Dietary glutamine supplementation alleviates age-related cardiac dysfunction by reducing elevated H3K27me3

Background

Changes to the epigenetic landscape play an important role in cardiovascular aging, where alterations in histone modifications influence gene expression by regulating DNA accessibility and chromatin structure. Our investigation into epigenetic changes during myocardial aging revealed that the repressive epigenetic mark H3K27me3 is significantly upregulated in aged mice and humans. This increase in H3K27me3 was shown to impair cardiomyocyte autophagy and drive metabolic reprogramming, key features of myocardial aging and causatively linked to dysfunction. Notably, by alleviating this repressive mark through a modified diet, we successfully mitigated the aged myocardial phenotype.

Methods

Heart tissue from young and aged mice and humans was analyzed for H3K27me3 levels using immunoblotting and immunofluorescence staining. Genes regulated by H3K27me3 were identified through CUT&RUN-Seq and RNA-Seq, while metabolites were profiled using metabolomics. In neonatal rat ventricular myocytes (NRVMs), H3K27me3 levels were elevated by siRNA-mediated knockdown of UTX. Cellular metabolism was investigated using a Seahorse analyzer in cardiomyocytes with basal or elevated H3K27me3 levels. In further human studies, we assessed how circulating glutamine levels associate with the incidence of heart failure and the association of genetic variants within the SLC1A5 region with heart disease. In aged mice, H3K27me3 levels were reduced through a modified diet, and heart function was evaluated using echocardiography. Subsequently, hearts were processed for biochemical analysis, and autophagy was assessed using electron microscopy.

Results

H3K27me3 was significantly elevated in the aged mouse and human myocardium. This observed elevation in H3K27me3 was found to be attributed to impaired glutamine metabolism, resulting from reduced expression of the glutamine transporter SLC1A5 in the aged myocardium. Furthermore, elevation in H3K27me3 was found to contribute to impaired cardiomyocyte autophagy and metabolic dysfunction. In aged mice supplemented with a high glutamine diet this attenuated myocardial H3K27me3 and improved cardiac function. Furthermore, a high-glutamine diet reversed H3K27me3-mediated impairment in cardiac autophagy in aged mice.

Conclusions

Reduction in SLC1A5 during aging is likely to lead to increased myocardial H3K27me3 that results in impaired autophagy and metabolic reprogramming that contribute to the aged cardiac phenotype. Our findings also suggest glutamine may improve cardiac health in the aged population by lowering H3K27me3.

Clinical Perspective