Caffeine has no effect on submaximal running in hypoxia in low caffeine consuming males and females.

BACKGROUND: Exposure to hypoxia immediately challenges a variety of physiologic systems that limit exercise capacity. Under normoxia, caffeine (CAFF) increases ventilation and subsequent oxygenation of hemoglobin (SpO2) and skeletal muscle (SmO2). CAFF improves exercise performance at altitude. However, little attention has been given to submaximal exercise in hypoxia, particularly regarding low CAFF consumers and female participants. The aim of this study was to determine the effect of CAFF on pulmonary, metabolic, and perceptual variables in response to submaximal running in hypoxia in low CAFF consuming males and females. METHODS: In a double blinded, counterbalanced design, 14 (6 females) individuals (24.1±5.1 years; VO2max: 40.6±5.6 mL × kg-1 × min-1; 20.8±8.0% body fat), who habitually consumed ≤150 mg/day of CAFF performed treadmill running at workloads of 25%, 40%, 60%, and 75% of sea level VO2max in normobaric hypoxia (FIO2=0.15) on two separate occasions: 1) 60 minutes after 6 mg/kg of CAFF; or 2) placebo. RESULTS: CAFF had no effect on any variable measured. Specifically, VE (condition: P=0.12; interaction: P=0.19), VT (condition: P=0.16; interaction: P=0.57), and Ve:VO2 (condition: P=0.07; interaction: P=0.69) were similar between groups. Further, CAFF had no effect on relative VO2 (condition: P=0.84; interaction: P=0.95), HR (condition: P=0.28; interaction: P=0.35), SmO2 (condition: P=0.66; interaction: P=0.82), or SpO2 (condition: P=0.16; interaction: P=0.97). Finally, rating of perceived exertion (RPE; P=0.92) and acute mountain sickness scores (P=0.29) were similar across conditions. CONCLUSIONS: These data demonstrate that CAFF provides no physiologic advantage to submaximal exercise in acute, normobaric hypoxia with low CAFF consuming males and females.

New Zealand blackcurrant extract modulates the heat shock response in men during exercise in hot ambient conditions.

PURPOSE: To determine if 7d of New Zealand blackcurrant (NZBC) extract alters the heat shock, inflammatory and apoptotic response during prolonged exertional-heat stress. METHODS: Ten men (Age: 29 ± 2 years, Stature: 1.82 ± 0.02 m, Mass: 80.3 ± 2.7 kg, V̇O2max: 56 ± 2 mL·kg-1·min-1) ingested two capsules of CurraNZ™ (NZBC extract: 210 mg anthocyanins·day-1) or PLACEBO for 7d prior to 1 h treadmill run (65% V̇O2max) in hot ambient conditions (34 °C/40% RH). Blood samples were collected before (Pre), immediately after (Post), 1 h after (1-Post), and 4 h after (4-Post) exercise. Heat shock proteins (HSP90, HSP70, HSP32) were measured in plasma. HSP and protein markers of inflammatory capacity (TLR4, NF-κB) and apoptosis (BAX/BCL-2, Caspase 9) were measured in peripheral blood mononuclear cells (PBMC). RESULTS: eHSP32 was elevated at baseline in NZBC(+ 31%; p < 0.001). In PLACEBO HSP32 content in PBMC was elevated at 4-Post(+ 98%; p = 0.002), whereas in NZBC it fell at Post(- 45%; p = 0.030) and 1-Post(- 48%; p = 0.026). eHSP70 was increased at Post in PLACEBO(+ 55.6%, p = 0.001) and NZBC (+ 50.7%, p = 0.010). eHSP90 was increased at Post(+ 77.9%, p < 0.001) and 1-Post(+ 73.2%, p < 0.001) in PLACEBO, with similar increases being shown in NZBC (+ 49.0%, p = 0.006 and + 66.2%, p = 0.001; respectively). TLR4 and NF-κB were both elevated in NZBC at PRE(+ 54%, p = 0.003 and + 57%, p = 0.004; respectively). Main effects of study condition were also shown for BAX/BCL-2(p = 0.025) and Caspase 9 (p = 0.043); both were higher in NZBC. CONCLUSION: 7d of NZBC extract supplementation increased eHSP32 and PBMC HSP32 content. It also increased inflammatory and apoptotic markers in PBMC, suggesting that NZBC supports the putative inflammatory response that accompanies exertional-heat stress.

Repeated short cold-water immersions are sufficient to habituate to the cold, but do not lead to adaptations during exercise in normobaric hypoxia.

We sought to assess the effects of repeated cold-water immersions (CWI) on respiratory, metabolic, and sympathoadrenal responses to graded exercise in hypoxia. Sixteen (2 female) participants (age: 21.2 ± 1.3 years; body fat: 12.3 ± 7.7%; body surface area 1.87 ± 0.16 m2, VO2peak: 48.7 ± 7.9 mL/kg/min) underwent 6 CWI in 12.0 ± 1.2 °C. Each CWI was 5 min, twice daily, separated by ≥4 h, for three consecutive days, during which metabolic data were collected. The day before and after the repeated CWI intervention, participants ran in normobaric hypoxia (FIO2 = 0.135) for 4 min at 25%, 40%, 60%, and 75% of their sea level peak oxygen consumption (VO2peak). CWI had no effect on VO2 (p > 0.05), but reduced the VE (CWI #1: 27.1 ± 17.8 versus CWI #6: 19.9 ± 12.1 L/min) (p < 0.01), VT (CWI #1: 1.3 ± 0.4 vs CWI #6: 1.1 ± 0.4 L) (p < 0.01), and VE:VO2 (CWI #1: 53.5 ± 24.1 vs CWI #6: 41.6 ± 20.5) (p < 0.01) during subsequent CWI. Further, post exercise plasma epinephrine was lower after CWI compared to before (103.3 ± 43.1; 73.4 ± 34.6 pg/mL) (p = 0.03), with no change in pre-exercising values (75.4 ± 30.7; 72.5 ± 25.9 pg/mL). While these changes were noteworthy, it is important to acknowledge there were no changes in pulmonary (VE, VT, and VE:VO2) or metabolic (VO2, SmO2, and SpO2) variables across multiple hypoxic exercise workloads following repeated CWI. CWI habituated participants to cold water, but this did not lead to adaptations during exercise in normobaric hypoxia.

Exercise induced plasma volume expansion lowers cardiovascular strain during 15-km cycling time-trial in acute normobaric hypoxia.

The purpose of our study was to assess the influence of a single high-intensity interval exercise (HIIE) bout in normoxia on plasma volume (PV) and consequent cycling performance in normobaric hypoxia (0.15 FiO2, simulating ~2,500 m). Eight males (VO2peak: 48.8 ± 3.4 mL/kg/min, 24.0 ± 1.6 years) completed a hypoxic 15 km cycling time trial (TT), followed by a crossover intervention of either HIIE (8x4 min cycling bouts at 85% of VO2peak) or CON (matched kJ production from HIIE at 50% of VO2peak). 48 hours post intervention, an identical TT was performed. Cardiovascular parameters were measured via impedance cardiography during each TT. Changes in PV was measured 24 and 48 hours post HIIE and CON. HIIE increased PV at 24 (4.1 ± 3.9%, P = 0.031) and 48 (6.7 ± 1.7, P = 0.006) hours post, while no difference was observed following the CON (1.3 ± 1.1% and 0.3 ± 2.8%). The higher PV led to an increased stroke volume (P = 0.03) and cardiac output (P = 0.02) during the hypoxic TT, while heart rate was not changed (P = 0.49). We observed no changes in time to completion (-0.63 ± 0.57 min, P = 0.054) and power output (7.37 ± 7.98 W, P = 0.078) between TTs. In the absence of environmental stress, a single bout of HIIE was an effective strategy to increase PV and reduce the cardiovascular strain during a cycling TT at moderate simulated altitude but did not impact hypoxic exercise performance. Trial registration: Clinical Trials ID: NCT05800808.

Effect of Combined Grape Seed Extract and L-Citrulline Supplementation on Hemodynamic Responses to Exercise in Young Males.

Grape seed extract (GSE) or L-citrulline supplement has been known to increase nitric oxide (NO) bioavailability and enhance endothelial-mediated vasodilation. Accordingly, to examine the additive benefits of combination of the two supplementations on hemodynamic responses to dynamic exercise, young, healthy males were recruited for this study. Effects of 7 days of 1) GSE + L-citrulline, 2) GSE, 3) L-citrulline, and 4) placebo supplementation on systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), cardiac output, total vascular conductance (TVC), and oxygen (O2) consumption were examined at rest and during cycling exercise. Compared with placebo, GSE, L-citrulline, and combined supplementations did not reduce SBP, DBP, and MAP, while cardiac output (placebo; 23.6 ± 1.3 L/min, GSE; 25.7 ± 1.1 L/min; L-citrulline, 25.2 ± 1.2 L/min; GSE + L-citrulline; 25.3 ± 0.9 L/min) and TVC (placebo; 234.7 ± 11.3 ml/min/mmHg, GSE; 258.3 ± 10.6 ml/min/mmHg; L-citrulline, 255.2 ± 10.6 ml/min/mmHg; GSE + L-citrulline; 260.4 ± 8.9 ml/min/mmHg) were increased at only the 80% workload (p < 0.05). Compared with placebo and L-citrulline, GSE and combined supplementations had a reduction in VO2 across workloads (p < 0.05). However, there was no additive benefits on these variables. We conclude that supplementation with GSE, L-citrulline, and combined supplementations increased cardiac output due partially to decreased vascular resistance. Our findings suggest that GSE may act as an ergogenic aid that can improve O2 delivery to exercising muscles.

Ibuprofen Increases Markers of Intestinal Barrier Injury But Suppresses Inflammation at Rest and After Exercise in Hypoxia.

PURPOSE: The purpose of this study was to evaluate the effects of acute ibuprofen consumption (2 × 600-mg doses) on markers of enterocyte injury, intestinal barrier dysfunction, inflammation, and symptoms of gastrointestinal (GI) distress at rest and after exercise in hypobaric hypoxia. METHODS: Using a randomized double-blind placebo-controlled crossover design, nine men (age, 28 ± 3 yr; weight, 75.4 ± 10.5 kg; height, 175 ± 7 cm; body fat, 12.9% ± 5%; V̇O 2 peak at 440 torr, 3.11 ± 0.65 L·min -1 ) completed a total of three visits including baseline testing and two experimental trials (placebo and ibuprofen) in a hypobaric chamber simulating an altitude of 4300 m. Preexercise and postexercise blood samples were assayed for intestinal fatty acid binding protein (I-FABP), ileal bile acid binding protein, soluble cluster of differentiation 14, lipopolysaccharide binding protein, monocyte chemoattractant protein-1, tumor necrosis factor α (TNF-α), interleukin-1ß, and interleukin-10. Intestinal permeability was assessed using a dual sugar absorption test (urine lactulose-to-rhamnose ratio). RESULTS: Resting I-FABP (906 ± 395 vs 1168 ± 581 pg·mL -1 ; P = 0.008) and soluble cluster of differentiation 14 (1512 ± 297 vs 1642 ± 313 ng·mL -1 ; P = 0.014) were elevated in the ibuprofen trial. Likewise, the urine lactulose-to-rhamnose ratio (0.217 vs 0.295; P = 0.047) and the preexercise to postexercise change in I-FABP (277 ± 308 vs 498 ± 479 pg·mL -1 ; P = 0.021) were greater in the ibuprofen trial. Participants also reported greater upper GI symptoms in the ibuprofen trial ( P = 0.031). However, monocyte chemoattractant protein-1 ( P = 0.007) and TNF-α ( P = 0.047) were lower throughout the ibuprofen trial compared with placebo (main effect of condition). CONCLUSIONS: These data demonstrate that acute ibuprofen ingestion aggravates markers of enterocyte injury and intestinal barrier dysfunction at rest and after exercise in hypoxia. However, ibuprofen seems to suppress circulating markers of inflammation.

High-altitude exposures and intestinal barrier dysfunction.

Gastrointestinal complaints are often reported during ascents to high altitude (>2,500 m), though their etiology is not known. One potential explanation is injury to the intestinal barrier which has been implicated in the pathophysiology of several diseases. High-altitude exposures can reduce splanchnic perfusion and blood oxygen levels causing hypoxic and oxidative stress. These stressors might injure the intestinal barrier leading to consequences such as bacterial translocation and local/systemic inflammatory responses. The purpose of this mini-review is to 1) discuss the impact of high-altitude exposures on intestinal barrier dysfunction and 2) present medications and dietary supplements which may have relevant impacts on the intestinal barrier during high-altitude exposures. There is a small but growing body of evidence which shows that acute exposures to high altitudes can damage the intestinal barrier. Initial data also suggest that prolonged hypoxic exposures can compromise the intestinal barrier through alterations in immunological function, microbiota, or mucosal layers. Exertion may worsen high-altitude-related intestinal injury via additional reductions in splanchnic circulation and greater hypoxemia. Collectively these responses can result in increased intestinal permeability and bacterial translocation causing local and systemic inflammation. More research is needed to determine the impact of various medications and dietary supplements on the intestinal barrier during high-altitude exposures.

Effects of chronic dietary grape seed extract supplementation on aortic stiffness and hemodynamic responses in obese/overweight males during submaximal exercise.

We investigated the effect of chronic grape seed extract (GSE) on blood pressure and aortic stiffness (AoS) among overweight and obese males. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (Q), total vascular conductance (TVC), and AoS were measured during two submaximal cycling exercises (40% and 60% VO2max), after 7 consecutive days of GSE or placebo (PL) ingestion with one week washout period. Compared with PL, GSE supplementation significantly decreased MAP at rest (85 ± 3 mmHg vs. 82 ± 3 mmHg), 40% (102 ± 3 mmHg vs. 99 ± 3 mmHg), and 60% workloads (109 ± 3 mmHg vs. 107 ± 3 mmHg) (P = 0.001, ES = 0.2). AoS was significantly reduced (13.0 ± 1.9 AU vs. 10.2 ± 1.0 AU) at rest (P = 0.002, ES = 0.6). Q was decreased at rest and across all workloads, but there were no significant differences (7.5 ± 0.4 L/min vs. 7.1 ± 0.4 L/min; 20.4 ± 1.2 L/min vs. 19.6 ± 0.9 L/min; 26.3 ± 1.1 L/min vs. 25.5 ± 1.6 L/min, respectively). GSE had no effect on HR, TVC, and SV. Our study indicates that chronic supplementation with GSE reduces arterial pressure at rest and during exercise primarily via the substantial reduction in AoS. Thus, GSE can be a dietary supplement to treat augmented blood pressure responses in obese and overweight males at rest and during exercise.Trial registration: ClinicalTrials.gov identifier: NCT04465110.

Short-term hot water immersion results in substantial thermal strain and partial heat acclimation; comparisons with heat-exercise exposures.

OBJECTIVE: To examine the effectiveness of hot water immersion (HWI) as a heat acclimation strategy in comparison to time and temperature matched, exercise-heat acclimation (EHA). METHODS: 8 males performed heat stress tests (HST) (45 min of cycling at 50% of VO2max in 40 °C, 40% RH) before and after heat acclimation sessions. Acclimation sessions were either three consecutive bouts of HWI (40 min of submersion at 40 °C) or EHA (40 min of cycling at 50% VO2max in 40 °C, 40% RH). RESULTS: Average change in tympanic temperature (TTympanic) was significantly higher following HWI (2.1 °C ± 0.4) compared to EHA (1.5 °C ± 0.4) (P < 0.05). Decreases in peak heart rate (HR) (HWI: -10 bpm ± 8; EHA: -6 ± 7), average HR (-7 bpm ± 6; -3 ± 4), and average core temperature (-0.4 °C ± 0.3; -0.2 ± 0.4) were evident following acclimation (P < 0.05), but not different between interventions (P > 0.05). Peak rate of perceived exertion (RPEPeak) decreased for HWI and EHA (P < 0.05). Peak thermal sensation (TSPeak) decreased following HWI (P < 0.05) but was not different between interventions (P > 0.05). Plasma volume increased in both intervention groups (HWI: 5.9% ± 5.1; EHA: 5.4% ± 3.7) but was not statistically different (P > 0.05). CONCLUSION: HWI induced significantly greater thermal strain compared to EHA at equivalent temperatures during time-matched exposures. However, the greater degree of thermal strain did not result in between intervention differences for cardiovascular, thermoregulatory, or perceptual variables. Findings suggest three HWI sessions may be a potential means to lower HR, TCore, and perceptual strain during exercise in the heat.

Effects of exercise in hot and humid conditions and bovine colostrum on salivary immune markers.

The purpose of this study was to examine the effects of exercise in a hot and humid environment on salivary lactoferrin and lysozyme. A secondary aim was to quantify the effects of 14-day bovine colostrum (BC) supplementation on salivary lactoferrin and lysozyme at rest and following exercise in hot and humid conditions. Using a randomized, double-blind, and counterbalanced design, ten males (20 ± 2 years, VO2max 55.8 ± 3.7 mL kg-1 min-1, 11.8 ± 2.7% body fat) ran for 46 ± 7.7 min at 95% of ventilatory threshold in a 40 °C and 50% RH environment after 14-days of supplementation with either BC or placebo. Saliva was collected pre, post, 1-h, and 4-h post exercise, and was analyzed for lactoferrin and lysozyme using ELISA. There was an immediate increase in the concentration and secretion rate of lactoferrin and lysozyme (p < 0.05) with exercise, but BC had no effect (p > 0.05). Saliva flow rate was not different between conditions [(PLA: pre: 0.54 ± 0.3, post: 0.44 ± 0.3, 1-h: 0.67 ± 0.3, 4-h: 1.0 ± 0.4 mL min-1); (BC: pre: 0.58 ± 0.2, post: 0.37 ± 0.1, 1-h: 0.63 ± 0.2, 4-h: 0.83 ± 0.4 mL min-1)]. There were no differences in thermoregulatory markers (core temperature or physiological strain index) between BC and placebo trials. Interestingly, exercise-induced heat stress did not impair mucosal immune parameters, instead participants showed a transient increase in salivary lactoferrin and lysozyme. Further, 14-day BC supplementation had no effect on mucosal immunity at any time point.

Physiological and Biomechanical Differences Between Seated and Standing Uphill Cycling.

Despite differences in economy, cyclists climb in seated and standing positions. Prompted by gaps in research, we compared VO2 and heart rate (HR) (Study 1), muscle activation (Study 2) and breathing and pedaling entrainment (Study 3). METHODS: Subjects rode their bicycles on a treadmill in seated and standing positions. In Study 1, VO2 and HR of four male cyclists (21.3 ± 1.7 yrs; 69.1 ± 6 ml/kg/min) were collected, alternating positions every 5 minutes for 20 minutes (8 mph, 8% grade). In Study 2, muscle activations of eight male cyclists (24 ± 5 yrs, 67.6 ± 5.5 ml/kg/min) were collected on Rectus Femoris (RF), Biceps Femoris, Vastus Medialis (VM) and Gastrocnemius alternating positions every minute (8 mph, 8% grade). In Study 3, flow rate and entrainment of nine male cyclists (28 ± 7 yrs, 62.7 ± 7.7 ml/kg/min) were collected in 2-minute stages at 6, 8 and 10 mph, (8% grade) alternating positions every minute. RESULTS: VO2 and HR increased standing (3.17± 0.43 L/min, 175 ± 4 bpm) compared to seated (3.06 ± 0.37 L/min, 166 ± 5 bpm) (p < 0.05). Normalized EMG for RF and VM increased standing (47 ± 5%, 57 ± 15%) compared to seated (34 ± 3%, 36 ± 8%) (p < 0.05). Peak Inspiratory and Expiratory Flow increased standing (3.44±0.07 and 2.45±0.05 L/sec) compared to seated (3.09 ±0.06 and 2.21±0.04 L/sec) (p < 0.05). CONCLUSION: Uphill cycling while standing results in decreased cycling economy due to physiological and biomechanical variations compared to riding seated.

The Independent and Combined Effects of Aerobic Physical Activity and Muscular Strengthening Activity on All-Cause Mortality: An Analysis of Effect Modification by Race-Ethnicity.

BACKGROUND: The effects of aerobic physical activity (PA) and muscular strengthening activity (MSA) on all-cause mortality risk need further exploration among ethnically diverse populations. PURPOSE: To examine potential effect modification of race-ethnicity on meeting the PA guidelines and on all-cause mortality. METHODS: The study sample (N = 14,384) included adults (20-79 y of age) from the 1999-2006 National Health and Nutrition Examination Survey. PA was categorized into 6 categories based on the 2018 PA guidelines: category 1 (inactive), category 2 (insufficient PA and no MSA), category 3 (active and no MSA), category 4 (no PA and sufficient MSA), category 5 (insufficient PA and sufficient MSA), and category 6 (meeting both recommendations). Race-ethnic groups examined included non-Hispanic white, non-Hispanic black, and Mexican American. Cox-proportional hazard models were used. RESULTS: Significant risk reductions were found for categories 2, 3, and 6 for non-Hispanic white and non-Hispanic black. Among Mexican American, significant risk reductions were found in category 6. CONCLUSION: In support of the 2018 PA guidelines, meeting both the aerobic PA and MSA guidelines significantly reduced risk for all-cause mortality independent of race-ethnicity. The effects of aerobic PA alone seem to be isolated to non-Hispanic white and non-Hispanic black.

Effects of combined histamine H1 and H2 receptor blockade on hemodynamic responses to dynamic exercise in males with high-normal blood pressure.

While postexercise hypotension is associated with histamine H1 and H2 receptor-mediated postexercise vasodilation, effects of histaminergic vasodilation on blood pressure (BP) in response to dynamic exercise are not known. Thus, in 20 recreationally active male participants (10 normotensive and 10 with high-normal BP) we examined the effects of histamine H1 and H2 receptor blockade on cardiac output (CO), mean atrial pressure (MAP), aortic stiffness (AoStiff), and total vascular conductance (TVC) at rest and during progressive cycling exercise. Compared with the normotensive group, MAP, CO, and AoStiff were higher in the high-normal group before and after the blockade at rest, while TVC was similar. At the 40% workload, the blockade significantly increased MAP in both groups, while no difference was found in the TVC. CO was higher in the high-normal group than the normotensive group in both conditions. At the 60% workload, the blockade substantially increased MAP and decreased TVC in the normotensive group, while there were no changes in the high-normal group. A similar CO response pattern was observed at the 60% workload. These findings suggest that the mechanism eliciting an exaggerated BP response to exercise in the high-normal group may be partially due to the inability of histamine receptors. Novelty Males with high-normal BP had an exaggerated BP response to exercise. The overactive BP response is known due to an increase in peripheral vasoconstriction. Increase in peripheral vasoconstriction is partially due to inability of histamine receptors.

Prolonged treadmill running in normobaric hypoxia causes gastrointestinal barrier permeability and elevates circulating levels of pro- and anti-inflammatory cytokines.

This study examined the impact of treadmill running in normobaric hypoxia on gastrointestinal barrier permeability and the systemic inflammatory response. Ten recreationally active participants completed two 1-h bouts of matched-workload treadmill exercise (65% normoxic maximal oxygen consumption) in counterbalanced order. One bout was performed in normoxia (NORM: fraction of inspired oxygen (FIO2) = 20.9%) and the other in normobaric hypoxia (HYP: FIO2 = 13.5%). Minute ventilation, respiratory rate (RR), tidal volume (VT), oxygen consumption, carbon dioxide production, respiratory exchange ratio (RER), and heart rate (HR) were measured with a metabolic cart. Peripheral oxygen saturation (SpO2) was measured with pulse oximetry. Absolute tissue saturation (StO2) was measured with near-infrared spectroscopy. Fatty acid-binding protein (I-FABP) and circulating cytokine concentrations (interleukin (IL)-1Ra, IL-6, IL-10) were assayed from plasma samples that were collected pre-exercise, postexercise, 1 h-postexercise, and 4 h-postexercise. Data were analyzed with 2-way (condition × time) repeated-measures ANOVAs. Newman-Keuls post hoc tests were run where appropriate (p < 0.05). As compared with NORM, 1 h of treadmill exercise in HYP caused greater (p < 0.05) changes in minute ventilation (+30%), RR (+16%), VT (+10%), carbon dioxide production (+18%), RER (+16%), HR (+4%), SpO2 (-16%), and StO2 (-10%). Gut barrier permeability and circulating cytokine concentrations were also greater (p < 0.05) following HYP exercise, where I-FABP was shown increased at postexercise (+68%) and IL-1Ra at 1 h-postexercise (+266%). I-FABP and IL-1Ra did not change (p > 0.05) following NORM exercise. IL-6 and IL-10 increased with exercise in both study conditions but were increased more (p < 0.05) following HYP at postexercise (+705% and +127%, respectively) and 1 h-postexercise (+400% and +128%, respectively). Novelty Normobaric hypoxia caused significant desaturation and increased most cardiopulmonary responses by 10%-30%. Significant gut barrier permeability and increased pro- and anti-inflammatory cytokine concentrations could promote an "open window" in the hours following HYP exercise.

Reduced inflammatory and phagocytotic responses following normobaric hypoxia exercise despite evidence supporting greater immune challenge.

This study examined changes in immune markers following sustained treadmill exercise in normobaric hypoxia. Ten subjects performed 1 h of treadmill exercise (65% maximal oxygen uptake) under normoxic (NORM: fraction of inspired oxygen (FIO2) = 20.9%) and normobaric hypoxic (HYP: FIO2 = 13.5%) conditions. Blood samples, collected before, after (Post), 1 h after (1-Post), and 4 h after (4-Post) exercise, were assayed for plasma cytokines (interleukin (IL)-1RA/IL-1ß/IL-8/tumor necrosis factor alpha (TNF-α)) and markers of leukocyte activation (macrophage inflammatory protein-1ß (MIP-1ß)/myeloperoxidase (MPO)/soluble intercellular adhesion molecule-1 (sICAM-1)) using ELISA. Pro- to anti-inflammatory cytokine ratios (TNF-α/IL-1RA; IL-1ß/IL-1RA) were calculated. Peripheral blood mononuclear cells (PBMC) were analyzed for changes in inflammatory status (phosphorylated nuclear factor kappa B/nuclear factor kappa B) using Western Blot. Data were analyzed with 2-way (condition × time) repeated-measure ANOVAs with Newman-Keuls post hoc tests. MIP-1ß was elevated at 1-Post HYP exercise (+11%; p < 0.01) but did not increase following exercise in NORM. TNF-α/IL-1RA and IL-1ß/IL-1RA ratios were both reduced (p < 0.05) following HYP exercise (-16% and -52%, respectively, at 1-Post and -7% and -32%, respectively, at 4-Post). IL-8 increased (p < 0.05) at Post and 1-Post NORM (+33% and +57%, respectively) and HYP (+60% and +83%, respectively) exercise, but was not different between conditions (p > 0.05). Interestingly, plasma sICAM-1 did not increase (p > 0.05) following NORM exercise but was increased (p < 0.05) at Post (+17%), 1-Post (+16%), and 4-Post (+14%) HYP exercise. There was also a delayed peak in plasma MPO concentrations following HYP exercise and PBMC exhibited a reduced (p < 0.05) inflammatory capacity at Post (-38%) and 1-Post (-49%). Novelty Following HYP exercise, participants exhibited (i) circulatory bias towards anti-inflammation; (ii) elevated sICAM; (iii) delayed peak in plasma MPO; and (iv) diminished inflammatory response in PBMC. Collectively, these data suggest immunosuppression. This is undesirable, given that elevated MIP-1ß (reported here) and elevated intestinal fatty acid binding protein (reported previously) both suggest higher lipopolysaccharide concentrations following HYP exercise.

Dietary curcumin supplementation does not alter peripheral blood mononuclear cell responses to exertional heat stress.

INTRODUCTION: Curcumin reduces gut barrier damage and plasma cytokine responses to exertional heat stress. However, the role of peripheral blood mononuclear cell (PBMC) in this response remains unclear. PURPOSE: This work investigated the effect of 3 days of 500 mg/day dietary curcumin supplementation on PBMC responses to exertional heat stress in non-heat acclimated humans. METHODS: Eight participants ran (65% VO2max) for 60 min in an environmental chamber (37 °C/25% RH) two times (curcumin/placebo). Blood samples were collected pre, post, 1 h post, and 4 h post-exercise. PBMC were isolated from blood samples and the protein content of markers along the TLR4 signaling pathway (TLR4, MyD88, pNF-κB, NF-κB), indicators of cellular energy status (SIRT1 and p-AMPK), and mediators of cellular heat shock response (pHSF-1 and HSP70) were examined with Western blot. Data were analyzed with two-way (condition × time) RM-ANOVAs with Newman-Keuls post hocs. RESULTS: As compared to placebo, curcumin did not alter protein expression in PBMC (p > 0.05). However, in both study conditions at 1 h post-reductions were noted in TLR 4 (- 21.5%; p = 0.03), HSP70 (- 11.0%; p = 0.04), pAMPK (- 48.5%; p < 0.01), and SIRT1 (- 47.8%; p < 0.01). Remarkably, the ratio of pNF-κB to NF-κB was elevated in both conditions at this same timepoint (+ 75.4%; p = 0.02). CONCLUSIONS: Inflammatory protein expression in PBMC did not differ between curcumin and placebo conditions. Downregulation of pAMPK/SIRT1 and release of HSP70 to the bloodstream may compensate for reduced TLR4, allowing PBMC to maintain inflammatory capacity and preventing an "open window" during the hours following hyperthermic exercise.

Heat acclimation increases inflammatory and apoptotic responses to subsequent LPS challenge in C2C12 myotubes.

This work investigated the ability of a 6-day heat acclimation protocol to impart heat acclimation-mediated cross-tolerance (HACT) in C2C12 myotubes, as indicated by changes in inflammatory and apoptotic responses to subsequent lipopolysaccharide (LPS) challenge. Myotubes were incubated at 40 °C for 2 h/day over 6 days (HA) or maintained for 6 days at 37 °C (C). Following 24 h recovery, myotubes from each group received either no stimulation or 500 ng/ml LPS for 2 h (HA + LPS and C + LPS, respectively). Cell lysates were collected and analyzed for protein markers of the heat shock response, inflammation, and apoptosis. As compared to C, HA exhibited an elevated heat shock response [HSP70 (+ 99%); HSP60 (+ 216%); HSP32 (+ 40%); all p < 0.01] and reduced inflammatory and apoptotic signaling [p-NF-ĸB:NF-ĸB (- 99%%); p-JNK (- 49%); all p < 0.01]. When compared to C + LPS, HA + LPS also exhibited an elevated heat shock response [HSP70 (+ 68%); HSP60 (+ 32%); HSP32 (+ 38%); all p < 0.01]. However, inflammatory and apoptotic responses in HA + LPS were increased [p-IKBa:IKBa (+ 432%); p-NF-ĸB:NF-ĸB (+ 283%); caspase-8p18 (+ 53%); p-JNK (+ 41%); all p < 0.05]. This unanticipated finding may be due to increased TLR4-mediated signaling capacity in HA + LPS, as indicated by upregulation of TLR4 [(+ 24%); MyD88 (+ 308%); p-NIK (+ 199%); and p-IKKα/b (+ 81%); all p < 0.05]. Data suggest HA reduces inflammatory and apoptotic signaling in skeletal muscle cells that are maintained under basal conditions. However, HACT is selective and does not apply to TLR4 signaling in the present model.

Heat acclimation increases mitochondrial respiration capacity of C2C12 myotubes and protects against LPS-mediated energy deficit.

This work investigated the effect of a 6-day heat acclimation (HA) protocol on myotube metabolic responses at baseline and in response to a subsequent lipopolysaccharide (LPS) challenge. C2C12 myotubes were incubated for 2 h/day at 40 °C for 6 days (HA) or maintained at 37 °C (C). Following 24-h recovery, myotubes were challenged with 500 ng/ml LPS for 2 h, then collected for analysis of protein markers of mitochondrial biogenesis and macronutrient storage. Functional significance of these changes was confirmed with mitochondrial respiration and glycolytic measurements on a Seahorse XF-96 analyzer. HA stimulated mitochondrial biogenesis and increased indicators of mitochondrial content [SIRT1 (+ 62%); PGC-1α (+ 57%); NRF-1 (+ 40%); TFAM (+ 141%); CS (+ 25%); CytC (+ 38%); all p < 0.05]. Altered lipid biosynthesis enzymes [p-ACCa:ACC (+ 59%; p = 0.04) and FAS (- 86%; p < 0.01)] suggest fatty acid generation may have been downregulated, whereas increased GLUT4 (+ 69%; p < 0.01) and LDH-B (+ 366%; p < 0.01) suggest aerobic glycolytic capacity may have been improved. Mitochondrial biogenesis signaling in HA myotubes was suppressed by 500 ng/ml LPS (PGC-1α, NRF-1, TFAM; all p > 0.05) but increased LDH-B (+ 30%; p = 0.02) and CPT-1 (+ 55%; p < 0.01) suggesting improved catabolic function. Basal respiration was increased in HA myotubes (+ 8%; p < 0.01) and HA myotubes maintained elevated basal respiration during LPS challenge (+ 8%; p < 0.01). LPS reduced peak respiration in C myotubes (- 6%; p < 0.01) but did not impair peak respiration in HA myotubes (p > 0.05). Oxidative reliance was elevated in HA over that in control (+ 25%; p < 0.01) and in HA + LPS over C + LPS (+ 30%; p < 0.01). In summary, HA stimulated mitochondrial biogenesis in C2C12 myotubes. HA myotubes exhibited (1) elevated basal/peak mitochondrial respiration capacities; (2) greater oxidative reliance; and (3) protection against LPS-mediated respiration impairment. Collectively, these data suggest HA may improve aerobic metabolism in skeletal muscle and protect against LPS-mediated energy deficit.

Short-term dietary curcumin supplementation reduces gastrointestinal barrier damage and physiological strain responses during exertional heat stress.

Szymanski MC, Gillum TL, Gould LM, Morin DS, Kuennen MR. Short-term dietary curcumin supplementation reduces gastrointestinal barrier damage and physiological strain responses during exertional heat stress. J Appl Physiol 124: 330-340, 2018. First published September 21, 2017; doi: 10.1152/japplphysiol.00515.2017 .-This work investigated the effect of 3 days of 500 mg/day dietary curcumin supplementation on gastrointestinal barrier damage and systems-physiology responses to exertional heat stress in non-heat-acclimated humans. Eight participants ran (65% V̇o2max) for 60 min in a Darwin chamber (37°C/25% relative humidity) two times (Curcumin/Placebo). Intestinal fatty acid-binding protein (I-FABP) and associated proinflammatory [monocyte chemoattractant protein-1, tumor necrosis factor-α (TNF-α), interleukin-6] and anti-inflammatory [interleukin-1 receptor antagonist (IL-1RA), interleukin-10 (IL-10)] cytokines were assayed from plasma collected before (Pre), after (Post) and 1 (1-Post) and 4 (4-Post) h after exercise. Core temperature and HR were measured throughout exercise; the physiological strain index (PSI) was calculated from these variables. Condition differences were determined with 2-way (condition × time) repeated-measures ANOVAs. The interaction of condition × time was significant ( P = 0.05) for I-FABP and IL-1RA. Post hoc analysis indicated I-FABP increased more from Pre to Post (87%) and 1-Post (33%) in Placebo than in Curcumin (58 and 18%, respectively). IL-1RA increased more from Pre to 1-Post in Placebo (153%) than in Curcumin (77%). TNF-α increased ( P = 0.01) from Pre to Post (19%) and 1-Post (24%) in Placebo but not in Curcumin ( P > 0.05). IL-10 increased ( P < 0.01) from Pre to Post (61%) and 1-Post (42%) in Placebo not in Curcumin ( P > 0.05). The PSI, which indicates exertional heatstroke risk, was also lower ( P < 0.01) in Curcumin than Placebo from 40 to 60 min of exercise. These data suggest 3 days curcumin supplementation may improve gastrointestinal function, associated cytokines, and systems-level physiology responses during exertional heat stress. This could help reduce exertional heatstroke risk in non-heat-acclimated individuals. NEW & NOTEWORTHY Exercise-heat stress increases gastrointestinal barrier damage and risk of exertional heatstroke. Over the past decade at least eight different dietary supplements have been tested for potential improvements in gastrointestinal barrier function and systems-level physiology responses during exercise-heat stress. None have been shown to protect against both insults simultaneously. In this report 3 days of 500 mg/day dietary curcumin supplementation are shown to improve gastrointestinal barrier function, associated cytokine responses, and systems-level physiology parameters. Further research is warranted.

Bovine colostrum supplementation does not affect plasma I-FABP concentrations following exercise in a hot and humid environment.

PURPOSE: To quantify the impact of a 14-day bovine colostrum (BC) supplementation on intestinal cell damage following exercise in a hot and humid environment. METHODS: Ten male participants (20 ± 2 years, VO2max 55.80 ± 3.79 mL kg-1 min-1, 11.81 ± 2.71% body fat) ran for 46 ± 7.75 min at 95% of ventiliatory threshold in 40 °C and 50% RH following a 14-day double-blinded supplementation with either BC or placebo (Plac). Core temperature, skin temperature, heart rate, and rating of perceived exertion were recorded every 5 min during exercise. Blood was taken pre, post, 1 h, and 4 h post exercise. Intestinal cell damage was assessed via intestinal fatty acid binding protein (I-FABP). RESULTS: I-FABP concentrations were similar between conditions at all time points [pre 989.39 ± 490.88 pg ml-1 (BC) 851.35 ± 450.71 pg ml-1 (Plac) post 1505.10 ± 788.63 pg ml-1 (BC) 1267.12 ± 521.51 pg ml-1 (Plac) 1-h, 1087.77 ± 397.06 pg ml-1 (BC) 997.25 ± 524.74 pg ml-1 (Plac) 4-h, 511.35 ± 243.10 pg ml-1 (BC) 501.46 ± 222.54 pg ml-1 (Plac)]. I-FABP was elevated pre to post exercise for both BC (162 ± 50%) and Plac (162 ± 56%) (p < 0.05). BC had no effect on mean body temperature [beginning 36.11 ± 0.30 °C, ending: 39.52 ± 0.28 °C (BC); beginning:35.96 ± 0.43 °C, ending:39.42 ± 0.38 °C (Plac)]. CONCLUSIONS: While BC supplementation may protect against enterocyte damage during exercise in thermonuetral environments, our data suggest that BC supplementation may not be an effective technique for preventing enterocyte damage during exercise when core temperature exceeds 39 °C.