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 6

Dietary BCAAs and propionate regulate pressure overload–induced gene expression.

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Dietary BCAAs and propionate regulate pressure overload–induced gene exp...
(A–E) RNA was extracted from the heart and analyzed by RNA-Seq (n = 3, each). The mRNA expression data for Clic1, Arrb2, RhoC, Pln, and Ankrd1 genes are graphed in parallel with those for the mice on the same diets with 1% propionate. The results are represented in bar graphs as the average of relative values after adjusting one of the sham data points in each group to 1. The P values shown on top of the bars are the padj calculated for the RNA-Seq data (Wald test). (F) Isolated neonatal rat cardiac myocytes were cultured overnight in reduced BCAA (0.1×) medium (DMEM) before they were treated with increasing doses of propionate. Histones were extracted and analyzed by WB for the protein listed on the left of each panel. (G) Lys-propionyl (Kpr) and H3K23Pr signals were quantified and graphed (n = 3). *P ≤ 0.05 versus control (no propionate) using 2-tailed t test. (H) Mice were treated as described in Figure 2, with the exception that both the BCAA control and BCAA-free diets were supplemented with 1% propionate. Chromatin was extracted from the heart and analyzed by H3K23Pr ChIP-Seq 1 week after TAC (date were pooled from 3 hearts each). The average sequence tags from the ChIP-Seq results were graphed across gene bodies (–2 kb from the gene start (distal 0 bp) to +2 kb from the gene end (proximal 0 bp).