Abstract
Branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) are elevated in an array of cardiometabolic diseases. Here we demonstrate that the major metabolic fate of uniformly-13C-labeled α-ketoisovalerate ([U-13C]KIV) in the heart is reamination to valine. Activation of cardiac branched-chain α-ketoacid dehydrogenase (BCKDH) by treatment with the BCKDH kinase inhibitor, BT2, does not impede the strong flux of [U-13C]KIV to valine. Sequestration of BCAA and BCKA away from mitochondrial oxidation is likely due to low levels of expression of the mitochondrial BCAA transporter SLC25A44 in the heart, as its overexpression significantly lowers accumulation of [13C]-labeled valine from [U-13C]KIV. Finally, exposure of perfused hearts to levels of BCKA found in obese rats increases phosphorylation of the translational repressor 4E-BP1 as well as multiple proteins in the MEK-ERK pathway, leading to a doubling of total protein synthesis. These data suggest that elevated BCKA levels found in obesity may contribute to pathologic cardiac hypertrophy via chronic activation of protein synthesis.
Highlights
Branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) are elevated in an array of cardiometabolic diseases
In this study, we demonstrate that the heart preferentially reaminates branched-chain α-ketoacids (BCKA) to BCAA in a branched-chain amino acid transaminase (BCAT)-dependent manner
The degree of reamination is not influenced by increasing branched-chain α-ketoacid dehydrogenase (BCKDH) enzyme activity via treatment with the BCKDH kinase (BDK) inhibitor, b]thiophene-2carboxylic acid (BT2)
Summary
Branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) are elevated in an array of cardiometabolic diseases. Because the foregoing studies involved whole-body knockout of PPM1K and/or administration of a small molecule inhibitor of the BCKDH kinase (BDK), 3,6-dichlorobenzo[b]thiophene-2carboxylic acid (BT2)[14], which serves to activate BCKDH in all tissues, the impact of specific alteration of cardiac BCAA metabolism on cardiovascular disease phenotypes remains to be defined. This is especially true given that BCAA metabolism is differentially regulated in various organs and tissues in response to cardiometabolic disease-inducing conditions such as obesity and overnutrition[6,15]. These results outline mechanisms by which the chronic elevations of BCKA observed in obese, insulin-resistant states may activate cardiac hypertrophy to contribute to the pathogenesis of cardiovascular diseases
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