Regulation of fatty acid metabolism by mTOR in adult murine hearts occurs independently of changes in PGC-1α

Yi Zhu; Jamie Soto; Brandon Anderson; Christian Riehle; Yi Cheng Zhang; Adam R Wende; Deborah Jones; Donald A McClain; E. Dale Abel

doi:10.1152/ajpheart.00877.2012

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Regulation of fatty acid metabolism by mTOR in adult murine hearts occurs independently of changes in PGC-1α

Journal article

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Regulation of fatty acid metabolism by mTOR in adult murine hearts occurs independently of changes in PGC-1α

Yi Zhu, Jamie Soto, Brandon Anderson, Christian Riehle, Yi Cheng Zhang, Adam R Wende, Deborah Jones, Donald A McClain and E. Dale Abel

American journal of physiology. Heart and circulatory physiology, Vol.305(1), pp.H41-H51

07/01/2013

DOI: 10.1152/ajpheart.00877.2012

PMCID: PMC3727103

PMID: 23624629

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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/d t 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.

Energetics and Metabolism

peroxisome proliferator-activated receptor-γ coactivator-1α

mechanistic target of rapamycin

cardiac substrate metabolism

mitochondrial respiration

Details

Title: Subtitle: Regulation of fatty acid metabolism by mTOR in adult murine hearts occurs independently of changes in PGC-1α
Creators: Yi Zhu - Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, School of Medicine, Salt Lake City, Utah; and
Jamie Soto - Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, School of Medicine, Salt Lake City, Utah; and
Brandon Anderson - Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, School of Medicine, Salt Lake City, Utah; and
Christian Riehle - Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, School of Medicine, Salt Lake City, Utah; and
Yi Cheng Zhang - Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, School of Medicine, Salt Lake City, Utah; and
Adam R Wende - Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, School of Medicine, Salt Lake City, Utah; and
Deborah Jones - Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, School of Medicine, Salt Lake City, Utah; and
Donald A McClain - Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, School of Medicine, Salt Lake City, Utah; and
E. Dale Abel - Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah, School of Medicine, Salt Lake City, Utah; and
Resource Type: Journal article
Publication Details: American journal of physiology. Heart and circulatory physiology, Vol.305(1), pp.H41-H51
DOI: 10.1152/ajpheart.00877.2012
PMID: 23624629
PMCID: PMC3727103
NLM abbreviation: Am J Physiol Heart Circ Physiol
ISSN: 0363-6135
eISSN: 1522-1539
Publisher: American Physiological Society; Bethesda, MD
Language: English
Date published: 07/01/2013
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024547002771

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