Reducing branched-chain amino acids improves cardiac stress response in mice by decreasing histone H3K23 propionylation
Zhi Yang, … , Danish Sayed, Maha Abdellatif
Zhi Yang, … , Danish Sayed, Maha Abdellatif
Published September 5, 2023
Citation Information: J Clin Invest. 2023;133(22):e169399. https://doi.org/10.1172/JCI169399.
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Reducing branched-chain amino acids improves cardiac stress response in mice by decreasing histone H3K23 propionylation

Abstract

Identification of branched-chain amino acid (BCAA) oxidation enzymes in the nucleus led us to predict that they are a source of the propionyl-CoA that is utilized for histone propionylation and, thereby, regulate gene expression. To investigate the effects of BCAAs on the development of cardiac hypertrophy and failure, we applied pressure overload on the heart in mice maintained on a diet with standard levels of BCAAs (BCAA control) versus a BCAA-free diet. The former was associated with an increase in histone H3K23-propionyl (H3K23Pr) at the promoters of upregulated genes (e.g., cell signaling and extracellular matrix genes) and a decrease at the promoters of downregulated genes (e.g., electron transfer complex [ETC I–V] and metabolic genes). Intriguingly, the BCAA-free diet tempered the increases in promoter H3K23Pr, thus reducing collagen gene expression and fibrosis during cardiac hypertrophy. Conversely, the BCAA-free diet inhibited the reductions in promoter H3K23Pr and abolished the downregulation of ETC I–V subunits, enhanced mitochondrial respiration, and curbed the progression of cardiac hypertrophy. Thus, lowering the intake of BCAAs reduced pressure overload–induced changes in histone propionylation–dependent gene expression in the heart, which retarded the development of cardiomyopathy.

Authors

Zhi Yang, Minzhen He, Julianne Austin, Danish Sayed, Maha Abdellatif

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Figure 14

Lowering BCAAs or isoleucine enhances mitochondrial respiration.

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Lowering BCAAs or isoleucine enhances mitochondrial respiration. (A) Mit...
(A) Mitochondria were freshly isolated from the heart, and the OCR (pmol/h, y axis) over time (x axis) was measure using the Seahorse analyzer, before and after the addition of rotenone (Rtn), succinate (succ), antimycin A (AA), and TMPD plus ascorbic acid (TMPD+Asc), at the time points indicated by the arrows on the curve. (B) Basal (CI–IV), CxII, and CxIV OCRs (pmol/h) were graphed (n = 3 independent hearts; n = 15 replicas each) after normalization to mitochondrial protein. Error bars represent the SEM. *P ≤ 0.05, by 1-way ANOVA. (C) Neonatal rat cardiac myocytes were cultured in DMEM (with glucose, without FBS) with either 1× or 0.1× BCAAs, or with 0.1× of the individual aa Leu, Ile, or Val, as indicated by the color key, without FBS. After 16 hours, the OCR (pmol/h, y axis) versus time (h, x axis) was measured using the Seahorse analyzer, before and after the addition of oligomycin (Oligo), FCCP, and rotenone, at the time points indicated by arrows. (D) The mitochondrial spare respiratory capacity, proton leak, and ATP-linked OCRs were calculated and graphed (n = 3 independent cultures; n = 6–10 replicas each). Error bars represent the SEM. *P ≤ 0.05, by 1-way ANOVA. (E) Hap1 and Hap1ΔPCCA were cultured in DMEM with increasing doses of BCAAs as indicated by the color key, without FBS. After 16 hours, the OCR was measured (n = 3 independent cultures; n = 10 replicas each), as described in H. (F) The data were graphed and analyzed by 1-way ANOVA, as described in D.