TY - JOUR T1 - Intermittent Fasting Activates AMP-Kinase to Restructure Right Ventricular Lipid Metabolism and Microtubules in Two Rodent Models of Pulmonary Arterial Hypertension JF - bioRxiv DO - 10.1101/2022.03.07.483333 SP - 2022.03.07.483333 AU - Felipe Kazmirczak AU - Lynn M. Hartweck AU - Neal T. Vogel AU - Jenna B. Mendelson AU - Anna K. Park AU - Rashmi M. Raveendran AU - Jin O-Uchi AU - Bong Sook Jhun AU - Sasha Z. Prisco AU - Kurt W. Prins Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/09/24/2022.03.07.483333.abstract N2 - 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.Highlights- Intermittent fasting activates AMPK to restructure right ventricular mitochondrial and peroxisomal fatty acid fatty acid metabolism in two rodent models of PAH.- Intermittent fasting prevents downregulation of multiple electron transport chain proteins in both monocrotaline and Sugen-hypoxia RVs.- Pathological microtubule-mediated junctophilin-2 dysregulation and subsequent t-tubule remodeling is mitigated by intermittent fasting.- Intermittent fasting suppresses the induction of both the canonical and peroxisomal ferroptosis pathways in RV failure.Competing Interest StatementKWP serves as a consultant for Edwards and received a grant from United Therapeutics.ACAA1Peroxisome 3-ketoacyl-CoA thiolaseACADAcyl-CoA dehydrogenaseACSLAcyl-CoA Synthetase Long ChainAGPAT31-acylglycerol-3-phosphate O-acyltransferase 3AGPSAlkylglycerone phosphate synthaseAMPKAdenosine monophosphate-activated protein kinaseCLIP170Cytoplasmic linker protein-170Ees/EaEnd-systolic elastance/arterial elastanceEHHADHL-bifunctional enzymeETCElectron transport chainFAR1Fatty acyl-CoA reductase 1GNPATGlyceronephosphate O-acyltransferaseIFIntermittent fastingMAP4Microtubule-associated protein 4MCTMonocrotalinePAHPulmonary arterial hypertensionPHYHPhytanoyl-CoA 2-hydroxylasepMAP4Microtubule-associated protein 4 Ser941 phosphorylatedRKIP/PEBP1Raf kinase inhibitor proteinRVRight ventricularSCP2Sterol carrier protein 2SuHxSugen-hypoxiaTAPSEtricuspid plane annular systolic excursionT-tubuleTransvere tubule ER -