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Exercise and metabolic health: beyond skeletal muscle.

ABSTRACT: Regular exercise is a formidable regulator of insulin sensitivity and overall systemic metabolism through both acute events driven by each exercise bout and through chronic adaptations. As a result, regular exercise significantly reduces the risks for chronic metabolic disease states, including type 2 diabetes and non-alcoholic fatty liver disease. Many of the metabolic health benefits of exercise depend on skeletal muscle adaptations; however, there is plenty of evidence that exercise exerts many of its metabolic benefit through the liver, adipose tissue, vasculature and pancreas. This review will highlight how exercise reduces metabolic disease risk by activating metabolic changes in non-skeletal-muscle tissues. We provide an overview of exercise-induced adaptations within each tissue and discuss emerging work on the exercise-induced integration of inter-tissue communication by a variety of signalling molecules, hormones and cytokines collectively named 'exerkines'. Overall, the evidence clearly indicates that exercise is a robust modulator of metabolism and a powerful protective agent against metabolic disease, and this is likely to be because it robustly improves metabolic function in multiple organs. Graphical abstract.

SUBMITTER: Thyfault JP

PROVIDER: S-EPMC7377236 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveThe 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.MethodsMice 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 14C-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.ResultsWe 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-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.ConclusionsWe 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.

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Exercise and metabolic health: beyond skeletal muscle.

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