期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 33, 页码 E7871-E7880出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1800680115
关键词
heart; Smyd1; PGC-1a; metabolism; systems biology
资金
- NIH [R01HL130424-01, 1S10OD021505-01, R01CA31534]
- Diabetes Research Center at Washington University [5 P30 DK020579]
- Nora Eccles Treadwell Foundation
- American Heart Association [17GRNT33440031]
- New Jersey Health Foundation [PC56-16, PC80-17]
- Cancer Prevention Research Institute of Texas [RP120459]
- Marie Betzner Morrow Centennial Endowment
- Undergraduate Research Opportunity Program of the University of Utah
- NIH Medical Research Scholars Program Fellowship
- NATIONAL CANCER INSTITUTE [R01CA031534] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL007576, R01HL130424] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK020579, T35DK103596] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD021505] Funding Source: NIH RePORTER
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 alpha, PPAR alpha, and RXR alpha, the master regulators of cardiac energetics. The effect of Smyd1 on PGC-1 alpha 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 alpha expression without affecting that of PPARa or RXRa. In addition, enrichment of histone H3 lysine 4 trimethylation (a mark of gene activation) at the PGC-1 alpha locus was markedly reduced in Smyd1-KO mice, and Smyd1-induced transcriptional activation of PGC-1 alpha 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 alpha knockdown. Conversely, overexpression of PGC-1 alpha rescued transcript expression andmitochondrial 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 alpha.
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