Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice

Increasing evidence indicates the involvement of myocardial oxidative injury and mitochondrial dysfunction in the pathophysiology of heart failure (HF). Alpha-ketoglutarate (AKG) is an intermediate metabolite of the tricarboxylic acid (TCA) cycle that participates in different cellular metabolic and regulatory pathways. The circulating concentration of AKG was found to decrease with ageing and is elevated after acute exercise and resistance exercise and in HF. Recent studies in experimental models have shown that dietary AKG reduces reactive oxygen species (ROS) production and systemic inflammatory cytokine levels, regulates metabolism, extends lifespan and delays the occurrence of age-related decline. However, the effects of AKG on HF remain unclear. In the present study, we explored the effects of AKG on left ventricular (LV) systolic function, the myocardial ROS content and mitophagy in mice with transverse aortic constriction (TAC). AKG supplementation inhibited pressure overload-induced myocardial hypertrophy and fibrosis and improved cardiac systolic dysfunction; in vitro, AKG decreased the Ang II-induced upregulation of beta-MHC and ANP, reduced ROS production and cardiomyocyte apoptosis, and repaired Ang II-mediated injury to the mitochondrial membrane potential (MMP). These benefits of AKG in the TAC mice may have been obtained by enhanced mitophagy, which cleared damaged mitochondria. In summary, our study suggests that AKG improves myocardial hypertrophy remodelling, fibrosis and LV systolic dysfunction in the pressure-overloaded heart by promoting mitophagy to clear damaged mitochondria and reduce ROS production; thus, AKG may have therapeutic potential for HF.

Automated summary

Alpha-ketoglutarate (AKG) shows potential as a therapeutic agent for heart failure by reducing myocardial hypertrophy and fibrosis, improving cardiac systolic dysfunction, and promoting mitophagy to clear damaged mitochondria and reduce ROS production. Studies suggest that AKG could enhance heart function and delay the progression of heart failure via these mechanisms.