Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction

Abstract

Cardiac metabolic remodeling is a central event during heart failure (HF) development following myocardial infarction (MI). It is well known that myocardial glucose and fatty acid dysmetabolism contribute to post-MI cardiac dysfunction and remodeling. However, the role of amino acid metabolism in post-MI HF remains elusive. Branched chain amino acids (BCAAs) are an important group of essential amino acids and function as crucial nutrient signaling in mammalian animals. The present study aimed to determine the role of cardiac BCAA metabolism in post-MI HF progression. Utilizing coronary artery ligation-induced murine MI models, we found that myocardial BCAA catabolism was significantly impaired in response to permanent MI, therefore leading to an obvious elevation of myocardial BCAA abundance. In MI-operated mice, oral BCAA administration further increased cardiac BCAA levels, activated the mammalian target of rapamycin (mTOR) signaling, and exacerbated cardiac dysfunction and remodeling. These data demonstrate that BCAAs act as a direct contributor to post-MI cardiac pathologies. Furthermore, these BCAA-mediated deleterious effects were improved by rapamycin cotreatment, revealing an indispensable role of mTOR in BCAA-mediated adverse effects on cardiac function/structure post-MI. Of note, pharmacological inhibition of branched chain ketoacid dehydrogenase kinase (BDK), a negative regulator of myocardial BCAA catabolism, significantly improved cardiac BCAA catabolic disorders, reduced myocardial BCAA levels, and ameliorated post-MI cardiac dysfunction and remodeling. In conclusion, our data provide the evidence that impaired cardiac BCAA catabolism directly contributes to post-MI cardiac dysfunction and remodeling. Moreover, improving cardiac BCAA catabolic defects may be a promising therapeutic strategy against post-MI HF.

Alteration of myocardial GRK2 produces a global metabolic phenotype

“…Additionally, another BCAA metabolite released from skeletal muscle cells increases endothelial and skeletal muscle fatty acid uptake and can cause glucose intolerance (44), emphasizing the importance of BCAA metabolism in regulating metabolic health. Interestingly, myocardial BCAA metabolism is also altered in heart failure, a condition known to increase GRK2 signaling within the myocardium (45,46). It is possible that altered BCAA metabolism during HF due to enhanced GRK2 signaling could play an important role in modulating global health and insulin signaling.…”

Role of branched‐chain amino acid–catabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis

“…These observations suggest that defects in BCAA catabolism could directly result in cardiac dysfunction and accelerate TAC-induced cardiomyopathy. Indeed, pharmacological inactivation of BCKDK by BT2 rescued the cardiac dysfunction, improved structural remodeling, and ameliorated post-MI heart failure progression (181), as well as preserving cardiac contractility and function in TAC-subjected mice (118), thus highlighting the potential of targeting BCAA catabolism as a therapeutic intervention for heart failure.…”

Changing Metabolism in Differentiating Cardiac Progenitor Cells—Can Stem Cells Become Metabolically Flexible Cardiomyocytes?

“…However, there is also evidence of their accumulation during HF, as seen in a study on failing mouse hearts where genes associated with amino acid catabolism were downregulated during compensated hypertrophy and overt failure ( 130 ). Transcriptomic analyses reflected downregulation of genes involved in amino acid degradation pathways [proline, alanine, tryptophan, and mainly branched-chain amino acids (BCAAs)] ( 131 – 133 ). Using a genetic mouse model, Sun et al demonstrated that a deficiency in BCAA catabolism induced heart failure under mechanical overload, resulting from increased oxidative stress ( 132 ).…”