Intermittent Fasting Activates AMP-Kinase to Restructure Right Ventricular Lipid Metabolism and Microtubules in Two Rodent Models of Pulmonary Arterial Hypertension

Abstract

Intermittent fasting (IF) extends lifespan via pleotropic mechanisms, but one important molecular mediator of the beneficial effects of IF is AMP-kinase (AMPK). AMPK enhances lipid metabolism and modulates microtubule dynamics. Dysregulation of these two molecular pathways causes right ventricular (RV) failure in pulmonary arterial hypertension (PAH). In two models of rodent PAH, we show IF activates RV AMPK, which restores mitochondrial morphology and peroxisomal density and restructures mitochondrial/peroxisomal lipid metabolism protein regulation. IF also increases electron transport chain (ETC) protein abundance and activity in the RV. Echocardiographic and hemodynamic measures of RV function are positively associated with fatty acid oxidation and ETC protein levels in correlational heatmapping analyses. IF also combats heightened microtubule density, which normalizes t-tubule structure. In summation, we demonstrate IF-mediated AMPK signaling counteracts two key molecular drivers of RV failure. Thus, IF may be a novel treatment approach for RV dysfunction, a currently untreatable and lethal consequence of PAH.