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

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 , thus preventing dilated cardiomyopathy leading to lethal heart failure. Deletion of in mouse cardiomyocytes increased H3K36me2 with activation of and repression of target genes in the NAD pathway before dilated cardiomyopathy initiated. NAD supplementation prevented dilated cardiomyopathy in mutant mice, and overexpression blunted NAD-activated cardiomyocyte respiration. Furthermore, was downregulated in human hearts affected by dilated cardiomyopathy, and higher expression defines a subgroup of affected hearts with the strongest downregulation of genes encoding mitochondrial proteins. Thus, KDM8 represses to maintain cardiac metabolism. Our results suggest that epigenetic dysregulation of metabolic gene networks initiates myocardium deterioration toward heart failure and could underlie heterogeneity of dilated cardiomyopathy.