{"doi":"10.1016/j.molmet.2020.101160","title":"Nox4 mediates skeletal muscle metabolic responses to exercise","abstract":"OBJECTIVE: 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: C-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: 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-1α). 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: 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.","journal":"Molecular Metabolism","year":2021,"id":154346,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":63,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9508,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":653944,"name":"Shashi Kant","orcid":"0000-0001-8772-6813","position":1,"is_corresponding":false},{"id":653945,"name":"Adele K. Addington","orcid":"0000-0002-4013-2484","position":2,"is_corresponding":false},{"id":653946,"name":"Ryan P. McMillan","orcid":"0000-0002-7711-8846","position":3,"is_corresponding":false},{"id":653947,"name":"Matthew W. Hulver","orcid":"0000-0003-2096-9006","position":4,"is_corresponding":false},{"id":653948,"name":"Heather Learnard","orcid":"0000-0002-9218-2213","position":5,"is_corresponding":false},{"id":643884,"name":"Maura Campbell","orcid":null,"position":6,"is_corresponding":false},{"id":654549,"name":"Sarah R. Donnelly","orcid":null,"position":7,"is_corresponding":false},{"id":654550,"name":"Amada D. Caliz","orcid":null,"position":8,"is_corresponding":false},{"id":653949,"name":"Yongmei Pei","orcid":"0000-0001-8683-2219","position":9,"is_corresponding":false},{"id":654551,"name":"Michaella M. Reif","orcid":null,"position":10,"is_corresponding":false},{"id":653950,"name":"Jacob Bond","orcid":"0000-0001-6397-7669","position":11,"is_corresponding":false},{"id":653951,"name":"Anthony DeMarco","orcid":"0000-0003-1710-903X","position":12,"is_corresponding":false},{"id":653952,"name":"Branch Craige","orcid":"0000-0003-3180-5947","position":13,"is_corresponding":false},{"id":653953,"name":"John F. Keaney","orcid":"0000-0002-0866-1837","position":14,"is_corresponding":false},{"id":654552,"name":"Siobhan M. Craige","orcid":null,"position":15,"is_corresponding":false},{"id":654548,"name":"Kalyn S. Specht","orcid":null,"position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-18T23:43:49.684414Z","pmid":"33400973","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}