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Circ Heart Fail. 2015 Jan;8(1):188-97. doi: 10.1161/CIRCHEARTFAILURE.114.001540. Epub 2014 Dec 11.

Enhanced skeletal muscle expression of extracellular superoxide dismutase mitigates streptozotocin-induced diabetic cardiomyopathy by reducing oxidative stress and aberrant cell signaling.

Author information

1
From the Departments of Medicine (J.A.C., K.H.C., V.A.L., M.O., M.Z., Z.Y.), Pharmacology (Z.Y.), Molecular Physiology and Biological Physics (Z.Y.), Center for Skeletal Muscle Research at the Robert M. Berne Cardiovascular Research Center (J.A.C., K.H.C., V.A.L., M.O., M.Z., Z.Y.), and Department of Biomedical Engineering (K.S.M.), University of Virginia, Charlottesville.
2
From the Departments of Medicine (J.A.C., K.H.C., V.A.L., M.O., M.Z., Z.Y.), Pharmacology (Z.Y.), Molecular Physiology and Biological Physics (Z.Y.), Center for Skeletal Muscle Research at the Robert M. Berne Cardiovascular Research Center (J.A.C., K.H.C., V.A.L., M.O., M.Z., Z.Y.), and Department of Biomedical Engineering (K.S.M.), University of Virginia, Charlottesville. zhen.yan@virginia.edu.

Abstract

BACKGROUND:

Exercise training enhances extracellular superoxide dismutase (EcSOD) expression in skeletal muscle and elicits positive health outcomes in individuals with diabetes mellitus. The goal of this study was to determine if enhanced skeletal muscle expression of EcSOD is sufficient to mitigate streptozotocin-induced diabetic cardiomyopathy.

METHODS AND RESULTS:

Exercise training promotes EcSOD expression in skeletal muscle and provides protection against diabetic cardiomyopathy; however, it is not known if enhanced expression of EcSOD in skeletal muscle plays a functional role in this protection. Here, we show that skeletal muscle-specific EcSOD transgenic mice are protected from cardiac hypertrophy, fibrosis, and dysfunction under the condition of type 1 diabetes mellitus induced by streptozotocin injection. We also show that both exercise training and muscle-specific transgenic expression of EcSOD result in elevated EcSOD protein in the blood and heart without increased transcription in the heart, suggesting that enhanced expression of EcSOD from skeletal muscle redistributes to the heart. Importantly, cardiac tissue in transgenic mice displayed significantly reduced oxidative stress, aberrant cell signaling, and inflammatory cytokine expression compared with wild-type mice under the same diabetic condition.

CONCLUSIONS:

Enhanced expression of EcSOD in skeletal muscle is sufficient to mitigate streptozotocin-induced diabetic cardiomyopathy through attenuation of oxidative stress, aberrant cell signaling, and inflammation, suggesting a cross-organ mechanism by which exercise training improves cardiac function in diabetes mellitus.

KEYWORDS:

antioxidants; cardiomyocyte; diabetic cardiomyopathies; exercise; hypertrophy; oxidative stress

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