Histone methyltransferase Smyd1 regulates mitochondrial energetics in the heart.

ABSTRACT: Smyd1, a muscle-specific histone methyltransferase, has established roles in skeletal and cardiac muscle development, but its role in the adult heart remains poorly understood. Our prior work demonstrated that cardiac-specific deletion of Smyd1 in adult mice (Smyd1-KO) leads to hypertrophy and heart failure. Here we show that down-regulation of mitochondrial energetics is an early event in these Smyd1-KO mice preceding the onset of structural abnormalities. This early impairment of mitochondrial energetics in Smyd1-KO mice is associated with a significant reduction in gene and protein expression of PGC-1?, PPAR?, and RXR?, the master regulators of cardiac energetics. The effect of Smyd1 on PGC-1? was recapitulated in primary cultured rat ventricular myocytes, in which acute siRNA-mediated silencing of Smyd1 resulted in a greater than twofold decrease in PGC-1? expression without affecting that of PPAR? or RXR?. In addition, enrichment of histone H3 lysine 4 trimethylation (a mark of gene activation) at the PGC-1? locus was markedly reduced in Smyd1-KO mice, and Smyd1-induced transcriptional activation of PGC-1? was confirmed by luciferase reporter assays. Functional confirmation of Smyd1's involvement showed an increase in mitochondrial respiration capacity induced by overexpression of Smyd1, which was abolished by siRNA-mediated PGC-1? knockdown. Conversely, overexpression of PGC-1? rescued transcript expression and mitochondrial respiration caused by silencing Smyd1 in cardiomyocytes. These findings provide functional evidence for a role of Smyd1, or any member of the Smyd family, in regulating cardiac energetics in the adult heart, which is mediated, at least in part, via modulating PGC-1?.

SUBMITTER: Warren JS 

PROVIDER: S-EPMC6099878 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other