| First Author | Warren JS | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 33 | Pages | E7871-E7880 |
| PubMed ID | 30061404 | Mgi Jnum | J:265092 |
| Mgi Id | MGI:6195570 | Doi | 10.1073/pnas.1800680115 |
| Citation | Warren JS, et al. (2018) Histone methyltransferase Smyd1 regulates mitochondrial energetics in the heart. Proc Natl Acad Sci U S A 115(33):E7871-E7880 |
| abstractText | 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-1alpha, PPARalpha, and RXRalpha, the master regulators of cardiac energetics. The effect of Smyd1 on PGC-1alpha 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-1alpha expression without affecting that of PPARalpha or RXRalpha. In addition, enrichment of histone H3 lysine 4 trimethylation (a mark of gene activation) at the PGC-1alpha locus was markedly reduced in Smyd1-KO mice, and Smyd1-induced transcriptional activation of PGC-1alpha 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-1alpha knockdown. Conversely, overexpression of PGC-1alpha 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-1alpha. |
