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. 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. 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. 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.

The mechanisms by which regular exercise prevents the development and progression of chronic inflammatory diseases are largely unknown. We find that exercise enhances resolution of acute inflammation by augmenting resolvin D1 (RvD1) levels and by promoting macrophage phagocytosis. When compared with sedentary controls, mice that performed a four-week treadmill exercise regimen displayed higher macrophage phagocytic activity, enhanced RvD1 levels, and earlier neutrophil clearance following an acute inflammatory challenge. In acute inflammatory cell extracts from exercised mice, we found elevated expression of Alox15 and Alox5 and higher RvD1 levels. Because exercise stimulates release of epinephrine, which has immunomodulatory effects, we questioned whether epinephrine exerts proresolving actions on macrophages. Epinephrine-treated macrophages displayed higher RvD1 levels and 15-lipoxygenase-1 protein abundance, which were prevented by incubation with the α1 adrenergic receptor (α1-AR) antagonist prazosin. Likewise, stimulation of the α1-AR with phenylephrine enhanced macrophage phagocytosis and RvD1 production. During acute inflammation, prazosin abrogated exercise-enhanced neutrophil clearance, macrophage phagocytosis, and RvD1 biosynthesis. These results suggest that exercise-stimulated epinephrine enhances resolution of acute inflammation in an α1-AR–dependent manner. To our knowledge, our findings provide new mechanistic insights into the proresolving effects of exercise that could lead to the identification of novel pathways to stimulate resolution.

Immune system dysregulation is among the many adverse effects incurred by astronauts during space flights. Omega-3 fatty acids, β-alanine, and carnosine are among the many nutrients that contribute to immune system health. For space flight, crewmembers are prescribed a diet with a macronutrient composition of 55% carbohydrate, 30% fat, and 15% protein. To quantify omega-3 fatty acid, β-alanine and carnosine intakes from such a diet, and to examine each nutrient’s impact on exercise performance, 21 participants adhered to the aforementioned macronutrient ratio for 14 days which was immediately followed by a workout performed on gravity-independent resistive exercise hardware. Results included daily omega-3 fatty acid intakes below the suggested dietary intake. Daily omega-3 fatty acid, β-alanine and carnosine intakes each correlated with non-significant amounts of variance from the workout’s volume of work. Given the nutritional requirements to maintain immune system function and the demands of in-flight exercise countermeasures for missions of increasingly longer durations current results, in combination with previously published works, imply in-flight supplementation may be a prudent approach to help address the physiological and mental challenges incurred by astronauts on future space flights.

Do Changes in Innate Immunity Underlie the Cardiovascular Benefits of Exercise?

BACKGROUND: Diet-induced white adipose tissue inflammation is associated with insulin resistance and metabolic perturbations. Conversely, exercise protects against the development of diet-induced chronic inflammation and insulin resistance independent of weight loss; however, the mechanisms remain largely unknown. We have recently shown that through adrenergic stimulation of macrophages, exercise promotes resolution of acute peritoneal inflammation by enhancing the biosynthesis of specialized proresolving lipid mediators. In this study, we sought to determine whether exercise stimulates proresolving pathways in adipose tissue and whether this response is modified by diet. Specifically, we hypothesized that exercise stimulates proresolving pathways by adrenergic signaling, which is inhibited by high-fat diet, priming the development of chronic inflammation in the adipose tissue. METHODS: To explore the dietary dependence of the proresolving effects of exercise, mice were fed either a control or high-fat diet for 2 weeks before, and throughout, a 4-week period of daily treadmill running. Glucose handling, body weight and composition, lipemia, and exercise performance were evaluated at the end of the feeding and exercise interventions. Likewise, changes in catecholamines and their biosynthetic enzymes were measured along with adipose tissue specialized proresolving lipid mediator levels and macrophage phenotype and abundance. RESULTS: When compared with sedentary controls, macrophages isolated from mice exposed to 4 weeks of exercise display elevated expression of the specialized proresolving lipid mediator biosynthetic enzyme Alox15 , while adipose tissue specialized proresolving lipid mediator levels and anti-inflammatory CD301 ⁺ M2 macrophages increased. These changes were dependent upon diet as 6 weeks of feeding with high-fat diet abrogated the proresolving effect of exercise when compared with control diet–fed animals. Interestingly, exercise-induced epinephrine production was inhibited by high-fat diet, which diminished the expression of the epinephrine biosynthetic enzyme PNMT (phenylethanolamine N-methyltransferase) in adrenal glands. CONCLUSIONS: Taken together, these results suggest that a diet high in fat diminishes the proresolving effects of exercise in the adipose tissue via decreasing the biosynthesis of catecholamines.