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Autophagy is a critical molecular process in promoting cell survival against apoptosis. This study examined whether maximal aerobic exercise-mediated apoptosis in obesity might be underlying the involvement of autophagy in the peripheral blood mononuclear cells (PBMCs). Twelve healthy male subjects (6 obese and 6 normal-weight) were recruited to participate in a maximal graded exercise test on a treadmill. Obese subjects exhibited a significantly lower Bax, but a higher Bcl-2 protein level in conjunction with a reduced Bax/Bcl-2 AUCi compared to normal-weight subjects following exercise. Furthermore, a greater LC3-II/LC3-I ratio and LC3-II/LC3-I AUCi was observed in obese subjects compared to normal-weight subjects. LC3-II/LC3-I AUCi was also positively associated with obesity-associated parameters (BMI, waist/hip circumference, and fasting insulin level), but was negatively correlated with Bax/Bcl-2 AUCi. These findings demonstrate that maximal aerobic exercise differentially mediates the intrinsic apoptotic pathway and autophagic activity in human PBMCs isolated from obese compared to normal-weight individuals.

Study Design: Family members caring for chronically ill relatives are typically sedentary, chronically stressed, and at high risk of disease. Observational reports suggest caregivers have accelerated cellular aging as indicated by shorter leukocyte telomere lengths. We performed a randomized controlled trial to examine the effect of aerobic exercise on changes in telomerase levels (primary outcome) and telomere lengths (secondary outcome) in inactive caregivers., Methods: 68 female and male community dwelling dementia caregivers who reported high stress and physical inactivity were randomly assigned to a highly supervised aerobic exercise intervention vs. waitlist control group for 24 weeks. Average leukocyte telomere lengths and peripheral blood mononuclear cells' telomerase activity were measured pre- and post-intervention. All staff completing blood draws, fitness testing and bioassays were blinded to group assignment., Results: The intervention group completed approximately 40 min of aerobic exercise 3-5 times per week, verified by actigraphy. There was high (81%) adherence to 120 min/week of aerobic exercise. Groups did not significantly differ in telomerase activity changes across time, but had significant different telomere length changes across time (67.3 base pairs, 95%CI 3.1, 131.5). There were also significant reductions in body mass index and perceived stress and an increase in cardiorespiratory fitness (i.e., VO 2peak ) in the exercising caregivers versus controls., Conclusion: In the context of a highly controlled intervention, exercise can induce apparent telomere lengthening, though the mechanisms remain elusive. Our study underscores the importance of increasing participation in aerobic exercise to improve markers of health and attenuate cellular aging in high-risk samples., (Copyright © 2018. Published by Elsevier Ltd.)

Pentraxin 3 (PTX3) is mainly synthesized and released by neutrophils to help regulate innate immunity. While plasma PTX3 concentrations are associated with improved glucose metabolism and overall metabolic health, there is evidence that significant elevations in plasma glucose downregulate circulating levels of PTX3. To examine whether this relationship would be altered in response to exercise, this study investigated the kinetics of the plasma glucose and PTX3 responses following high-intensity interval exercise (HIIE) and continuous moderate-intensity exercise (CMIE). It was hypothesized that the increased concentrations of plasma glucose following HIIE compared with CMIE would be associated with an attenuated plasma PTX3 response. Eight healthy male subjects participated in both HIIE and CMIE protocols administered as a randomized, counterbalanced design. Linear mixed models for repeated measures revealed that the overall plasma glucose response was greater following HIIE compared with CMIE (protocol × time effect: p = 0.037). Although the plasma PTX3 response was higher only at 19 min into HIIE compared with CMIE (protocol × time effect: p = 0.013), no relationships were observed between plasma glucose and PTX3 either at baseline or in response to both exercise protocols, as indicated by the area under the curve "with respect to increase" analysis. Our results indicate that exercise-mediated plasma PTX3 concentrations are independent of the plasma glucose response. In addition, the present study suggests that the neutrophil-mediated innate immune response, as indicated by plasma PTX3 response, may be activated earlier during HIIE compared with CMIE.

Introduction/purpose: MicroRNAs (miRNAs), a class of non-coding RNAs, are involved in the regulation of gene expression and numerous biological processes, including inflammation and metabolism in obese populations. Emerging research indicates that physical activity provides health-related benefits in obesity-associated inflammatory diseases. This study examined how acute aerobic exercise would mediate the changes in plasma level of inflammation-related circulating miRNA (ci-miRNA) expression (miR-21, miR-126, miR-130b, miR-221, and miR-222) in obese and normal-weight subjects., Methods: Twenty-four subjects (12 obese and 12 normal-weight) were recruited to participate in a 30-min aerobic exercise (75% VO 2max ). Blood samples were taken prior to exercise, immediately following exercise, 1 h, and 2 h into recovery for analysis of target ci-miRNAs in plasma., Results: A higher baseline levels of ci-miRNAs (miR-126, miR-130b, miR-221, and miR-222) were found in obese subjects than normal-weight subjects. In response to acute aerobic exercise, obese subjects exhibited a higher increase in plasma level of all ci-miRNAs: miR-21, miR-126, miR-130b, miR-221 and miR-222, even after controlling for VO 2max and insulin resistance (HOMA-IR). Furthermore, all miRNA area-under-the curves "with respect to increase" (AUCi) were higher in obese subjects and also positively correlated with each other, even after controlling for VO 2max and HOMA-IR., Conclusion: These findings indicate that acute aerobic exercise elicits a higher elevation in plasma level of inflammatory ci-miRNAs in obese than normal-weight individuals, irrespective of cardiorespiratory fitness and indicator of metabolic syndrome (HOMA-IR)., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Pentraxin 3 (PTX3) is a vital regulator of innate immune function. Although plasma PTX3 concentrations are elevated with aerobic fitness, the cellular functions of PTX3 remain unknown in aerobically trained and untrained subjects., Methods: Thirty individuals (aerobically trained = 15 and untrained = 15) participated in a maximal exercise protocol to examine ex vivo PTX3 production from isolated peripheral blood mononuclear cells (PBMCs) exposed to LPS or palmitate. The capacity of PTX3 to stimulate inflammatory cytokine production ex vivo was also examined., Results: Elevated plasma PTX3 concentrations prior to exercise were positively associated with the percent change (pre to post exercise) in plasma PTX3 concentrations in all subjects, independent of cardiorespiratory fitness (VO 2max ). In addition, elevated plasma PTX3 concentrations in aerobically trained subjects at rest predicted changes in the LPS- and palmitate-stimulated PTX3 production from isolated PBMCs following acute exercise. In response to PTX3 simulation, the capacity of PBMCs to produce the anti-inflammatory cytokine IL-10 was decreased following acute exercise in all subject (no changes in IL-6, TGF-β1, and TNF-α observed). However, the percent change in IL-6 production was positively associated with VO 2max in all subjects, and in aerobically trained subjects only, positively associated with elevated plasma PTX3 concentrations at rest and in response to acute exercise., Conclusion: These results suggest that aerobic training enhances the utilization of plasma PTX3 concentrations to predict the capacity of mononuclear cells to produce PTX3, and potentially, its reciprocal role of PTX3 as an initiator of the innate immune response following maximal exercise.

Background: Prefrontal cortex (PFC)-dependent executive function is enhanced immediately following high intensity interval exercise (HIIE). Brain-derived neurotrophic factor (BDNF) is considered a biomarker associated with enhanced execute functioning capacity at rest and in response to exercise. However, the mechanisms responsible for the acute exercise-induced BDNF response in plasma and serum differ, and it is likely that the utilization of BDNF in plasma and/or serum as a biomarker of improved executive function following HIIE may be limited. Therefore, this study examined the impact of HIIE on the plasma and serum BDNF response to understand the efficaciousness of BDNF as a peripheral biomarker associated with improvements in PFC-dependent executive function. Thirteen healthy males (age: 23.62 ± 1.06 years) participated in a randomized, counterbalanced study, performing the Wisconsin Card Sorting Task (WCST) immediately following a 5-minute seated rest (control) and participation in a HIIE protocol administered two weeks apart. HIIE consisted of ten maximal bouts of all out pedaling on a cycle ergometer for 20 s (separated by 10 s of active recovery) against 5.5% of the subject's body weight. Whole blood was collected for the assessment of BDNF in both plasma and serum. Compared to the control session, HIIE elicited significant improvements in WCST performance, yet improvements in PFC-dependent executive function were independent of BDNF concentrations in plasma and serum. Results from this investigation demonstrate that a single session of low-volume, supramaximal HIIE significantly increases PFC-dependent executive function, thereby providing additional evidence to support the powerful benefits on HIIE on cognitive functioning., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Monocytes express the CD14 receptor that facilitates lipopolysaccharide (LPS) ligation to toll-like receptor 4 (TLR4) to elicit production of interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNF-α). However, proinflammatory conditions, such as strenuous exercise, increase the percentage of monocytes expressing CD16, a receptor that enhances LPS stimulated TNF-α production. Therefore, we examined whether maximal treadmill exercise would alter the inflammatory phenotype of classical (CD14/CD16) and proinflammatory monocytes (intermediate [CD14/CD16] and nonclassical [CD14/CD16]), evidenced by changes in TLR4, CD14, and CD16 receptor expression, and their inflammatory response to ex vivo LPS stimulation., Methods: Human mononuclear cells from 25 male participants (age, 24.2 ± 4.0 yr) were isolated before and after exercise to assess TLR4, CD14, and CD16 expression by flow cytometry and ex vivo production of LPS-stimulated inflammatory cytokines (IL-6, IL-10, and TNF-α)., Results: Exercise reduced the percentage of classical monocytes and increased the percentage of intermediate and nonclassical monocytes. In addition, TLR4 expression decreased on classical and intermediate monocytes, but not the nonclassical monocyte subset. Furthermore, although CD14 expression decreased on all monocyte subsets, CD16 expression increased on intermediate monocytes only. In parallel with these phenotypic changes, the inflammatory milieu shifted toward a proinflammatory response after LPS stimulation (decreased IL-6 and IL-10 and increased IL-6 to IL-10 ratio and TNF-α production)., Conclusions: These findings demonstrate that acute maximal exercise elicits a proinflammatory phenotype of isolated monocytes exposed to LPS and highlight potential mechanisms that will help elucidate the role of acute and chronic exercise on the innate immune response of circulating monocytes.

Purpose: Calprotectin promotes the release of inflammatory mediators (e.g., monocyte chemoattractant protein-1 [MCP-1] and myeloperoxidase [MPO]) during the innate immune response as a mechanism to augment leukocyte chemotaxis and phagocytosis. Although plasma calprotectin is elevated with traditional continuous moderate-intensity exercise (CME) as an indicator of the inflammatory response, high-intensity interval exercise (HIIE) has been shown to attenuate systemic inflammation while providing similar improvements in cardiovascular health. Therefore, the purpose of this study was to compare plasma levels of calprotectin, MCP-1, and MPO between acute HIIE vs. CME., Methods: Nine healthy males (24.67±3.27yrs) were recruited to participate in HIIE and CME on a cycle ergometer. HIIE consisted of 10 repeated 60s of cycling at 90% max watts (W max ) separated by 2min of active recovery intensity of interval exercise, whereas CME consisted of 28min of cycling at 60% W max . Blood samples were collected prior to, immediately post, and 30 and 60min into recovery following exercise., Results: Acute HIIE elicited a lower elevation in calprotectin and MPO compared to CME. An increase in MCP-1 was observed across time in both exercise protocols. Furthermore, our analyses did not reveal any significant correlation in percent change (baseline to immediately following exercise) among calprotectin, MCP1, and MPO in neither HIIE nor CME. However, a significant positive correlation was observed in the overall release of calprotectin and MPO across all four time points in both HIIE and CME. Conclusions Our findings indicate that acute HIIE may potentially diminish the systemic release of inflammatory mediators (calprotectin and MPO) compared to CME., (Published by Elsevier Inc.)

The purpose of this study was to determine whether obesity would reduce the capacity of peripheral blood mononuclear cells (PBMCs) to produce the anti-inflammatory protein pentraxin 3 (PTX3) in response to ex vivo stimulation with lipopolysaccharide (LPS), and if acute aerobic exercise would enhance this PTX3 production capacity. In addition, the inter-relationships of LPS-induced PTX3 with the inflammatory cytokines (interleukin 6 [IL-6], IL-10, and tumor necrosis factor alpha) were examined. Twenty-one healthy subjects (10 obese and 11 normal-weight) performed an acute bout of aerobic exercise at 75% VO 2max . The capacity of PBMCs to produce PTX3 ex vivo following LPS stimulation was the same in obese and normal-weight subjects at rest, and decreased equally in both subject groups following acute aerobic exercise. This is in contrast to plasma PTX3, which is lower in obese subjects at rest and increased equally in both obese and normal-weight subjects following exercise. In addition, ex vivo PTX3 production was positively associated with IL-6 and IL-10 in response to acute aerobic exercise ( r = 0.686, P = 0.020; r = 0.744, P = 0.009, respectively) in normal-weight, but not in obese individuals ( r = 0.429, P = 0.249; r = 0.453, P = 0.189, respectively). These findings indicate that concentrations of PTX3 observed in plasma are relatively independent of those produced by PBMCs ex vivo and the mechanisms associated with PTX3-mediated anti-inflammatory signaling may differ during obesity. Impact statement Our laboratory has previously demonstrated that obese individuals present with lower plasma concentrations of the anti-inflammatory protein pentraxin 3 (PTX3), whereas acute aerobic exercise increases plasma PTX3 levels similarly compared to normal-weight individuals. As a follow-up, the present study demonstrates that PBMCs isolated from obese and normal-weight individuals produce comparable amounts of PTX3 ex vivo in response to lipopolysaccharide (LPS). Furthermore, given that acute aerobic exercise reduced the ex vivo production of PTX3 in both groups, our results clearly indicate that plasma PTX3 levels are relatively independent of those produced by PBMCs ex vivo. In addition, our findings suggest that the mechanisms associated with PTX3-mediated production of the anti-inflammatory cytokine interleukin 10 may be impaired in obese individuals, and thus provides a key finding necessary for the elucidation of PTX3's role in the mediation of anti-inflammatory profiles and the subsequent amelioration of inflammatory disease during obesity.

Obesity is defined as the excess accumulation of intra-abdominal body fat, resulting in a state of chronic, low-grade proinflammation that can directly contribute to the development of insulin resistance. Pentraxin 3 (PTX3) is an acute-phase protein that is expressed by a variety of tissue and cell sources and provides an anti-inflammatory property to downregulate the production of proinflammatory cytokines, in particular interleukin-1 beta and tumor necrosis factor alpha. Although PTX3 may therapeutically aid in altering the proinflammatory milieu in obese individuals, and despite elevated expression of PTX3 mRNA observed in adipose tissue, the circulating level of PTX3 is reduced with obesity. Interestingly, aerobic activity has been demonstrated to elevate PTX3 levels. Therefore, the purpose of this review is to discuss the therapeutic potential of PTX3 to positively regulate obesity-related inflammation and discuss the proposition for utilizing aerobic exercise as a nonpharmacological anti-inflammatory treatment strategy to enhance circulating PTX3 concentrations in obese individuals.

Pentraxin 3 (PTX3), a cardioprotective protein, has recently been shown to be associated with improved insulin resistance (IR) and glucose metabolism. Therefore, the primary purpose of this study was to examine whether or not increased plasma PTX3 following maximal aerobic exercise would differ between obese and normal-mass subjects, and its association with the homeostatic model assessment of insulin resistance (HOMA-IR) and glucose response. Twenty-five untrained obese (n = 13 [6 males and 7 females]) and normal-mass (n = 12 [5 males and 7 females]) subjects performed an acute bout of maximal aerobic exercise to assess maximal oxygen consumption (VO2max). At baseline, plasma PTX3 concentrations are decreased in obese compared with normal-mass subjects and are negatively associated with plasma insulin and HOMA-IR values. In response to maximal exercise, plasma PTX3 responses were similar in obese and normal-mass subjects while the intensity of plasma PTX3 response as indicated by area under the curve analysis (AUCi) was not associated with HOMA-IR or glucose AUCi. However, PTX3 AUCi was positively associated with cardiorespiratory fitness levels (relative VO2max). These findings suggest that PTX3 could serve as a biomarker for both metabolic health, as well as a measurement to monitor the effectiveness of exercise interventions in obesity.

The objective of this study was to examine whether acute aerobic exercise-mediated calprotectin in plasma would be associated with monocyte chemotactic protein-1 (MCP-1), myeloperoxidase (MPO), and interleukin-6 (IL-6) in healthy individuals. Eleven healthy participants, aged 18 to 30 years, were recruited to perform a 30-min bout of aerobic exercise at 75% maximal oxygen uptake. Acute aerobic exercise elicited a significant elevation across time in plasma calprotectin, MCP-1, MPO, and IL-6. Body mass index (BMI) was positively correlated with calprotectin area-under-the-curve with "respect to increase" (AUCi) and IL-6 AUCi. Furthermore, calprotectin AUCi was positively correlated with IL-6 AUCi and MPO AUCi, even after controlling for BMI. Although MPO AUCi was positively correlated with IL-6 AUCi, this relationship no longer existed after controlling for BMI. These results suggest that acute aerobic exercise could mediate innate immune response associated with calprotectin and its related leukocyte chemotactic and inflammatory mediators, especially in individuals with elevated BMI.

Chitinase 3-like 1 (CHI3L1) and intelectin 1 (ITLN-1) recognize microbial N-acetylglucosamine polymer and galactofuranosyl carbohydrates, respectively. Both lectins are highly abundant in plasma and seem to play pro- and anti-inflammatory roles, respectively, in obesity and inflammatory-related illnesses. The aim of this study was to examine whether plasma levels of these lectins in obese subjects are useful for monitoring inflammatory conditions immediately influenced by acute aerobic exercise. Plasma interleukin-6, a pro-inflammatory cytokine, was also examined. Twenty-two (11 obese and 11 normal-weight) healthy subjects, ages 18-30 years, were recruited to perform a 30 min bout of acute aerobic exercise at 75% VO2max. We confirmed higher baseline levels of plasma CHI3L1, but lower ITLN-1, in obese subjects than in normal-weight subjects. The baseline levels of CHI3L1 were negatively correlated with cardiorespiratory fitness (relative VO2max). However, when controlled for BMI, the relationship between baseline level of CHI3L1 and relative VO2max was no longer observed. While acute aerobic exercise elicited an elevation in these parameters, we found a lower ITLN-1 response in obese subjects compared to normal-weight subjects. Our study clearly indicates that acute aerobic exercise elicits a pro-inflammatory response (e.g. CHI3L1) with a lower anti-inflammatory effect (e.g. ITLN-1) in obese individuals. Furthermore, these lectins could be predictors of outcome of exercise interventions in obesity-associated inflammation., (© 2015 by the Society for Experimental Biology and Medicine.)

Aims: G protein-coupled receptor kinase 2 (GRK2), a cytosolic enzyme desensitizing G protein-couple receptors (e.g., β-adrenergic receptors [β-ARs]), is involved in regulation of hypertension, congestive heart failure, and inflammatory response. Since cellular GRK2 levels change quickly in response to exogenous/endogenous stimuli, this study examined whether GRK2 levels in human peripheral blood mononuclear cells (PBMCs) would increase during acute aerobic exercise and be associated with plasma IL-6 and cardiorespiratory fitness levels., Main Methods: Eighteen subjects (8 men and 10 women), ages 18 to 30 years, were recruited to perform a 30-minute bout of acute aerobic exercise at 75% VO2max., Key Findings: Our results demonstrated that women exhibited significantly greater exercise-induced GRK2 expression in PBMCs compared to men. IL-6 modulation is independent of GRK2 expression. Furthermore, the percent change in GRK2 expression was negatively correlated with cardiorespiratory fitness levels (relative VO2max), but not plasma IL-6., Significance: Acute aerobic exercise induces a greater GRK2 expression in women than men, while increased cardiorespiratory fitness is associated with exercise-induced GRK2 expression in PBMCs. Gender could be a contributor to regulate this GRK2 responsiveness to acute aerobic exercise., (Published by Elsevier Inc.)

Pentraxin 3 (PTX3) has recently been linked to obesity-associated inflammation, serving as a cardioprotective modulator against cardiovascular disease (CVD). Aerobic exercise has been shown to enhance plasma PTX3 levels; however, the impact of obesity on PTX3 response to exercise remains unknown. Objective Therefore, this study sought to examine whether obese subjects would have an attenuated plasma PTX3 response compared to normal-weight subjects following acute aerobic exercise. The relationship of plasma PTX3 with pro-inflammatory cytokines (IL-6 and TNF-α) was also examined. Methods Twenty healthy subjects (10 obese [4 males and 6 females] and 10 normal-weight [4 males, 6 females]) performed 30 min of continuous submaximal aerobic exercise. Results At baseline, obese subjects exhibited approximately 40% lower plasma PTX3 and a 7-fold greater IL-6 concentration compared to normal-weight subjects. In response to exercise, no difference was observed in PTX3 or IL-6 as indicated by area-under-the-curve “with respect to increase” (AUCi) analyses. Furthermore, PTX3 AUCi was positively correlated with cardiorespiratory fitness levels (VO 2max ) (r = 0.594, p = 0.006), even after controlling for body mass index. Conclusion These findings suggest that in addition to obesity-associated complications, low cardiorespiratory fitness levels could impact exercise-induced PTX3 elevations, thereby potentially diminishing PTX3’s effects of anti-inflammation and/or cardioprotection. [ABSTRACT FROM AUTHOR]

Full length human telomerase reverse transcriptase (FL hTERT) is the rate-limiting, catalytic component necessary for telomerase enzyme activity and telomere length maintenance. Unlike rodents, humans evolved elongated introns with cis-elements that when bound by specific RNA binding proteins (RNAbp) splice hTERT to FL transcripts or produce inactive variants through alternative splicing (AS). Our working hypothesis is that hTERT AS regulates the amount of active telomerase. Evidence from human studies have shown that aerobic exercise maintains telomere length through increased hTERT expression and telomerase enzyme activity, however the impact of acute exercise on hTERT AS is unknown. PURPOSE: To examine hTERT AS regulation in response to acute treadmill running. METHODS: A bacterial artificial chromosome mouse model containing the full hTERT gene (5' and 3' regulatory elements; 16 exons and 15 introns) inserted into its genome (hTERT-BAC) was utilized. Gastrocnemius (Gas.) and heart (Hrt.) were excised from 10-week old hTERT-BAC mice prior to (PRE), upon cessation (POST), and during recovery (1, 24, 48, and 72H; n = 5/time point) from 30 min. of treadmill running (60% max. speed). Primers specific to hTERT were utilized to measure FL and the most common AS variant minus beta (-β, which skips exons 7 and 8) by two different RT-PCR methods - gel based and droplet digital PCR. Gene expression of the RNAbp PTBP1 was also measured. RESULTS: The expected human patterns of hTERT AS was recapitulated across all tissues examined. Compared to PRE, FL hTERT gene expression increased at POST before decreasing in the Gas. (48 and 72H; p ≤ 0.001) and Hrt. (24H; p = 0.004). Acute exercise also increased the percentage of FL hTERT in the Gas. at 1 and 72H (p ≤ 0.017), whereas a decrease was observed in the Hrt. at 1, 24, and 48H (p ≤ 0.041). Finally, Ptbp1 decreased at POST (Gas.) and at 1, 24, 48, and 72H (Gas. and Hrt.; p ≤ 0.05). CONCLUSIONS: Evolutionarily conserved mouse splicing machinery (RNAbp) recognize hTERT cis-elements to recapitulate human AS patterns and highlight the importance of the intronic elements in regulating hTERT splicing choice in humans. The hTERT-BAC mouse is a valuable resource to study the exercise-induced adaptive mechanisms that maintain telomere lengths in endurance trained individuals across the lifespan. [ABSTRACT FROM AUTHOR]