title: Enhanced skeletal muscle expression of extracellular superoxide dismutase mitigates streptozotocin-induced diabetic cardiomyopathy by reducing oxidative stress and aberrant cell signaling.
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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Call
authors.affiliation: 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.
authors.forename: Kristopher H
authors.initials: KH
authors.lastname: Chain
authors.affiliation: 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.
authors.forename: Kyle S
authors.initials: KS
authors.lastname: Martin
authors.affiliation: 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.
authors.forename: Vitor A
authors.initials: VA
authors.lastname: Lira
authors.affiliation: 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.
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Okutsu
authors.affiliation: 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.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004247:DNA / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental; D058065:Diabetic Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004247:DNA; D013482:Superoxide Dismutase
keywords: antioxidants; cardiomyocyte; diabetic cardiomyopathies; exercise; hypertrophy; oxidative stress