Nox4 mediates skeletal muscle metabolic responses to exercise

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dc.contributor.authorSpecht, Kalyn S.en
dc.contributor.authorKant, Shashien
dc.contributor.authorAddington, Adele K.en
dc.contributor.authorMcMillan, Ryan P.en
dc.contributor.authorHulver, Matthew W.en
dc.contributor.authorLearnard, Heatheren
dc.contributor.authorCampbell, Mauraen
dc.contributor.authorDonnelly, Sarah R.en
dc.contributor.authorCaliz, Amada D.en
dc.contributor.authorPei, Yongmeien
dc.contributor.authorReif, Michaella M.en
dc.contributor.authorBond, Jacob M.en
dc.contributor.authorDeMarco, Anthonyen
dc.contributor.authorCraige, Branchen
dc.contributor.authorKeaney, John F. Jr.en
dc.contributor.authorCraige, Siobhan M.en
dc.contributor.departmentHuman Nutrition, Foods, and Exerciseen
dc.contributor.departmentFralin Life Sciences Instituteen
dc.contributor.departmentBiochemistryen
dc.date.accessioned2021-04-28T14:49:35Zen
dc.date.available2021-04-28T14:49:35Zen
dc.date.issued2021-03en
dc.description.abstractObjective: The immediate signals that couple exercise to metabolic adaptations are incompletely understood. Nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) produces reactive oxygen species (ROS) and plays a significant role in metabolic and vascular adaptation during stress conditions. Our objective was to determine the role of Nox4 in exercise-induced skeletal muscle metabolism. Methods: Mice were subjected to acute exercise to assess their immediate responses. mRNA and protein expression responses to Nox4 and hydrogen peroxide (H2O2) were measured by qPCR and immunoblotting. Functional metabolic flux was measured via ex vivo fatty acid and glucose oxidation assays using C-14-labeled palmitate and glucose, respectively. A chronic exercise regimen was also utilized and the time to exhaustion along with key markers of exercise adaptation (skeletal muscle citrate synthase and beta-hydroxyacyl-coA-dehydrogenase activity) were measured. Endothelial-specific Nox4-deficient mice were then subjected to the same acute exercise regimen and their subsequent substrate oxidation was measured. Results: We identified key exercise-responsive metabolic genes that depend on H2O2 and Nox4 using catalase and Nox4-deficient mice. Nox4 was required for the expression of uncoupling protein 3 (Ucp3), hexokinase 2 (Hk2), and pyruvate dehydrogenase kinase 4 (Pdk4), but not the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1 alpha). Global Nox4 deletion resulted in decreased UCP3 protein expression and impaired glucose and fatty acid oxidization in response to acute exercise. Furthermore, Nox4-deficient mice demonstrated impaired adaptation to chronic exercise as measured by the time to exhaustion and activity of skeletal muscle citrate synthase and beta-hydroxyacyl-coA-dehydrogenase. Importantly, mice deficient in endothelial-Nox4 similarly demonstrated attenuated glucose and fatty acid oxidation following acute exercise. Conclusions: We report that H2O2 and Nox4 promote immediate responses to exercise in skeletal muscle. Glucose and fatty acid oxidation were blunted in the Nox4-deficient mice post-exercise, potentially through regulation of UCP3 expression. Our data demonstrate that endothelial-Nox4 is required for glucose and fatty acid oxidation, suggesting inter-tissue cross-talk between the endothelium and skeletal muscle in response to exercise. (C) 2021 The Authors. Published by Elsevier GmbH.en
dc.description.notesThis study was supported by K01AR073332 (to SMC) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, HL098407 and HL151626 (to JFK) from the National Heart, Lung, and Blood Institute, and 16SDG29660007 (to SK) from the American Heart Association.en
dc.description.sponsorshipNational Institute of Arthritis and Musculoskeletal and Skin DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [K01AR073332]; National Heart, Lung, and Blood InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [HL098407, HL151626]; American Heart AssociationAmerican Heart Association [16SDG29660007]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1016/j.molmet.2020.101160en
dc.identifier.issn2212-8778en
dc.identifier.other101160en
dc.identifier.pmid33400973en
dc.identifier.urihttp://hdl.handle.net/10919/103161en
dc.identifier.volume45en
dc.language.isoenen
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivs 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectExerciseen
dc.subjectNox4en
dc.subjectROSen
dc.subjectMetabolic adaptationen
dc.subjectSkeletal muscle metabolismen
dc.subjectEndotheliumen
dc.titleNox4 mediates skeletal muscle metabolic responses to exerciseen
dc.title.serialMolecular Metabolismen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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