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 5

Dietary BCAAs and propionate regulate pressure overload–induced promoter H3K23Pr during cardiac hypertrophy.

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Dietary BCAAs and propionate regulate pressure overload–induced promoter...
(A–E) IGB images showing H3K23Pr ChIP sequence tags from the sham-operated and TAC hearts of mice on the different diets without or with propionate supplementation, aligned across Clic1, Arrb2, RhoC, Pln, and Ankrd1 gene coordinates. The labels on the left of each track indicate the surgical and diet conditions applied in the mice: sham and TAC surgeries with the BCAA control diet (blue tracks), with the BCAA-free diets (green tracks); the differences (Diff) in the H3K23Pr sequence tags of TAC minus sham for the control diet (Diff-Control, brown tracks), and BCAA-free diet (Diff-0BCAA, gold tracks) are shown in separate tracks for the diets with or without propionate, as indicated.