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-1α, PPARα, and RXRα, the master regulators of cardiac energetics. The effect of Smyd1 on PGC-1α 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-1α expression without affecting that of PPARα or RXRα. In addition, enrichment of histone H3 lysine 4 trimethylation (a mark of gene activation) at the PGC-1α locus was markedly reduced in Smyd1-KO mice, and Smyd1-induced transcriptional activation of PGC-1α 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-1α knockdown. Conversely, overexpression of PGC-1α 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-1α.

Background: Anterior cruciate ligament (ACL) ruptures are potentially career-threatening injuries to National Football League (NFL) skill position players. A 2006 study showed a return-to-play (RTP) rate of 79% for NFL running backs (RBs) and wide receivers (WRs). Since then, a number of factors affecting RTP, including style of play as well as rules regarding hits to the head, have changed how defensive players tackle offensive ball carriers. Purpose/Hypothesis: To determine whether the RTP rate for RBs and WRs in the NFL has changed since data were collected in the 2000s. Additionally, we evaluated player performance before and after ACL reconstruction (ACLR). We hypothesized that there will be a lower RTP rate than previously reported as well as a decrease in performance statistics after ACLR. Study Design: Descriptive epidemiology study. Methods: Publicly available NFL injury reports between the 2009-2010 and 2015-2016 seasons were utilized for RBs and WRs who underwent ACLR. Successful RTP was indicated by playing in at least 1 NFL game after reconstruction. Position-specific performance statistics from before and after reconstruction were gathered for these players, and the RTP players were compared against the players who did not RTP (dnRTP group). Pre- and postinjury performance measures were also compared against a matched control group of NFL RBs and WRs who had not sustained an ACL injury. Results: Overall, 61.8% of players (64.5% of RBs, 60% of WRs) returned to play at a mean of 13.6 months. Prior to injury, the RTP group had played in significantly more career games and had significantly more rushes and receptions per game than the dnRTP group; however, there was no significant difference in performance after ACLR. The WR RTP group had significantly decreased performance in all measured categories when compared with the control group. Conclusion: Our study found a lower RTP rate in RBs and WRs than previous studies conducted in the early 2000s. WRs who achieved RTP had decreased performance when compared with noninjured controls.

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Epigenetic control of metabolism in the healthy and diseased heart remains poorly understood. We recently demonstrated that chromatin-bound Smyd1, a muscle-specific histone methyltransferase, is significantly upregulated in a mouse model of pressure overload-induced heart failure (HF) and that inducible, cardiac-specific Smyd1 knock-out (Smyd1-KO) mice develop cellular hypertrophy and fulminate HF. Bioinformatic analysis of transcripts differentially regulated in these mice revealed that cardiac metabolism was the most perturbed biological function in the heart. However, it was not clear whether alterations in cardiac metabolism were a direct consequence of Smyd1 deletion or were secondary to developed HF. Here we hypothesized that Smyd1 directly regulates cardiac metabolism; the effects of which should be detectable in Smyd1-KO mice before overt cardiac dysfunction. To test this hypothesis we performed unbiased metabolomic analysis of Smyd1-KO mice using GC/MS and MS/MS (n=9 control, n=10 KO) combined with targeted gene expression analysis. Our results showed significant changes in the metabolic profile of Smyd1-KO mice at the earliest time point (3 weeks after tamoxifen treatment) in which Smyd1 protein expression was significantly reduced while cardiac function remained normal. The most profound difference, in energetics-associated pathways in these mice, was found in fatty acid β-oxidation, manifested by the decreased myocardial content of carnitine and free fatty acids and downregulation of their transporters, OCTN2 and CD36. In addition, mRNA levels of the PPAR-α complex (PPAR-α;RXR-α;PGC-1α), an established regulator of fatty acid β-oxidation, and its target genes (CPT1b;CD36;Acox1;MCAD) were significantly reduced in Smyd1-KO mice prior to the onset of cardiac dysfunction (all p<0.05). To identify whether Smyd1 directly controls gene expression of PPAR-α, we examined the PPAR-α loci using chromatin-immunoprecipitation followed by qPCR and observed significant binding of Smyd1 upstream of the PPAR-α transcriptional start site. Overall, this study identifies Smyd1 as a novel regulator of fatty acid metabolism and suggests that Smyd1 controls cardiac energetics directly by regulating gene expression of PPAR-α.