Circulating MiR-21 expression is upregulated after 30 days of head-down tilt bed rest.

Relative expression of miR-21-5p in serum was upregulated in response to 30 days of bed rest, and miRNA fold changes were positively associated with serum calcium changes. INTRODUCTION: Circulating miRNAs (c-miRNAs) have potential as biomarkers of cellular activity, and they may play a role in cell-to-cell communication. The purpose of this study was to examine c-miRNA and bone marker responses to a 30-day six-degree head-down bed rest protocol at an ambient 0.5% CO2. METHODS: Eleven participants (6 males/5 females, 25-50 years) had fasting blood draws taken 3 days before and immediately after completing the 30-day bed rest protocol at the Institute for Aerospace Medicine in Germany. Serum relative expression of miRNAs associated with bone function (miR-21-5p, -100-5p, -125b-5p, -126-3p) were analyzed using qPCR, and serum bone markers were quantitated using ELISA. RESULTS: Serum bone markers, sclerostin, and calcium significantly increased (p ≤ 0.036), and total hip aBMD significantly decreased (p = 0.003) post bed rest. Serum miR-21-5p relative expression was significantly upregulated (p = 0.018) post bed rest. Fold changes in miR-126-3p (r = 0.82, p = 0.002) and miR-21-5p (r = 0.62, p = 0.042) were positively correlated with absolute change in serum calcium. There were no sex differences in miRNA responses; women had greater percent increases in TRAP5b (37.3% vs. 16.9% p = 0.021) and greater percent decreases in total hip aBMD (- 2.15% vs. - 0.69%, p = 0.034) than men. CONCLUSION: c-miR-21-5p has potential as a biomarker of bone resorption and bone loss in an unloading condition. The upregulation of miR-21-5p may reflect an increase in osteoclast activity after bed rest, which is corroborated by the increase in TRAP5b.

Lower cutaneous microvascular reactivity in adult cancer patients receiving chemotherapy.

Cancer patients with a history of anticancer chemotherapy are at an increased cardiovascular disease risk compared with cancer-free populations. Therefore, we tested the hypothesis that cancer patients receiving adjuvant chemotherapy would have a lower cutaneous microvascular reactivity and lower endothelium-dependent flow-mediated dilation (FMD) of the brachial artery compared with matched cancer-free control subjects. To test this hypothesis, we performed a case control study with seven cancer patients receiving adjuvant chemotherapy and seven matched healthy reference control subjects. Red blood cell flux was measured as an index of cutaneous blood flow via laser Doppler flowmetry. Acetylcholine (ACh)-mediated vasodilation was determined by iontophoresis. Data were expressed as percent increase in cutaneous vascular conductance. Endothelium-dependent FMD of the brachial artery via ultrasonography was determined as an index of macrovessel endothelial function. Cutaneous microvascular reactivity was attenuated in cancer patients compared with control subjects [cancer: 959.9 ± 187.3%, control: 1,556.8 ± 222.2%; P = 0.03, effect size (ES) = 1.1]. Additionally, cancer patients demonstrated a significantly lower area under the curve response to ACh iontophoresis compared with healthy control subjects. Brachial artery FMD was also significantly lower in cancer patients compared with control subjects (cancer: 2.2 ± 0.6%, control: 6.6 ± 1.4%; P = 0.006, ES = 1.6), which was significantly associated with measurements of microvascular reactivity. These findings suggest that decreases in vascular reactivity can occur during cancer chemotherapy, which may have implications for the long-term risk of cardiovascular disease morbidity and mortality. NEW & NOTEWORTHY Cancer survivors treated with chemotherapy experience an increased risk of cardiovascular events, linked to both cardiac and vascular toxicity. The major finding of this study is that microvascular reactivity and macrovascular endothelium-dependent flow-mediated dilation are lower in cancer patients currently receiving adjuvant chemotherapy compared with healthy counterparts.

Impact of shear rate pattern on post-occlusive near-infrared spectroscopy microvascular reactivity.

The primary aim of the present study was to determine the impact of acute changes in shear rate patterns, in particular retrograde shear rate, on microvascular function in 15 healthy, young men and women as determined via the post-occlusive near-infrared spectroscopy (NIRS) microvascular reactivity response. Microvascular reactivity, via NIRS-derived measurements of post-occlusion tissue saturation index (TSI%) and total microvascular hemoglobin+myoglobin concentration ([Hb]total), were assessed in each participant before and immediately after exposure to a 30min retrograde shear treatment. Retrograde shear was achieved via a blood pressure cuff placed below the knee inflated to 75mmHg. One leg was exposed to the retrograde shear (Treatment leg) and the contralateral leg served as a non-treatment control. In the Treatment leg, significant increases in retrograde shear rate occurred during the retrograde intervention. Following the intervention, the area under the TSI% post-occlusion response curve, which represents the total microvascular reactivity response, and the absolute peak TSI% response were significantly increased compared to pre-intervention in the Treatment leg, but not the Control leg. The absolute peak [Hb]total response was significantly increased post-intervention in both legs. These results are in contrast to our hypothesis that 75mmHg cuff inflation, designed to increase retrograde shear rate in the femoral artery would negatively affect post-occlusive microvascular reactivity. These data suggest that the current method of increasing retrograde shear rate in the intact human does not adversely impact NIRS derived measurements of microvascular reactivity.

Decreases in maximal oxygen uptake following long-duration spaceflight: Role of convective and diffusive O2 transport mechanisms.

We have previously predicted that the decrease in maximal oxygen uptake (V̇o2max) that accompanies time in microgravity reflects decrements in both convective and diffusive O2 transport to the mitochondria of the contracting myocytes. The aim of this investigation was therefore to quantify the relative changes in convective O2 transport (Q̇o2) and O2 diffusing capacity (Do2) following long-duration spaceflight. In nine astronauts, resting hemoglobin concentration ([Hb]), V̇o2max, maximal cardiac output (Q̇Tmax), and differences in arterial and venous O2 contents ([Formula: see text]-[Formula: see text]) were obtained retrospectively for International Space Station Increments 19-33 (April 2009-November 2012). Q̇o2 and Do2 were calculated from these variables via integration of Fick's Principle of Mass Conservation and Fick's Law of Diffusion. V̇o2max significantly decreased from pre- to postflight (-53.9 ± 45.5%, P = 0.008). The significant decrease in Q̇Tmax (-7.8 ± 9.1%, P = 0.05), despite an unchanged [Hb], resulted in a significantly decreased Q̇o2 (-11.4 ± 10.5%, P = 0.02). Do2 significantly decreased from pre- to postflight by -27.5 ± 24.5% (P = 0.04), as did the peak [Formula: see text]-[Formula: see text] (-9.2 ± 7.5%, P = 0.007). With the use of linear regression analysis, changes in V̇o2max were significantly correlated with changes in Do2 (R2 = 0.47; P = 0.04). These data suggest that spaceflight decreases both convective and diffusive O2 transport. These results have practical implications for future long-duration space missions and highlight the need to resolve the specific mechanisms underlying these spaceflight-induced changes along the O2 transport pathway.NEW & NOTEWORTHY Long-duration spaceflight elicited a significant decrease in maximal oxygen uptake. Given the adverse physiological adaptations to microgravity along the O2 transport pathway that have been reported, an integrative approach to the determinants of postflight maximal oxygen uptake is needed. We demonstrate that both convective and diffusive oxygen transport are decreased following ~6 mo International Space Station missions.

Discrepancy between femoral and capillary blood flow kinetics during knee extension exercise.

Capillary blood flow (QCAP) kinetics have previously been shown to be significantly slower than femoral artery (QFA) kinetics following the onset of dynamic knee extension exercise. If the increase in QCAP does not follow a similar time course to QFA, then a substantial proportion of the available blood flow is not distributed to the working muscle. One possible explanation for this discrepancy is that blood flow also increases to the nonworking lower leg muscles. Therefore, the present study aimed to determine if a reduction in lower limb blood flow, via arterial occlusion below the knee, alters the kinetics of QFA and QCAP during knee extension exercise, and thus provide insight into the potential mechanisms controlling the rapid increase in QFA. Subjects performed a ramp max test to determine the work rate at which gas exchange threshold (GET) occurred. At least four constant work rate trials with and without below-knee occlusion were conducted at work rates eliciting ∼ 80% GET. Pulmonary gas exchange, near-infrared spectroscopy and QFA measurements were taken continuously during each exercise bout. Muscle oxygen uptake (VO2m) and deoxy[hemoglobin+myoglobin] were used to estimate QCAP. There was no significant difference between the uncuffed and cuffed conditions in any response (P>0.05). The mean response times (MRT) of QFA were 18.7 ± 14.2s (uncuffed) and 24.6 ± 14.9s (cuffed). QCAP MRTs were 51.8 ± 23.4s (uncuffed) and 56.7 ± 23.2s (cuffed), which were not significantly different from the time constants (τ) of VO2m (39.7 ± 23.2s (uncuffed) and 46.3 ± 24.1s (cuffed). However, the MRT of QFA was significantly faster (P<0.05) than the MRT of QCAP and τVO2m. τVO2m and MRT QCAP were significantly correlated and estimated QCAP kinetics tracked VO2m following exercise onset. Cuffing below the knee did not significantly change the kinetics of QFA, QCAP or VO2m, although an effect size of 1.02 suggested that a significant effect on QFA may have been hidden by small subject number.

Influence of blood flow occlusion on muscle oxygenation characteristics and the parameters of the power-duration relationship.

It was previously (Monod H, Scherrer J. Ergonomics 8: 329-338, 1965) postulated that blood flow occlusion during exercise would reduce critical power (CP) to 0 Watts (W), while not altering the curvature constant (W'). We empirically assessed the influence of blood flow occlusion on CP, W', and muscle oxygenation characteristics. Ten healthy men (age: 24.8 ± 2.6 yr; height: 180 ± 5 cm; weight: 84.6 ± 10.1 kg) completed four constant-power handgrip exercise tests during both control blood flow (control) and blood flow occlusion (occlusion) for the determination of the power-duration relationship. Occlusion CP (-0.7 ± 0.4 W) was significantly (P < 0.001) lower than control CP (4.1 ± 0.7 W) and significantly (P < 0.001) lower than 0 W. Occlusion W' (808 ± 155 J) was significantly (P < 0.001) different from control W' (558 ± 129 J), and all 10 subjects demonstrated an increased occlusion W' with a mean increase of ∼49%. The present findings support the aerobic nature of CP. The findings also demonstrate that the amount of work that can be performed above CP is constant for a given condition, but can vary across conditions. Moreover, this amount of work that can be performed above CP does not appear to be the determinant of W', but rather a consequence of the depletion of intramuscular energy stores and/or the accumulation of fatigue-inducing metabolites, which limit exercise tolerance and determine W'.

The relationship between critical speed and the respiratory compensation point: Coincidence or equivalence.

It has previously been suggested that the respiratory compensation point (RCP) and critical speed (CS) parameters are equivalent and, therefore, like CS, RCP demarcates the boundary between the heavy- and severe-intensity domains. However, these findings are equivocal and therefore must be interpreted cautiously. Thus, we examined the relationship between CS and RCP across a wide range of subject fitness levels, in an attempt to determine if CS and RCP are equivalent. Forty men and 30 women (age: 23.2 ± 2.5 year, height: 174 ± 10 cm, body mass: 74.1 ± 15.7 kg) completed an incremental and four constant-speed protocols on a treadmill. RCP was determined as the point at which the minute ventilation increased disproportionately to CO2 production and the end-tidal CO2 partial pressure began to decrease. CS was determined from the constant-speed protocols using the linearized 1·time(-1) model. CS and RCP, expressed as speed or metabolic rate, were not significantly different (11.7 ± 2.3 km·h(-1) vs. 11.5 ± 2.3 km·h(-1), p = 0.208; 2.88 ± 0.80 l·min(-1) vs. 2.83 ± 0.72 l·min(-1), p = 0.293) and were significantly correlated (r(2) = 0.52, p < 0.0001; r(2) = 0.74, p < 0.0001, respectively). However, there was a high degree of variability between the parameters. The findings of the current study indicate that, while on average CS and RCP were not different, the high degree of variability between these parameters does not permit accurate estimation of one from the other variable and suggests that these parameters may not be physiologically equivalent.

Influence of pedal cadence on the respiratory compensation point and its relation to critical power.

It is not known if the respiratory compensation point (RCP) is a distinct work rate (Watts (W)) or metabolic rate V̇(O2) and if the RCP is mechanistically related to critical power (CP). To examine these relationships, 10 collegiate men athletes performed cycling incremental and constant-power tests at 60 and 100 rpm to determine RCP and CP. RCP work rate was significantly (p≤0.05) lower for 100 than 60 rpm (197±24 W vs. 222±24 W), while RCP V̇(O2) was not significantly different (3.00±0.33 l min(-1) vs. 3.12±0.41 l min(-1)). CP at 60 rpm (214±51 W; V̇(O2): 3.01±0.69 l min(-1)) and 100 rpm (196±46 W; V̇(O2): 2.95±0.54 l min(-1)) were not significantly different from RCP. However, RCP and CP were not significantly correlated. These findings demonstrate that RCP represents a distinct metabolic rate, which can be achieved at different power outputs, but that RCP and CP are not equivalent parameters and should not, therefore, be used synonymously.

Relationship between simulated extravehicular activity tasks and measurements of physical performance.

The purpose was to evaluate the relationships between tests of fitness and two activities that simulate components of Lunar- and Martian-based extravehicular activities (EVA). Seventy-one subjects completed two field tests: a physical abilities test and a 10km Walkback test. The relationships between test times and the following parameters were determined: running V˙O2max, gas exchange threshold (GET), speed at V˙O2max (s-V˙O2max), highest sustainable rate of aerobic metabolism [critical speed (CS)], and the finite distance that could be covered above CS (D'): arm cranking V˙O2peak, GET, critical power (CP), and the finite work that can be performed above CP (W'). CS, running V˙O2max, s-V˙O2max, and arm cranking V˙O2peak had the highest correlations with the physical abilities field test (r=0.66-0.82, P<0.001). For the 10km Walkback, CS, s-V˙O2max, and running V˙O2max were significant predictors (r=0.64-0.85, P<0.001). CS and to a lesser extent V˙O2max are most strongly associated with tasks that simulate aspects of EVA performance, highlighting CS as a method for evaluating astronaut physical capacity.

Influence of duty cycle on the power-duration relationship: observations and potential mechanisms.

The highest sustainable rate of aerobic metabolism [critical power (CP)] and the finite amount of work that can be performed above CP (W' [curvature constant]) were determined under two muscle contraction duty cycles. Eight men completed at least three constant-power handgrip tests to exhaustion to determine CP and W' for 50% and 20% duty cycles, while brachial artery blood flow (Q̇BA) and deoxygenated-[hemoglobin + myoglobin] (deoxy-[Hb+Mb]) were measured. CP was lower for the 50% duty cycle (3.9 ± 0.9 W) than the 20% duty cycle (5.1 ± 0.8 W; p < 0.001), while W' was not significantly different (50% duty cycle: 452 ± 141 J vs. 20% duty cycle: 432 ± 130 J; p > 0.05). At the same power output, Q̇BA and deoxy-[Hb + Mb] achieved higher end-exercise values for the 20% duty cycle (9.87 ± 1.73 ml·s(-1); 51.7 ± 4.7 µM) than the 50% duty cycle (7.37 ± 1.76 ml·s(-1), p < 0.001; 44.3 ± 2.4 µM, p < 0.03). These findings indicate that blood flow influences CP, but not W'.

Effects of body posture and exercise training on cardiorespiratory responses to exercise.

The primary aims of the present study were to evaluate cardiorespiratory responses to incremental head down tilt exercise and to determine if the cardiorespiratory adaptations obtained from endurance training in the head down tilt posture transfer to the upright posture. 22 men (25±3 years) performed V˙O2peak cycle exercise tests in the upright and head down tilt postures. Of these, 11 men were endurance trained on a cycle ergometer in the upright posture for 8 weeks (upright training group; UTG) or in the upright posture for 4 weeks followed by 4 weeks in the head down tilt posture (head down training group; HTG). During acute exercise, V˙O2peak was decreased in the head down tilt posture compared to upright (2.01±0.51 vs. 2.32±0.61l/min respectively, P<0.05). Stroke volume (SV) at 100 W was greater during head down tilt cycling compared to the upright (77±5 vs. 71±4 ml/beat, P<0.05). Following training V˙O2peak increased in both groups during upright exercise. However, V˙O2peak during head down tilt cycling was only increased in the HTG. Sub-maximal and peak SV in the HTG increased in both upright and head down tilt postures. SV in the UTG increased only in the upright posture and was unchanged during head down tilt cycling. In conclusion, acute head down tilt exercise increases sub-maximal SV compared to upright exercise. Furthermore, training in the head down tilt posture induces cardiorespiratory adaptations in both upright and head down tilt postures, while the adaptations to upright exercise training are primarily observed when upright exercise was performed.

A single test for the determination of parameters of the speed-time relationship for running.

A validated expeditious method is needed to determine critical speed (CS) and the finite distance that can be covered above CS (D'). We tested the hypothesis that a single all-out 3-min running test would accurately determine CS and D'. Seven healthy subjects completed three constant-speed runs on a treadmill for the determination of CS and D', as well as an all-out 3-min test on a track for the determination of end-test speed (ES) and the distance above end-test speed (DES). ES (13.4 ± 2.8 km h(-1)) was not significantly different from the speed-1/time model CS (13.3 ± 2.8 km h(-1)). While DES (141 ± 34 m) was not significantly different from D' (204 ± 103 m), it underestimated D' in 5 of 7 subjects. Thus, the speed-1/time model CS can be accurately determined using a single 3-min test, while caution should be used in relating DES to D'.

Anterograde and retrograde blood velocity profiles in the intact human cardiovascular system.

Current assessments of the effects of shear patterns on vascular function assume that a parabolic velocity profile is always present. Any substantial deviation in the profile away from this may result in misinterpretation of the importance that shear patterns have on vascular function. The present investigation tested the hypothesis that anterograde and retrograde blood flow would have a parabolic velocity profile at rest, during cold pressor test and exercise. Eight healthy subjects completed a cold pressor test and a graded knee-extension exercise test. Doppler ultrasound was used to determine time-averaged mean velocity (V(mean)) and time-averaged peak velocity (V(peak)) for both anterograde and retrograde flow in the femoral artery (FA) and brachial artery (BA). The V(mean)/V(peak) ratio was used to interpret the shape of the blood velocity profile (parabolic, V(mean)/V(peak) = 0.5; plug-like, V(mean)/V(peak) = 1.0). At rest, BA and FA V(mean)/V(peak) ratios of anterograde and retrograde flow were not significantly different from 0.5. During cold pressor test, anterograde V(mean)/V(peak) in the BA (0.56 ± 0.02) and FA (0.58 ± 0.03) were significantly greater than 0.5. During peak exercise, the V(mean)/V(peak) ratio of anterograde flow in the FA (0.53 ± 0.04) was not significantly different from 0.5. In all conditions, the retrograde V(mean)/V(peak) ratio was lower than anterograde. These data demonstrate that blood flow through two different conduit arteries during two different physiological stressors maintains a velocity profile that resembles a slightly blunted parabolic velocity profile.