Journal article
Extracellular superoxide dismutase ameliorates skeletal muscle abnormalities, cachexia, and exercise intolerance in mice with congestive heart failure
Circulation. Heart failure, Vol.7(3), pp.519-530
05/2014
DOI: 10.1161/CIRCHEARTFAILURE.113.000841
PMCID: PMC4080303
PMID: 24523418
Abstract
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.
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.
EcSOD plays an important antioxidant defense function in skeletal muscle against cardiac cachexia and exercise intolerance in CHF.
Details
- Title: Subtitle
- Extracellular superoxide dismutase ameliorates skeletal muscle abnormalities, cachexia, and exercise intolerance in mice with congestive heart failure
- Creators
- Mitsuharu Okutsu - University of VirginiaJarrod A Call - University of VirginiaVitor A Lira - University of VirginiaMei Zhang - University of VirginiaJean A Donet - University of VirginiaBrent A French - University of VirginiaKyle S Martin - University of VirginiaShayn M Peirce-Cottler - University of VirginiaChristopher M Rembold - University of VirginiaBrian H Annex - University of VirginiaZhen Yan - University of Virginia
- Resource Type
- Journal article
- Publication Details
- Circulation. Heart failure, Vol.7(3), pp.519-530
- DOI
- 10.1161/CIRCHEARTFAILURE.113.000841
- PMID
- 24523418
- PMCID
- PMC4080303
- ISSN
- 1941-3289
- eISSN
- 1941-3297
- Grant note
- T32-HL007284 / NHLBI NIH HHS R21 AR060444 / NIAMS NIH HHS HL082838 / NHLBI NIH HHS R01 HL082838 / NHLBI NIH HHS AR060444 / NIAMS NIH HHS T32 HL007284 / NHLBI NIH HHS
- Language
- English
- Date published
- 05/2014
- Academic Unit
- Health and Human Physiology
- Record Identifier
- 9984259654202771
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