Editors' ChoiceHeart Failure

Metabolic dysfunction branches out

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Science Translational Medicine  11 May 2016:
Vol. 8, Issue 338, pp. 338ec76
DOI: 10.1126/scitranslmed.aaf9189

The term “metabolism” was coined centuries ago by observing how the body constantly adapts to meet its energetic needs, and scores of studies have since revealed the complex interplay between energy metabolism and cellular function (and dysfunction). To meet its high energetic demands, the heart relies heavily on the oxidation of fatty acids to produce ATP to maintain contractile cardiomyocytes. However, during times of depleted oxygen or increased pressure demands, the heart switches from using fatty acids to glucose as a fuel source to maintain blood flow throughout the body. This metabolic switch is a hallmark of the failing heart and has been the target of therapeutic and diagnostic interventions for the millions of people worldwide who suffer from advanced heart failure. In contrast, the contribution of amino acid metabolism to cardiac diseases has been largely understudied. Now, Sun and colleagues assess how amino acid metabolism might directly contribute to the development of heart failure and whether this pathway could serve as both a biomarker and target for new therapies.

To explore which metabolic pathways were perturbed in failing mouse hearts, the authors performed transcriptome analysis coupled with an analysis of bioinformatic pathway enrichment and found that there was a profound dysregulation of metabolic pathways in the failing heart. Whereas defects in fatty acid metabolism and oxidative phosphorylation pathways were expected, the authors unexpectedly found that the most significantly dysregulated genes in the failing heart belonged to the valine-leucine-isoleucine degradation family—also known as the branched-chain amino acid (BCAA) catabolism pathway. Using traditional molecular analyses, they confirmed that BCAA-related genes and substrates were expressed at low levels in failing mouse hearts, and enzymatic activity of the rate limiting steps of BCAA catabolism were also impaired. Further bioinformatic, biochemical, and genetic analyses identified KLF15 as the coordinate transcriptional regulator for the expression BCAA pathway genes. Mechanistically, the build-up of BCAA led to impaired mitochondrial function, increased amount of reactive oxygen species, and worsening of heart failure.

But are any of these pathways relevant to human disease? Indeed, the authors confirmed that the expression of BCAA mediators and measures of BCAA enzymatic activity are impaired in the myocardium in humans with heart failure compared with healthy myocardium. Although this observation does not definitively pinpoint impaired BCAA metabolism as a causal factor in human heart failure, when combined with the mechanistic evidence from mice, it suggests that BCAA catabolism is a driver of heart failure in humans.

Furthermore, Sun and colleagues demonstrate that BCAA metabolism can be targeted therapeutically to prevent the pathological consequences in heart failure. Going back to a murine model, the authors showed that boosting BCAA flux by inhibiting a negative regulator of the catabolic pathway prevented pathological cardiac remodeling and preserved left-ventricle ejection fraction—a measure of cardiac function—after hemodynamic pressure overload. So by releasing the brake on the BCAA catabolic pathway, the mouse heart could withstand the metabolic perturbances associated with pathological stress. Although the authors did not examine the precise mechanistic underpinnings of this therapeutic benefit, they highlight that understanding more about BCAA metabolic flux could offer opportunities to enhance therapy through dietary and pharmacological means.

H. Sun et al., Catabolic defect of branched-chain amino acids promotes heart failure. Circulation 10.1161/CIRCULATIONAHA.115.020226 (2016). [Abstract]

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