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.
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 Statement
KWP serves as a consultant for Edwards and received a grant from United Therapeutics.
Footnotes
Funding: JOU is funded by NIH R01 HL136757, BSJ is funded by an American Heart Association Career Development Award 18CDA34110091, and KWP is funded by NIH K08 HL140100, NIH R01s HL158795 and HL162927, and an Innovation Grant from the American Lung Association (IA-816386).
Updated multiple figures due to inclusion of a second species.
Abbreviations
- ACAA1
- Peroxisome 3-ketoacyl-CoA thiolase
- ACAD
- Acyl-CoA dehydrogenase
- ACSL
- Acyl-CoA Synthetase Long Chain
- AGPAT3
- 1-acylglycerol-3-phosphate O-acyltransferase 3
- AGPS
- Alkylglycerone phosphate synthase
- AMPK
- Adenosine monophosphate-activated protein kinase
- CLIP170
- Cytoplasmic linker protein-170
- Ees/Ea
- End-systolic elastance/arterial elastance
- EHHADH
- L-bifunctional enzyme
- ETC
- Electron transport chain
- FAR1
- Fatty acyl-CoA reductase 1
- GNPAT
- Glyceronephosphate O-acyltransferase
- IF
- Intermittent fasting
- MAP4
- Microtubule-associated protein 4
- MCT
- Monocrotaline
- PAH
- Pulmonary arterial hypertension
- PHYH
- Phytanoyl-CoA 2-hydroxylase
- pMAP4
- Microtubule-associated protein 4 Ser941 phosphorylated
- RKIP/PEBP1
- Raf kinase inhibitor protein
- RV
- Right ventricular
- SCP2
- Sterol carrier protein 2
- SuHx
- Sugen-hypoxia
- TAPSE
- tricuspid plane annular systolic excursion
- T-tubule
- Transvere tubule