2.1.4. BCAAs

Similarly, BCAAs are an important group of essential amino acids and an integral part of myocardial energy metabolism and thus play a crucial role in the pathophysiology of end-stage failing hearts. BCAAs act as key building blocks for peptide synthesis and are effective sources for the biosynthesis of sterol, keto bodies, and glucose. In addition, BCAAs are essential for normal growth and function at the cellular and organism levels [61].

Cardiac BCAA absolute levels were found to be significantly enhanced in a mouse model of HF that underwent transverse aortic constriction [62]. This evidence was correlated with a significant reduction in BCAA catabolic enzymes and in the % of EF, and was associated with insulin resistance [62–64]. Moreover, recent studies reported that branched chain alpha-keto acids (BCKAs), which are produced after the initial step of BCAA metabolism, are also increased in the myocardium of HF patients [63]. Enhancing BCAA oxidation in the myocardium can ameliorate the progression of HF by improving cardiac function (increasing the % EF and reverting insulin sensitivity) in a mouse model, which suggests that the imbalance between BCAA availability and use in failing hearts might be correlated with contractile dysfunction [63]. The improved BCCA catabolism was obtained by using 3,6-dichlorobenzothiophene-2-carboxylic acid (BT2), an inhibitor of the branched-chain α-keto acid dehydrogenase kinase (BCKDK) which phosphorylates and

inactivates the key enzyme (branched-chain α-keto acid dehydrogenase) responsible for providing substrates used by the TCA cycle [64].

Cardiac BCAA catabolism is described to be deregulated also in myocardial infarction (MI)-operated mice, and this effect contributes to post-MI HF and remodeling by enhancing the mammalian target of rapamycin (mTOR) signaling, a modulator of various anabolic (e.g., protein synthesis) and catabolic (e.g., autophagy) pathways [65]. Alterations in mTOR signaling contribute to the progression of failing hearts [66,67]. Furthermore, the amino acids aspartate and glutamate play a key role in the transfer of reducing equivalents across the mitochondrial membrane for the oxidation of cytosolic NADH through the mitochondrial ETC.
