Santos, C. X. C. | bioRxiv Science

bioRxiv2026

Redox-activated induction of Warburg-type metabolism in the adult heart

Proliferating cells rewire glucose metabolism away from oxidative ATP production towards glycolysis and anabolic branch pathways (the Warburg effect). In contrast, the contractile function of terminally differentiated cardiomyocytes in the heart critically depends upon mitochondrial ATP generation. Adult cardiomyocytes are largely non-proliferative but undergo hypertrophy in response to increased heart workload. A fundamental question in the field is how cardiac metabolism is modified to balance competing energetic and anabolic demands. We previously reported that the redox-signalling H2O2-generating enzyme, NADPH oxidase 4 (NOX4), facilitates compensated cardiac function in hearts undergoing hypertrophic remodelling. Here, we show that NOX4 induces Warburg-type reprogramming of glucose metabolism in the healthy heart, with increased flux into the pentose phosphate, serine and nucleotide biosynthetic pathways. Using an integrated multiomics approach, we uncover a NOX4-regulated network involving interplay between direct transcriptional activation of metabolic genes via NRF2 [aka NFE2L2] and ATF4 and a broader epigenetic regulation. This reprogramming of glucose intermediary metabolism along with previously reported NOX4-mediated enhancement of fatty acid oxidation may serve to optimally support the dual requirements of increased energy demand and remodelling in the heart. Our findings identify a novel paradigm for redox-regulated Warburg-type metabolic reprogramming in the terminally differentiated heart.

physiology↗

bioRxiv2025

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

BackgroundChanges 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. MethodsHeart 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. ResultsH3K27me3 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. ConclusionsReduction 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 PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIElevation in H3K27me3 during aging is likely to lead to impaired myocardial autophagy and metabolic reprogramming. C_LIO_LIReduction in SLC1A5 during aging in humans is likely to contribute to myocardial dysfunction C_LIO_LIDietary supplementation of glutamine improves cardiac function in aged mice. C_LI What are the clinical implications?O_LITargeting H3K27me3 in the aged population may to mitigate cardiovascular disease C_LIO_LIDietary glutamine supplementation offers a promising strategy to improve cardiac function during aging. C_LI

cell biology↗