<i>PGRMC1</i> Ablation Protects from Energy-Starved Heart Failure by Promoting Fatty Acid/Pyruvate Oxidation

Heart failure (HF) is an emerging epidemic with a high mortality rate. Apart from conventional treatment methods, such as surgery or use of vasodilation drugs, metabolic therapy has been suggested as a new therapeutic strategy. The heart relies on fatty acid oxidation and glucose (pyruvate) oxidation for ATP-mediated contractility; the former meets most of the energy requirement, but the latter is more efficient. Inhibition of fatty acid oxidation leads to the induction of pyruvate oxidation and provides cardioprotection to failing energy-starved hearts. One of the non-canonical types of sex hormone receptors, progesterone receptor membrane component 1 (<i>Pgrmc1</i>), is a non-genomic progesterone receptor associated with reproduction and fertility. Recent studies revealed that <i>Pgrmc1</i> regulates glucose and fatty acid synthesis. Notably, <i>Pgrmc1</i> has also been associated with diabetic cardiomyopathy, as it reduces lipid-mediated toxicity and delays cardiac injury. However, the mechanism by which <i>Pgrmc1</i> influences the energy-starved failing heart remains unknown. In this study, we found that loss of <i>Pgrmc1</i> inhibited glycolysis and increased fatty acid/pyruvate oxidation, which is directly associated with ATP production, in starved hearts. Loss of <i>Pgrmc1</i> during starvation activated the phosphorylation of AMP-activated protein kinase, which induced cardiac ATP production. <i>Pgrmc1</i> loss increased the cellular respiration of cardiomyocytes under low-glucose conditions. In isoproterenol-induced cardiac injury, <i>Pgrmc1</i> knockout resulted in less fibrosis and low heart failure marker expression. In summary, our results revealed that <i>Pgrmc1</i> ablation in energy-deficit conditions increases fatty acid/pyruvate oxidation to protect against cardiac damage via energy starvation. Moreover, <i>Pgrmc1</i> may be a regulator of cardiac metabolism that switches the dominance of glucose-fatty acid usage according to nutritional status and nutrient availability in the heart.