Branched-chain amino acid metabolism in heart disease: an epiphenomenon or a real culprit?

Abstract

Metabolic remodelling is an integral part of the pathogenesis of heart failure. Although much progress has been made in our current understanding of the metabolic impairment involving carbohydrates and fatty acids in failing hearts, relatively little is known about the changes and potential impact of amino acid metabolism in the onset of heart diseases. Although most amino acid catabolic activities are found in the liver, branched-chain amino acid (BCAA) catabolism requires activity in several non-hepatic tissues, including cardiac muscle, diaphragm, brain and kidney. In this review, the new insights into the regulation of cardiac BCAA catabolism and functional impact on cardiac development and physiology will be discussed along with the potential contribution of impairment in BCAA catabolism to heart diseases. A particular focus will be the new information obtained from recently developed genetic models with BCAA catabolic defects and metabolomic studies in human and animal models. These studies have revealed the potential role of BCAA catabolism in cardiac pathophysiology and have helped to distinguish BCAA metabolic defects as an under-appreciated culprit in cardiac diseases rather than an epiphenomenon associated with metabolic remodelling in the failing heart.

Figures

Figure 1

Regulation of the branched-chain amino acid catabolic pathway. A schematic illustration of major steps and enzyme complexes involved in the BCAA catabolic pathway and targeted organs as well as genetic disorders associated with the specific steps. TCA, tricarboxylic acid cycle (also known as the Krebs cycle).

Figure 2

Potential role of BCAA/BCKA catabolism in heart failure. Illustration of the potential impact of reduced expression of PP2Cm in stressed heart in BCAA catabolism and cardiac remodelling. BCKD, branched-chain α-keto acid dehydrogenase; BCKDK, BCKD kinase; ETC, electron transfer chain; ROS, reactive oxygen species; BCAA, branched-chain amino acids; BCKA, branched-chain keto acids; MPTP, mitochondrial permeability transition pore.