KDM8 epigenetically controls cardiac metabolism to prevent initiation of dilated cardiomyopathy.

ABSTRACT: Cardiac metabolism is deranged in heart failure, but underlying mechanisms remain unclear. Here, we show that lysine demethylase 8 (Kdm8) maintains an active mitochondrial gene network by repressing Tbx15, thus preventing dilated cardiomyopathy leading to lethal heart failure. Deletion of Kdm8 in mouse cardiomyocytes increased H3K36me2 with activation of Tbx15 and repression of target genes in the NAD⁺ pathway before dilated cardiomyopathy initiated. NAD⁺ supplementation prevented dilated cardiomyopathy in Kdm8 mutant mice, and TBX15 overexpression blunted NAD⁺-activated cardiomyocyte respiration. Furthermore, KDM8 was downregulated in human hearts affected by dilated cardiomyopathy, and higher TBX15 expressi

SUBMITTER: Ahmed A 

PROVIDER: S-EPMC11041705 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature