, and adult PGC-1αβ-/- hearts (PGC DKO; n=5 per group). Each row represents the log2-transformed fold change compared with corresponding controls. The pathways are ranked according to the posterior probabilities in HF, top being the most significant. Downregulation in blue and upregulation in red. (B) Heat map containing the log2-transformed ratio of the mean relative levels of acylcarnitines, organic acids, and amino acids among CH, HF, PH, and adult PGC-1αβ-/- hearts (n=6) compared to corresponding controls. The intensity of color indicates the magnitude of the fold change.
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