Extracellular superoxide dismutase ameliorates skeletal muscle abnormalities, cachexia, and exercise intolerance in mice with congestive heart failure

Mitsuharu Okutsu, Jarrod A. Call, Vitor A. Lira, Mei Zhang, Jean A. Donet, Brent A. French, Kyle S. Martin, Shayn M. Peirce-Cottler, Christopher M. Rembold, Brian H. Annex, Zhen Yan

Research output: Contribution to journalArticle

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. Methods and 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.

Original languageEnglish (US)
Pages (from-to)519-530
Number of pages12
JournalCirculation: Heart Failure
Volume7
Issue number3
DOIs
StatePublished - May 2014
Externally publishedYes

Fingerprint

Cachexia
Superoxide Dismutase
Skeletal Muscle
Heart Failure
MM Form Creatine Kinase
Muscular Atrophy
Antioxidants
Nitric Oxide
Oxidative Stress
Calsequestrin
S-Nitrosoglutathione
Gene Transfer Techniques
Muscles
Messenger RNA
Nitric Oxide Donors
Myosin Heavy Chains
Genetic Models
Muscle Strength
Transgenic Mice
Glucocorticoids

Keywords

  • Capillaries
  • Exercise
  • Mitochondria
  • Muscular atrophy
  • Oxidative stress

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Extracellular superoxide dismutase ameliorates skeletal muscle abnormalities, cachexia, and exercise intolerance in mice with congestive heart failure. / Okutsu, Mitsuharu; Call, Jarrod A.; Lira, Vitor A.; Zhang, Mei; Donet, Jean A.; French, Brent A.; Martin, Kyle S.; Peirce-Cottler, Shayn M.; Rembold, Christopher M.; Annex, Brian H.; Yan, Zhen.

In: Circulation: Heart Failure, Vol. 7, No. 3, 05.2014, p. 519-530.

Research output: Contribution to journalArticle

Okutsu, M, Call, JA, Lira, VA, Zhang, M, Donet, JA, French, BA, Martin, KS, Peirce-Cottler, SM, Rembold, CM, Annex, BH & Yan, Z 2014, 'Extracellular superoxide dismutase ameliorates skeletal muscle abnormalities, cachexia, and exercise intolerance in mice with congestive heart failure', Circulation: Heart Failure, vol. 7, no. 3, pp. 519-530. https://doi.org/10.1161/CIRCHEARTFAILURE.113.000841
Okutsu, Mitsuharu ; Call, Jarrod A. ; Lira, Vitor A. ; Zhang, Mei ; Donet, Jean A. ; French, Brent A. ; Martin, Kyle S. ; Peirce-Cottler, Shayn M. ; Rembold, Christopher M. ; Annex, Brian H. ; Yan, Zhen. / Extracellular superoxide dismutase ameliorates skeletal muscle abnormalities, cachexia, and exercise intolerance in mice with congestive heart failure. In: Circulation: Heart Failure. 2014 ; Vol. 7, No. 3. pp. 519-530.
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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. Methods and 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.",
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T1 - Extracellular superoxide dismutase ameliorates skeletal muscle abnormalities, cachexia, and exercise intolerance in mice with congestive heart failure

AU - Okutsu, Mitsuharu

AU - Call, Jarrod A.

AU - Lira, Vitor A.

AU - Zhang, Mei

AU - Donet, Jean A.

AU - French, Brent A.

AU - Martin, Kyle S.

AU - Peirce-Cottler, Shayn M.

AU - Rembold, Christopher M.

AU - Annex, Brian H.

AU - Yan, Zhen

PY - 2014/5

Y1 - 2014/5

N2 - 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. Methods and 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.

AB - 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. Methods and 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.

KW - Capillaries

KW - Exercise

KW - Mitochondria

KW - Muscular atrophy

KW - Oxidative stress

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