title: Regulation of fatty acid metabolism by mTOR in adult murine hearts occurs independently of changes in PGC-1α.
abstract: Mechanistic target of rapamycin (mTOR) is essential for cardiac development, growth, and function, but the role of mTOR in the regulation of cardiac metabolism and mitochondrial respiration is not well established. This study sought to determine cardiac metabolism and mitochondrial bioenergetics in mice with inducible deletion of mTOR in the adult heart. Doxycycline-inducible and cardiac-specific mTOR-deficient mice were generated by crossing cardiac-specific doxycycline-inducible tetO-Cre mice with mice harboring mTOR floxed alleles. Deletion of mTOR reduced mTORC1 and mTORC2 signaling after in vivo insulin stimulation. Maximum and minimum dP/dt measured by cardiac catheterization in vivo under anesthesia and cardiac output, cardiac power, and aortic pressure in ex vivo working hearts were unchanged, suggesting preserved cardiac function 4 wk after doxycycline treatment. However, myocardial palmitate oxidation was impaired, whereas glucose oxidation was increased. Consistent with reduced palmitate oxidation, expression of fatty acid metabolism genes fatty acid-binding protein 3, medium-chain acyl-CoA dehydrogenase, and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein)-α and -β was reduced, and carnitine palmitoyl transferase-1 and -2 enzymatic activity was decreased. Mitochondrial palmitoyl carnitine respiration was diminished. However, mRNA for peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and -1β, protein levels of PGC-1α, and electron transport chain subunits, mitochondrial DNA, and morphology were unchanged. Also, pyruvate-supported and FCCP-stimulated respirations were unchanged, suggesting that mTOR deletion induces a specific defect in fatty acid utilization. In conclusion, mTOR regulates mitochondrial fatty acid utilization but not glucose utilization in the heart via mechanisms that are independent of changes in PGC expression.
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jamie
authors.initials: J
authors.lastname: Soto
authors.forename: Brandon
authors.initials: B
authors.lastname: Anderson
authors.forename: Christian
authors.initials: C
authors.lastname: Riehle
authors.forename: Yi Cheng
authors.initials: YC
authors.lastname: Zhang
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wende
authors.forename: Deborah
authors.initials: D
authors.lastname: Jones
authors.forename: Donald A
authors.initials: DA
authors.lastname: McClain
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002302:Cardiac Output; D004272:DNA, Mitochondrial / Q000378:metabolism; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000502:physiology; D055442:Metabolome; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic
chemical_list: D004272:DNA, Mitochondrial; D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: cardiac substrate metabolism; mechanistic target of rapamycin; mitochondrial respiration; peroxisome proliferator-activated receptor-γ coactivator-1α