title: Extracellular superoxide dismutase ameliorates skeletal muscle abnormalities, cachexia, and exercise intolerance in mice with congestive heart failure.
abstract: BACKGROUND
  Congestive heart failure (CHF) is a leading cause of morbidity and mortality, and oxidative stress has been implicated in the pathogenesis of cachexia (muscle wasting) and the hallmark symptom, exercise intolerance. We have previously shown that a nitric oxide-dependent antioxidant defense renders oxidative skeletal muscle resistant to catabolic wasting. Here, we aimed to identify and determine the functional role of nitric oxide-inducible antioxidant enzyme(s) in protection against cardiac cachexia and exercise intolerance in CHF.
  
  
  RESULTS
  We demonstrated that systemic administration of endogenous nitric oxide donor S-nitrosoglutathione in mice blocked the reduction of extracellular superoxide dismutase (EcSOD) protein expression, as well as the induction of MAFbx/Atrogin-1 mRNA expression and muscle atrophy induced by glucocorticoid. We further showed that endogenous EcSOD, expressed primarily by type IId/x and IIa myofibers and enriched at endothelial cells, is induced by exercise training. Muscle-specific overexpression of EcSOD by somatic gene transfer or transgenesis (muscle creatine kinase [MCK]-EcSOD) in mice significantly attenuated muscle atrophy. Importantly, when crossbred into a mouse genetic model of CHF (α-myosin heavy chain-calsequestrin), MCK-EcSOD transgenic mice had significant attenuation of cachexia with preserved whole body muscle strength and endurance capacity in the absence of reduced HF. Enhanced EcSOD expression significantly ameliorated CHF-induced oxidative stress, MAFbx/Atrogin-1 mRNA expression, loss of mitochondria, and vascular rarefaction in skeletal muscle.
  
  
  CONCLUSIONS
  EcSOD plays an important antioxidant defense function in skeletal muscle against cardiac cachexia and exercise intolerance in CHF.
authors: From the Departments of Medicine (M.O., J.A.C., V.A.L., M.Z., J.A.D., C.M.R., B.H.A., Z.Y.), Pharmacology (Z.Y.), and Molecular Physiology and Biological Physics (Z.Y.), Center for Skeletal Muscle Research (M.O., J.A.C., V.A.L., M.Z., J.A.D., Z.Y.), Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA; and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA (B.A.F., K.S.M., S.M.P.-C.).
authors: Mitsuharu
authors: M
authors: Okutsu
authors: From the Departments of Medicine (M.O., J.A.C., V.A.L., M.Z., J.A.D., C.M.R., B.H.A., Z.Y.), Pharmacology (Z.Y.), and Molecular Physiology and Biological Physics (Z.Y.), Center for Skeletal Muscle Research (M.O., J.A.C., V.A.L., M.Z., J.A.D., Z.Y.), Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA; and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA (B.A.F., K.S.M., S.M.P.-C.).
authors: Jarrod A
authors: JA
authors: Call
authors: From the Departments of Medicine (M.O., J.A.C., V.A.L., M.Z., J.A.D., C.M.R., B.H.A., Z.Y.), Pharmacology (Z.Y.), and Molecular Physiology and Biological Physics (Z.Y.), Center for Skeletal Muscle Research (M.O., J.A.C., V.A.L., M.Z., J.A.D., Z.Y.), Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA; and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA (B.A.F., K.S.M., S.M.P.-C.).
authors: Vitor A
authors: VA
authors: Lira
authors: From the Departments of Medicine (M.O., J.A.C., V.A.L., M.Z., J.A.D., C.M.R., B.H.A., Z.Y.), Pharmacology (Z.Y.), and Molecular Physiology and Biological Physics (Z.Y.), Center for Skeletal Muscle Research (M.O., J.A.C., V.A.L., M.Z., J.A.D., Z.Y.), Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA; and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA (B.A.F., K.S.M., S.M.P.-C.).
authors: Mei
authors: M
authors: Zhang
authors: From the Departments of Medicine (M.O., J.A.C., V.A.L., M.Z., J.A.D., C.M.R., B.H.A., Z.Y.), Pharmacology (Z.Y.), and Molecular Physiology and Biological Physics (Z.Y.), Center for Skeletal Muscle Research (M.O., J.A.C., V.A.L., M.Z., J.A.D., Z.Y.), Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA; and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA (B.A.F., K.S.M., S.M.P.-C.).
authors: Jean A
authors: JA
authors: Donet
authors: From the Departments of Medicine (M.O., J.A.C., V.A.L., M.Z., J.A.D., C.M.R., B.H.A., Z.Y.), Pharmacology (Z.Y.), and Molecular Physiology and Biological Physics (Z.Y.), Center for Skeletal Muscle Research (M.O., J.A.C., V.A.L., M.Z., J.A.D., Z.Y.), Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA; and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA (B.A.F., K.S.M., S.M.P.-C.).
authors: Brent A
authors: BA
authors: French
authors: From the Departments of Medicine (M.O., J.A.C., V.A.L., M.Z., J.A.D., C.M.R., B.H.A., Z.Y.), Pharmacology (Z.Y.), and Molecular Physiology and Biological Physics (Z.Y.), Center for Skeletal Muscle Research (M.O., J.A.C., V.A.L., M.Z., J.A.D., Z.Y.), Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA; and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA (B.A.F., K.S.M., S.M.P.-C.).
authors: Kyle S
authors: KS
authors: Martin
authors: From the Departments of Medicine (M.O., J.A.C., V.A.L., M.Z., J.A.D., C.M.R., B.H.A., Z.Y.), Pharmacology (Z.Y.), and Molecular Physiology and Biological Physics (Z.Y.), Center for Skeletal Muscle Research (M.O., J.A.C., V.A.L., M.Z., J.A.D., Z.Y.), Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA; and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA (B.A.F., K.S.M., S.M.P.-C.).
authors: Shayn M
authors: SM
authors: Peirce-Cottler
authors: From the Departments of Medicine (M.O., J.A.C., V.A.L., M.Z., J.A.D., C.M.R., B.H.A., Z.Y.), Pharmacology (Z.Y.), and Molecular Physiology and Biological Physics (Z.Y.), Center for Skeletal Muscle Research (M.O., J.A.C., V.A.L., M.Z., J.A.D., Z.Y.), Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA; and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA (B.A.F., K.S.M., S.M.P.-C.).
authors: Christopher M
authors: CM
authors: Rembold
authors: From the Departments of Medicine (M.O., J.A.C., V.A.L., M.Z., J.A.D., C.M.R., B.H.A., Z.Y.), Pharmacology (Z.Y.), and Molecular Physiology and Biological Physics (Z.Y.), Center for Skeletal Muscle Research (M.O., J.A.C., V.A.L., M.Z., J.A.D., Z.Y.), Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA; and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA (B.A.F., K.S.M., S.M.P.-C.).
authors: Brian H
authors: BH
authors: Annex
authors: From the Departments of Medicine (M.O., J.A.C., V.A.L., M.Z., J.A.D., C.M.R., B.H.A., Z.Y.), Pharmacology (Z.Y.), and Molecular Physiology and Biological Physics (Z.Y.), Center for Skeletal Muscle Research (M.O., J.A.C., V.A.L., M.Z., J.A.D., Z.Y.), Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA; and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA (B.A.F., K.S.M., S.M.P.-C.). zhen.yan@virginia.edu.
authors: Zhen
authors: Z
authors: Yan
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000502:physiology; D002100:Cachexia / Q000503:physiopathology* / Q000517:prevention & control*; D052283:Creatine Kinase, MM Form / Q000502:physiology; D004195:Disease Models, Animal; D017079:Exercise Tolerance / Q000502:physiology*; D006333:Heart Failure / Q000150:complications* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D010805:Physical Conditioning, Animal / Q000502:physiology; D012333:RNA, Messenger / Q000502:physiology; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D044843:SKP Cullin F-Box Protein Ligases / Q000502:physiology; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D000975:Antioxidants; D009124:Muscle Proteins; D012333:RNA, Messenger; D026422:S-Nitrosoglutathione; D013482:Superoxide Dismutase; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D052283:Creatine Kinase, MM Form
keywords: capillaries; exercise; mitochondria; muscular atrophy; oxidative stress