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Regulation of fatty acid metabolism by mTOR in adult murine hearts occurs independently of changes in PGC-1α.
Am J Physiol Heart Circ Physiol. 2013 Jul 01; 305(1):H41-51.AJ

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+Show Affiliations

Division of Endocrinology, Metabolism, and Diabetes, University of Utah, School of Medicine, Salt Lake City, UT 84112, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23624629

Citation

Zhu, Yi, et al. "Regulation of Fatty Acid Metabolism By mTOR in Adult Murine Hearts Occurs Independently of Changes in PGC-1α." American Journal of Physiology. Heart and Circulatory Physiology, vol. 305, no. 1, 2013, pp. H41-51.
Zhu Y, Soto J, Anderson B, et al. Regulation of fatty acid metabolism by mTOR in adult murine hearts occurs independently of changes in PGC-1α. Am J Physiol Heart Circ Physiol. 2013;305(1):H41-51.
Zhu, Y., Soto, J., Anderson, B., Riehle, C., Zhang, Y. C., Wende, A. R., Jones, D., McClain, D. A., & Abel, E. D. (2013). Regulation of fatty acid metabolism by mTOR in adult murine hearts occurs independently of changes in PGC-1α. American Journal of Physiology. Heart and Circulatory Physiology, 305(1), H41-51. https://doi.org/10.1152/ajpheart.00877.2012
Zhu Y, et al. Regulation of Fatty Acid Metabolism By mTOR in Adult Murine Hearts Occurs Independently of Changes in PGC-1α. Am J Physiol Heart Circ Physiol. 2013 Jul 1;305(1):H41-51. PubMed PMID: 23624629.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulation of fatty acid metabolism by mTOR in adult murine hearts occurs independently of changes in PGC-1α. AU - Zhu,Yi, AU - Soto,Jamie, AU - Anderson,Brandon, AU - Riehle,Christian, AU - Zhang,Yi Cheng, AU - Wende,Adam R, AU - Jones,Deborah, AU - McClain,Donald A, AU - Abel,E Dale, Y1 - 2013/04/26/ PY - 2013/4/30/entrez PY - 2013/4/30/pubmed PY - 2013/9/13/medline KW - cardiac substrate metabolism KW - mechanistic target of rapamycin KW - mitochondrial respiration KW - peroxisome proliferator-activated receptor-γ coactivator-1α SP - H41 EP - 51 JF - American journal of physiology. Heart and circulatory physiology JO - Am J Physiol Heart Circ Physiol VL - 305 IS - 1 N2 - 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. SN - 1522-1539 UR - https://www.unboundmedicine.com/medline/citation/23624629/Regulation_of_fatty_acid_metabolism_by_mTOR_in_adult_murine_hearts_occurs_independently_of_changes_in_PGC_1α_ L2 - https://journals.physiology.org/doi/10.1152/ajpheart.00877.2012?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -