Understanding the role of Retinoid X Receptors in cardiac homeostasis: from transcription to physiology

Abstract

The mammalian heart requires an enormous amount of ATP to maintain cardiac contraction. Cardiomyocytes (CMs) are thus considered as highly flexible metabolic cells able to consume a broad spectrum of substrates (glucose, lipids, lactate, amino acids, and ketone bodies) depending on physiological context and age. While fetal CMs and failing heart primarily rely on glucose and lactate to produce energy, mitochondrial lipid oxidation constitute the major ATP source in adult healthy myocardium. To maintain cardiac homeostasis, energy production is tightly coordinated by transcriptional circuits that remain poorly understood. In this study, we aimed to interrogate the molecular implications of CM-intrinsic Retinoid X Receptors (RXRs), a family of ligand-activated transcription factors, during prenatal and adult metabolic homeostasis. For this purpose, we conducted a multifaceted analysis that combined in vivo and in vitro CM-specific models, state-of-the-art genome-wide approaches, metabolomics and proteomics, advance imaging techniques, and diet-based nutritional intervention. We have found that CM-intrinsic RXRs are key transcription factors of lipid metabolism in newborn and adult hearts. Specifically, RXRs transactivate and shape the epigenetic landscape of genes encoding mitochondrial β-oxidation enzymatic components, allowing proper fatty acid-derived ATP synthesis. Despite the role of myocardial RXRs in maintaining lipid homeostasis is conserved, their physiological impact in the heart varies between stages. Newborn mice lacking RXRs in embryonic CMs (edKO) do not present cardiogenic problems but develop lethal systolic dysfunction shortly after birth. Mechanistically, edKO hearts displayed a defective metabolic status with blunted lipid-derived ATP and enhanced glucose oxidation, indicating that RXRs signaling is essential to promote perinatal mitochondrial maturation. We have further demonstrated γ-linolenic acid (GLA) in colostrum, a member of ω-6 pathway, as the endogenous ligand responsible for driving RXRs activity. These data uncovers GLA-RXR axis as the fundamental mechanism by which maternal physiology orchestrate transcriptional remodeling to allow metabolic adaptation and mitochondrial maturation in perinatal hearts. On the other hand, adult mice lacking RXRs in postnatal CMs (tKO) develop severe idiopathic dilated cardiomyopathy (DiCM) without affecting survival. Specifically, tKO hearts displayed profound systolic and diastolic dysfunction, together with abnormal cardiac remodeling and impaired mitochondrial integrity. Similarly to prenatal RXRs deletion, tKO hearts showed an altered metabolic landscape characterized by defective lipid oxidation and enhanced glucose consumption, that ultimately did not affected global energy production. This finding was explained by a compensatory increase in amino acid oxidation rate, highlighting this metabolic rewiring as an underlying feature of RXR-driven DiCM. Altogether, this work proves that CM-specific RXRs are crucial transcriptional regulators that orchestrate proper nutrient utilization in postnatal CMs, becoming an attractive therapeutic target against cardiometabolic disease