Exercise-induced specialized proresolving mediators stimulate AMPK phosphorylation to promote mitochondrial respiration in macrophages
Objective: Physical activity has been shown to reduce the risk of CVD mortality in large-cohort longitudinal studies; however, the mechanisms underpinning the beneficial effects of exercise remain incompletely understood. Emerging data suggest that the risk reducing effect of exercise extends beyond...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287782200206X |
| _version_ | 1811196914760155136 |
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| author | Ernesto Pena Calderin Jing-Juan Zheng Nolan L. Boyd Lindsey McNally Timothy N. Audam Pawel Lorkiewicz Bradford G. Hill Jason Hellmann |
| author_facet | Ernesto Pena Calderin Jing-Juan Zheng Nolan L. Boyd Lindsey McNally Timothy N. Audam Pawel Lorkiewicz Bradford G. Hill Jason Hellmann |
| author_sort | Ernesto Pena Calderin |
| collection | DOAJ |
| description | Objective: Physical activity has been shown to reduce the risk of CVD mortality in large-cohort longitudinal studies; however, the mechanisms underpinning the beneficial effects of exercise remain incompletely understood. Emerging data suggest that the risk reducing effect of exercise extends beyond changes in traditional CVD risk factors alone and involves alterations in immunity and reductions in inflammatory mediator production. Our study aimed to determine whether exercise-enhanced production of proresolving lipid mediators contribute to alterations in macrophage intermediary metabolism, which may contribute to the anti-inflammatory effects of exercise. Methods: Changes in lipid mediators and macrophage metabolism were assessed in C57Bl/6 mice following 4 weeks of voluntary exercise training. To investigate whether exercise-stimulated upregulation of specialized proresolving lipid mediators (SPMs) was sufficient to enhance mitochondrial respiration, both macrophages from control mice and human donors were incubated in vitro with SPMs and mitochondrial respiratory parameters were measured using extracellular flux analysis. Compound-C, an ATP-competitive inhibitor of AMPK kinase activity, was used to investigate the role of AMPK activity in SPM-induced mitochondrial metabolism. To assess the in vivo contribution of 5-lipoxygenase in AMPK activation and exercise-induced mitochondrial metabolism in macrophages, Alox5−/− mice were also subjected to exercise training. Results: Four weeks of exercise training enhanced proresolving lipid mediator production, while also stimulating the catabolism of inflammatory lipid mediators (e.g., leukotrienes and prostaglandins). This shift in lipid mediator balance following exercise was associated with increased macrophage mitochondrial metabolism. We also find that treating human and murine macrophages in vitro with proresolving lipid mediators enhances mitochondrial respiratory parameters. The proresolving lipid mediators RvD1, RvE1, and MaR1, but not RvD2, stimulated mitochondrial respiration through an AMPK-dependent signaling mechanism. Additionally, in a subset of macrophages, exercise-induced mitochondrial activity in vivo was dependent upon 5-lipoxygenase activity. Conclusion: Collectively, these results suggest that exercise stimulates proresolving lipid mediator biosynthesis and mitochondrial metabolism in macrophages via AMPK, which might contribute to the anti-inflammatory and CVD risk reducing effect of exercise. |
| first_indexed | 2024-04-12T01:06:38Z |
| format | Article |
| id | doaj.art-83e0761586174192b1983211da9c826c |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-12T01:06:38Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-83e0761586174192b1983211da9c826c2022-12-22T03:54:14ZengElsevierMolecular Metabolism2212-87782022-12-0166101637Exercise-induced specialized proresolving mediators stimulate AMPK phosphorylation to promote mitochondrial respiration in macrophagesErnesto Pena Calderin0Jing-Juan Zheng1Nolan L. Boyd2Lindsey McNally3Timothy N. Audam4Pawel Lorkiewicz5Bradford G. Hill6Jason Hellmann7Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA; Department of Physiology, University of Louisville School of Medicine, Louisville, KY, 40202, USADiabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USADiabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USADiabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USADiabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USADiabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USADiabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USADiabetes and Obesity Center, Christina Lee Brown Envirome Institute, Division of Environmental Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA; Corresponding author. 580 S. Preston St. Rm 204F, Delia Baxter II Building, University of Louisville, Louisville, KY 40202, USA.Objective: Physical activity has been shown to reduce the risk of CVD mortality in large-cohort longitudinal studies; however, the mechanisms underpinning the beneficial effects of exercise remain incompletely understood. Emerging data suggest that the risk reducing effect of exercise extends beyond changes in traditional CVD risk factors alone and involves alterations in immunity and reductions in inflammatory mediator production. Our study aimed to determine whether exercise-enhanced production of proresolving lipid mediators contribute to alterations in macrophage intermediary metabolism, which may contribute to the anti-inflammatory effects of exercise. Methods: Changes in lipid mediators and macrophage metabolism were assessed in C57Bl/6 mice following 4 weeks of voluntary exercise training. To investigate whether exercise-stimulated upregulation of specialized proresolving lipid mediators (SPMs) was sufficient to enhance mitochondrial respiration, both macrophages from control mice and human donors were incubated in vitro with SPMs and mitochondrial respiratory parameters were measured using extracellular flux analysis. Compound-C, an ATP-competitive inhibitor of AMPK kinase activity, was used to investigate the role of AMPK activity in SPM-induced mitochondrial metabolism. To assess the in vivo contribution of 5-lipoxygenase in AMPK activation and exercise-induced mitochondrial metabolism in macrophages, Alox5−/− mice were also subjected to exercise training. Results: Four weeks of exercise training enhanced proresolving lipid mediator production, while also stimulating the catabolism of inflammatory lipid mediators (e.g., leukotrienes and prostaglandins). This shift in lipid mediator balance following exercise was associated with increased macrophage mitochondrial metabolism. We also find that treating human and murine macrophages in vitro with proresolving lipid mediators enhances mitochondrial respiratory parameters. The proresolving lipid mediators RvD1, RvE1, and MaR1, but not RvD2, stimulated mitochondrial respiration through an AMPK-dependent signaling mechanism. Additionally, in a subset of macrophages, exercise-induced mitochondrial activity in vivo was dependent upon 5-lipoxygenase activity. Conclusion: Collectively, these results suggest that exercise stimulates proresolving lipid mediator biosynthesis and mitochondrial metabolism in macrophages via AMPK, which might contribute to the anti-inflammatory and CVD risk reducing effect of exercise.http://www.sciencedirect.com/science/article/pii/S221287782200206XExerciseMacrophageInflammationMitochondriaLipid mediators |
| spellingShingle | Ernesto Pena Calderin Jing-Juan Zheng Nolan L. Boyd Lindsey McNally Timothy N. Audam Pawel Lorkiewicz Bradford G. Hill Jason Hellmann Exercise-induced specialized proresolving mediators stimulate AMPK phosphorylation to promote mitochondrial respiration in macrophages Molecular Metabolism Exercise Macrophage Inflammation Mitochondria Lipid mediators |
| title | Exercise-induced specialized proresolving mediators stimulate AMPK phosphorylation to promote mitochondrial respiration in macrophages |
| title_full | Exercise-induced specialized proresolving mediators stimulate AMPK phosphorylation to promote mitochondrial respiration in macrophages |
| title_fullStr | Exercise-induced specialized proresolving mediators stimulate AMPK phosphorylation to promote mitochondrial respiration in macrophages |
| title_full_unstemmed | Exercise-induced specialized proresolving mediators stimulate AMPK phosphorylation to promote mitochondrial respiration in macrophages |
| title_short | Exercise-induced specialized proresolving mediators stimulate AMPK phosphorylation to promote mitochondrial respiration in macrophages |
| title_sort | exercise induced specialized proresolving mediators stimulate ampk phosphorylation to promote mitochondrial respiration in macrophages |
| topic | Exercise Macrophage Inflammation Mitochondria Lipid mediators |
| url | http://www.sciencedirect.com/science/article/pii/S221287782200206X |
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