Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise.

Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise encodes angiopoietin-like 4 (ANGPTL4), an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. Using a combination of human, animal, and in vitro data, we show that induction of ANGPTL4 in nonexercising muscle is mediated by elevated plasma free fatty acids via peroxisome proliferator-activated receptor-δ, presumably leading to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. In contrast, the induction of ANGPTL4 in exercising muscle likely is counteracted via AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles. Our data suggest that nonexercising muscle and the local regulation of ANGPTL4 via AMPK and free fatty acids have key roles in governing lipid homeostasis during exercise.

Muscle-specific inflammation induced by MCP-1 overexpression does not affect whole-body insulin sensitivity in mice.

AIMS/HYPOTHESIS: Obesity is associated with a state of chronic low-grade inflammation that is believed to contribute to the development of skeletal muscle insulin resistance. However, the extent to which local and systemic elevation of cytokines, such as monocyte chemoattractant protein 1 (MCP-1), interferes with the action of insulin and promotes insulin resistance and glucose intolerance in muscle remains unclear. Here, we aim to investigate the effect of muscle-specific overexpression of MCP-1 on insulin sensitivity and glucose tolerance in lean and obese mice. METHODS: We used Mck-Mcp-1 transgenic (Tg) mice characterised by muscle-specific overexpression of Mcp-1 (also known as Ccl2) and elevated plasma MCP-1 levels. Mice were fed either chow or high-fat diet for 10 weeks. Numerous metabolic variables were measured, including glucose and insulin tolerance tests, muscle insulin signalling and plasma NEFA, triacylglycerol, cholesterol, glucose and insulin. RESULTS: Despite clearly promoting skeletal muscle inflammation, muscle-specific overexpression of Mcp-1 did not influence glucose tolerance or insulin sensitivity in either lean chow-fed or diet-induced obese mice. In addition, plasma NEFA, triacylglycerol, cholesterol, glucose and insulin were not affected by MCP-1 overexpression. Finally, in vivo insulin-induced Akt phosphorylation in skeletal muscle did not differ between Mcp-1-Tg and wild-type mice. CONCLUSIONS/INTERPRETATION: We show that increased MCP-1 production in skeletal muscle and concomitant elevated MCP-1 levels in plasma promote inflammation in skeletal muscle but do not influence insulin signalling and have no effect on insulin resistance and glucose tolerance in lean and obese mice. Overall, our data argue against MCP-1 promoting insulin resistance in skeletal muscle and raise questions about the impact of inflammation on insulin sensitivity in muscle.

The search for exercise factors in humans.

Regular exercise reduces the risk for numerous chronic diseases. Exercise not only impacts the contracting skeletal muscle but also elicits systemic changes. The exact mechanisms driving the more systemic changes have yet to be resolved, but exercise factors are thought to be an important missing link. Exercise factors are proteins that are released from skeletal muscle into the circulation during exercise. They represent a subclass of myokines, which are classified as proteins secreted from skeletal muscle serving a signaling role. Here, we provide an overview of the current literature on myokines. Many studies have focused on the identification of new myokines using a variety of approaches. These studies have generated an extensive list of myokines, but so far, the functional relevance of many of these novel myokines remains unclear. Few of these myokines represent putative exercise factors. Currently, IL-6, secreted protein acidic and rich in cysteine, angiopoietin-like 4, chemokine (C-X3-C motif) ligand 1, and chemokine (C-C motif) ligand 2 have the highest potential to serve as exercise factors because for all these factors, there is clear evidence that plasma levels increase during exercise. In our view, the future focus should be on characterizing the functional role of myokines in the acute and chronic response to exercise and explore their potential as a target for metabolic diseases.

Identification of human exercise-induced myokines using secretome analysis.

Endurance exercise is associated with significant improvements in cardio-metabolic risk parameters. A role for myokines has been hypothesized, yet limited information is available about myokines induced by acute endurance exercise in humans. Therefore, the aim of the study was to identify novel exercise-induced myokines in humans. To this end, we carried out a 1 h one-legged acute endurance exercise intervention in 12 male subjects and a 12 wk exercise training intervention in 18 male subjects. Muscle biopsies were taken before and after acute exercise or exercise training and were subjected to microarray-based analysis of secreted proteins (secretome). For acute exercise, secretome analysis resulted in a list of 86 putative myokines, which was reduced to 29 by applying a fold-change cut-off of 1.5. Based on that shortlist, a selection of putative myokines was measured in the plasma by ELISA or multiplex assay. From that selection, CX3CL1 (fractalkine) and CCL2 (MCP-1) increased at both mRNA and plasma levels. From the known myokines, only IL-6 and FGF 21 changed at the mRNA level, whereas none of the known myokines changed at the plasma level. Secretome analysis of exercise training intervention resulted in a list of 69 putative myokines. Comparing putative myokines altered by acute exercise and exercise training revealed a limited overlap of only 13 genes. In conclusion, this study identified CX3CL1 and CCL2 as myokines that were induced by acute exercise at the gene expression and plasma level and that may be involved in communication between skeletal muscle and other organs.

Cooling vests alleviate perceptual heat strain perceived by COVID-19 nurses.

Cooling vests alleviate heat strain. We quantified the perceptual and physiological heat strain and assessed the effects of wearing a 21°C phase change material cooling vest on these measures during work shifts of COVID-19 nurses wearing personal protective equipment (PPE). Seventeen nurses were monitored on two working days, consisting of a control (PPE only) and a cooling vest day (PPE + cooling vest). Sub-PPE air temperature, gastrointestinal temperature (Tgi), and heart rate (HR) were measured continuously. Thermal comfort (2 [1-4] versus 1 [1-2], pcondtition < 0.001) and thermal sensation (5 [4-7] versus 4 [2-7], pcondition < 0.001) improved in the cooling vest versus control condition. Only 18% of nurses reported thermal discomfort and 36% a (slightly) warm thermal sensation in the cooling vest condition versus 81% and 94% in the control condition (OR (95%CI) 0.05 (0.01-0.29) and 0.04 (<0.01-0.35), respectively). Accordingly, perceptual strain index was lower in the cooling vest versus control condition (5.7 ± 1.5 versus 4.3 ± 1.7, pcondition < 0.001, respectively). No differences were observed for the physiological heat strain index Tgi and rating of perceived exertion across conditions. Average HR was slightly lower in the cooling vest versus the control condition (85 ± 12 versus 87 ± 11, pcondition = 0.025). Although the physiological heat strain among nurses using PPE was limited, substantial perceptual heat strain was experienced. A 21°C phase change material cooling vest can successfully alleviate the perceptual heat strain encountered by nurses wearing PPE.

The effects of mass, bulk and stiffness of personal protective equipment and clothing on physical performance when performing a military mobility obstacle course.

BACKGROUND: Soldiers are required to conduct tasks and operations in physically demanding situations, where the ability to move (mobility) quickly is important to lethality and survivability. This study employed a specially designed suit to try to isolate the main mass property characteristics of personal protective clothing/equipment (PPCE) including mass, bulk and stiffness as much as possible and evaluated their effects on soldier performance across operationally-relevant mobility tasks. METHOD: Eight male military subjects performed the load effects assessment program (LEAP) obstacle course while wearing 7 different configurations of specifically designed suit: unencumbered (control), 10 kg mass, 30 kg mass, 20 L bulk, medium stiffness, high stiffness and a mixed configuration consisting of 10 kg mass, 20 L bulk and medium stiffness. The primary outcome measure was total LEAP completion time. Additionally, heart rate, rating of perceived exertion (RPE), range of motion and vertical jump heights were measured and related to LEAP performance. RESULTS: All configurations degraded or tended to degrade the total LEAP completion times (p-value < 0.05), except for the medium stiffness configuration. Heart rate did not differ significantly between configurations, while RPE scores of configurations 30 kg and mix were significantly higher compared to control (p < 0.01). CONCLUSION: Mass, bulk and stiffness all negatively influence LEAP obstacle performance. Therefore, all three have to be considered when trying to reduce the physical burden on soldiers.

Effectiveness of collagen supplementation on pain scores in healthy individuals with self-reported knee pain: a randomized controlled trial.

The purpose of this study was to examine the effects of 12 weeks collagen peptide (CP) supplementation on knee pain and function in individuals with self-reported knee pain. Healthy physically active individuals (n = 167; aged 63 [interquartile range = 56-68] years) with self-reported knee pain received 10 g/day of CP or placebo for 12 weeks. Knee pain and function were measured with the Visual Analog Scale (VAS), the Lysholm questionnaire, and the Knee injury and Osteoarthritis Outcome Score (KOOS). Furthermore, we assessed changes in inflammatory, cartilage, and bone (bio)markers. Measurements were conducted at baseline and after 12 weeks of supplementation. Baseline VAS did not differ between CP and placebo (4.7 [2.5-6.1] vs. 4.7 [2.8-6.2], p = 0.50), whereas a similar decrease in VAS was observed after supplementation (-1.6 ± 2.4 vs. -1.9 ± 2.6, p = 0.42). The KOOS and Lysholm scores increased after supplementation in both groups (p values < 0.001), whereas the increase in the KOOS and Lysholm scores did not differ between groups (p = 0.28 and p = 0.76, respectively). Furthermore, CP did not impact inflammatory, cartilage, and bone (bio)markers (p values > 0.05). A reduced knee pain and improved knee function were observed following supplementation, but changes were similar between groups. This suggests that CP supplementation over a 12-week period does not reduce knee pain in healthy, active, middle-aged to elderly individuals. Novelty CP supplementation over a 12-week period does not reduce knee pain in healthy, active, middle-aged to elderly individuals. CP supplementation over a 12-week period does not impact on inflammatory, cartilage, and bone (bio)markers in healthy, active, middle-aged to elderly individuals.

Cytokine responses to repeated, prolonged walking in lean versus overweight/obese individuals.

OBJECTIVES: Obesity is characterized by a pro-inflammatory state, which plays a role in the pathogenesis of metabolic and cardiovascular disease. An exercise bout causes a transient increase in pro-inflammatory cytokines, whilst training has anti-inflammatory effects. No previous study examined whether the exercise-induced increase in pro-inflammatory cytokines is altered with repeated prolonged exercise bouts and whether this response differs between lean and overweight/obese individuals. DESIGN: Lean (n=25, BMI 22.9±1.5kg/m2) and age-/sex-matched overweight/obese (n=25; BMI 27.9±2.4kg/m2) individuals performed walking exercise for 30, 40 or 50km per day on four consecutive days (distances similar between groups). METHODS: Circulating cytokines (IL-6, IL-10, TNF-α, IL-1ß and IL-8) were examined at baseline and <30min after the finish of each exercise day. RESULTS: At baseline, no differences in circulating cytokines were present between groups. In response to prolonged exercise, all cytokines increased on day 1 (IL-1ß: P=0.02; other cytokines: P<0.001). IL-6 remained significantly elevated during the 4 exercise days, when compared to baseline. IL-10, TNF-α, IL-1ß and IL-8 returned to baseline values from exercise day 2 (IL-10, IL-1ß, IL-8) or exercise day 3 (TNF-α) onward. No significant differences were found between groups for all cytokines, except IL-8 (Time*Group Interaction P=0.02). CONCLUSIONS: These data suggest the presence of early adaptive mechanisms in response to repeated prolonged walking, demonstrated by attenuated exercise-induced elevations in cytokines on consecutive days that occur similar in lean and overweight/obese individuals.

Post-Exercise Rehydration: Effect of Consumption of Beer with Varying Alcohol Content on Fluid Balance after Mild Dehydration.

PURPOSE: The effects of moderate beer consumption after physical activity on rehydration and fluid balance are not completely clear. Therefore, in this study, we investigated the effect of beer consumption, with varying alcohol content, on fluid balance after exercise-induced dehydration. METHODS: Eleven healthy males were included in this cross over study (age 24.5 ± 4.7 years, body weight 75.4 ± 3.3 kg, VO2max 58.3 ± 6.4 mL kg min-1). Subjects exercised on a cycle ergometer for 45 min at 60% of their maximal power output (Wmax) until mild dehydration (1% body mass loss). Thereafter, in random order, one of five experimental beverages was consumed, in an amount equal to 100% of their sweat loss: non-alcoholic beer (0.0%), low-alcohol beer (2.0%), full-strength beer (5.0%), an isotonic sports drink, and water. Fluid balance was assessed up till 5 h after rehydration. RESULTS: After 1 h, urine production was significantly higher for 5% beer compared to the isotonic sports drink (299 ± 143 vs. 105 ± 67 mL; p < 0.01). At the end of the 5-h observation period, net fluid balance (NFB) was negative for all conditions (p = 0.681), with the poorest fluid retention percentage for 5% beer (21% fluid retention) and the best percentage for the isotonic sports drink (42%). Non-alcoholic beer, low-alcoholic beer, and water resulted in fluid retention of 36, 36, and 34%, respectively (p = 0.460). CONCLUSION: There was no difference in NFB between the different beverages. Only a short-lived difference between full-strength beer and the isotonic sports drink in urine output and NFB was observed after mild exercise-induced dehydration. Fluid replacement - either in the form of non-alcoholic beer, low-alcoholic beer, full-strength beer, water, or an isotonic sports drink of 100% of body mass loss was not sufficient to achieve full rehydration. The combination of a moderate amount of beer, with varying alcohol content, enough water or electrolyte- and carbohydrate beverages, and salty foods might improve rehydration, but more research is needed.

Exercise Improves Insulin Sensitivity in the Absence of Changes in Cytokines.

PURPOSE: The benefits of aerobic exercise training on insulin sensitivity in subjects with metabolic syndrome (MetS) are, at least in part, associated with changes in cytokines. Recent studies identified novel cytokines (e.g., fractalkine, omentin, and osteopontin) that are strongly involved in glucose homeostasis and therefore potentially contribute in the exercise-induced changes in insulin sensitivity. Therefore, we aim to examine changes in skeletal muscle RNA expression and plasma levels of novel cytokines after exercise training and correlate these changes to the exercise-induced changes in insulin sensitivity. METHODS: Women with metabolic syndrome (MetS, n = 11) and healthy women (n = 10) participated in a 6-month aerobic exercise training intervention (three times a week, 45 min per session at 65%-85% of individual heart rate reserve). Before and after training, we examined insulin sensitivity (M value during hyperinsulinemic euglycemic clamp) and circulating blood levels of cytokines (venous blood sample; leptin, adiponectin, omentin, fraktalkin, and osteopontin). The skeletal muscle RNA expression of these cytokines (muscle biopsy) was examined in two subgroups (MetS, n = 6; healthy women, n = 6). RESULTS: At baseline, plasma levels of omentin (85.8 ± 26.2 ng·mL) and adiponectin (5.0 ± 1.7 µg·mL) levels were significantly higher in controls compared with MetS (51.1 ± 27.1; 3.6 ± 1.1 respectively), and leptin levels were lower in controls (18.7 ± 11.5 vs 53.0 ± 23.5 ng·mL). M value was significantly higher in controls (8.1 ± 1.9 mg·kg·min) than in MetS (4.0 ± 1.7). Exercise training significantly improved M values in both groups (P < 0.01). Exercise training did not alter plasma and skeletal muscle RNA expression levels of cytokines, but no correlation was observed between changes in cytokine level/RNA expression and M values (P > 0.05). CONCLUSION: Although exercise training successfully improves insulin sensitivity in MetS and healthy women, we found no change in plasma and mRNA expression levels of novel cytokines.

Pronounced effects of acute endurance exercise on gene expression in resting and exercising human skeletal muscle.

Regular physical activity positively influences whole body energy metabolism and substrate handling in exercising muscle. While it is recognized that the effects of exercise extend beyond exercising muscle, it is unclear to what extent exercise impacts non-exercising muscles. Here we investigated the effects of an acute endurance exercise bouts on gene expression in exercising and non-exercising human muscle. To that end, 12 male subjects aged 44-56 performed one hour of one-legged cycling at 50% W(max). Muscle biopsies were taken from the exercising and non-exercising leg before and immediately after exercise and analyzed by microarray. One-legged cycling raised plasma lactate, free fatty acids, cortisol, noradrenalin, and adrenalin levels. Surprisingly, acute endurance exercise not only caused pronounced gene expression changes in exercising muscle but also in non-exercising muscle. In the exercising leg the three most highly induced genes were all part of the NR4A family. Remarkably, many genes induced in non-exercising muscle were PPAR targets or related to PPAR signalling, including PDK4, ANGPTL4 and SLC22A5. Pathway analysis confirmed this finding. In conclusion, our data indicate that acute endurance exercise elicits pronounced changes in gene expression in non-exercising muscle, which are likely mediated by changes in circulating factors such as free fatty acids. The study points to a major influence of exercise beyond the contracting muscle.