Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome

Olesya Ilkun; Nicole Wilde; Joseph Tuinei; Karla M P Pires; Yi Zhu; Heiko Bugger; Jamie Soto; Benjamin Wayment; Curtis Olsen; Sheldon E Litwin; E Dale Abel

doi:10.1016/j.yjmcc.2015.05.012

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Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome

Journal article

Peer reviewed

Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome

Olesya Ilkun, Nicole Wilde, Joseph Tuinei, Karla M P Pires, Yi Zhu, Heiko Bugger, Jamie Soto, Benjamin Wayment, Curtis Olsen, Sheldon E Litwin, …

Journal of molecular and cellular cardiology, Vol.85, pp.104-116

08/2015

DOI: 10.1016/j.yjmcc.2015.05.012

PMCID: PMC4530070

PMID: 26004364

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Abstract

Cardiac dysfunction in obesity is associated with mitochondrial dysfunction, oxidative stress and altered insulin sensitivity. Whether oxidative stress directly contributes to myocardial insulin resistance remains to be determined. This study tested the hypothesis that ROS scavenging will improve mitochondrial function and insulin sensitivity in the hearts of rodent models with varying degrees of insulin resistance and hyperglycemia. The catalytic antioxidant MnTBAP was administered to the uncoupling protein-diphtheria toxin A (UCP-DTA) mouse model of insulin resistance (IR) and obesity, at early and late time points in the evolution of IR, and to db/db mice with severe obesity and type-two diabetes. Mitochondrial function was measured in saponin-permeabilized cardiac fibers. Aconitase activity and hydrogen peroxide emission were measured in isolated mitochondria. Insulin-stimulated glucose oxidation, glycolysis and fatty acid oxidation rates were measured in isolated working hearts, and 2-deoxyglucose uptake was measured in isolated cardiomyocytes. Four weeks of MnTBAP attenuated glucose intolerance in 13-week-old UCP-DTA mice but was without effect in 24-week-old UCP-DTA mice and in db/db mice. Despite the absence of improvement in the systemic metabolic milieu, MnTBAP reversed cardiac mitochondrial oxidative stress and improved mitochondrial bioenergetics by increasing ATP generation and reducing mitochondrial uncoupling in all models. MnTBAP also improved myocardial insulin mediated glucose metabolism in 13 and 24-week-old UCP-DTA mice. Pharmacological ROS scavenging improves myocardial energy metabolism and insulin responsiveness in obesity and type 2 diabetes via direct effects that might be independent of changes in systemic metabolism.

Mitochondria, Heart - metabolism

Oxidative Stress

Signal Transduction

Mice, Inbred C57BL

Insulin Resistance

Homeostasis

Antioxidants - pharmacology

Insulin - blood

Metabolic Syndrome - drug therapy

Metalloporphyrins - pharmacology

Metabolic Syndrome - blood

Antioxidants - therapeutic use

Metalloporphyrins - therapeutic use

Animals

Energy Metabolism

Myocardium - metabolism

Mice, Obese

Drug Evaluation, Preclinical

Fatty Acids - metabolism

Details

Title: Subtitle: Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome
Creators: Olesya Ilkun - Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Nicole Wilde - Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Joseph Tuinei - Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Karla M P Pires - Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Yi Zhu - Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Heiko Bugger - Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Jamie Soto - Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Fraternal Order of Eagles Diabetes Research Center, Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Benjamin Wayment - Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT84112, USA
Curtis Olsen - Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT84112, USA
Sheldon E Litwin - Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT84112, USA
E Dale Abel - Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Fraternal Order of Eagles Diabetes Research Center, Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: DRCAdmin@uiowa.edu
Resource Type: Journal article
Publication Details: Journal of molecular and cellular cardiology, Vol.85, pp.104-116
DOI: 10.1016/j.yjmcc.2015.05.012
PMID: 26004364
PMCID: PMC4530070
NLM abbreviation: J Mol Cell Cardiol
ISSN: 0022-2828
eISSN: 1095-8584
Publisher: England
Grant note: T32 DK091317 / NIDDK NIH HHS U01 HL070525 / NHLBI NIH HHS UO1HL70525 / NHLBI NIH HHS R01HL73167 / NHLBI NIH HHS U54 HL112311 / NHLBI NIH HHS T32DK091317 / NIDDK NIH HHS R01 HL073167 / NHLBI NIH HHS
Language: English
Date published: 08/2015
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: 9984025275102771

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