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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Research Article Cardiology Metabolism

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 11

Lowering BCAAs decreases KI67 expression in cardiac fibroblasts.

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Lowering BCAAs decreases KI67 expression in cardiac fibroblasts. (A) Rel...
(A) Relative fold change of MKi67 mRNA expression in the heart under the conditions described in the legend to Figure 2 (n = 3). Error bars represent the SEM, and the padj (Wald test) of 0.05 or less is given above the lines encompassing the bars. (B) IGB images showing H3K23Pr ChIP sequence tags from similarly treated mice, aligned across Mki67 gene coordinates (data were pooled from of 3 hearts each). See the legend to Figure 4 for more details on the IGB tracks. (C) Neonatal rat heart fibroblasts were isolated and cultured. After 20 hours, the medium was replaced with DMEM with standard levels of BCAA (1× BCAA) or low BCAA (0.1× BCAA), without FBS, with 1 ng/mL TGF-β or vehicle, and incubated for another 24 hours (n = 3 each). Protein was then extracted and fractionated into cytosol (C), membrane/mitochondria (M), nucleoplasm (N), chromatin-bound (Ch), and cytoskeletal (Cs) fractions and analyzed by WB, with antibodies for the proteins listed on the left in each panel. (D) The WB signals were quantified and graphed for MKI67, normalized to POL II. The results were analyzed by 1-way ANOVA after adjusting the signal of the 1× BCAA, vehicle-treated cells, to 1. Error bars represent the SEM and the results were analyzed by 1-way ANOVA. P values of 0.05 or less are shown above the brackets encompassing the bars.