O2 uptake and blood pressure regulation at the onset of exercise: interaction of circadian rhythm and priming exercise

Circadian rhythm has an influence on several physiological functions that contribute to athletic performance. We tested the hypothesis that circadian rhythm would affect blood pressure (BP) responses but not O(2) uptake (Vo(2)) kinetics during the transitions to moderate and heavy cycling exercises. Nine male athletes (peak Vo(2): 60.5 ± 3.2 ml·kg(-1)·min(-1)) performed multiple rides of two different cycling protocols involving sequences of 6-min bouts at moderate or heavy intensities interspersed by a 20-W baseline in the morning (7 AM) and evening (5 PM). Breath-by-breath Vo(2) and beat-by-beat BP estimated by finger cuff plethysmography were measured simultaneously throughout the protocols. Circadian rhythm did not affect Vo(2) onset kinetics determined from the phase II time constant (τ(2)) during either moderate or heavy exercise bouts with no prior priming exercise (τ(2) moderate exercise: morning 22.5 ± 4.6 s vs. evening 22.2 ± 4.6 s and τ(2) heavy exercise: morning 26.0 ± 2.7 s vs. evening 26.2 ± 2.6 s, P > 0.05). Priming exercise induced the same robust acceleration in Vo(2) kinetics during subsequent moderate and heavy exercise in the morning and evening. A novel finding was an overshoot in BP (estimated from finger cuff plethysmography) in the first minutes of each moderate and heavy exercise bout. After the initial overshoot, BP declined in association with increased skin blood flow between the third and sixth minute of the exercise bout. Priming exercise showed a greater effect in modulating the BP responses in the evening. These findings suggest that circadian rhythm interacts with priming exercise to lower BP during exercise after an initial overshoot with a greater influence in the evening associated with increased skin blood flow.     

The intramuscular contribution to the slow oxygen uptake kinetics during exercise in chronic heart failure is related to the severity of the condition

The mechanism for slow pulmonary O(2) uptake (Vo(2)) kinetics in patients with chronic heart failure (CHF) is unclear but may be due to limitations in the intramuscular control of O(2) utilization or O(2) delivery. Recent evidence of a transient overshoot in microvascular deoxygenation supports the latter. Prior (or warm-up) exercise can increase O(2) delivery in healthy individuals. We therefore aimed to determine whether prior exercise could increase muscle oxygenation and speed Vo(2) kinetics during exercise in CHF. Fifteen men with CHF (New York Heart Association I-III) due to left ventricular systolic dysfunction performed two 6-min moderate-intensity exercise transitions (bouts 1 and 2, separated by 6 min of rest) from rest to 90% of lactate threshold on a cycle ergometer. Vo(2) was measured using a turbine and a mass spectrometer, and muscle tissue oxygenation index (TOI) was determined by near-infrared spectroscopy. Prior exercise increased resting TOI by 5.3 ± 2.4% (P = 0.001), attenuated the deoxygenation overshoot (-3.9 ± 3.6 vs. -2.0 ± 1.4%, P = 0.011), and speeded the Vo(2) time constant (τVo(2); 49 ± 19 vs. 41 ± 16 s, P = 0.003). Resting TOI was correlated to τVo(2) before (R(2) = 0.51, P = 0.014) and after (R(2) = 0.36, P = 0.051) warm-up exercise. However, the mean response time of TOI was speeded between bouts in half of the patients (26 ± 8 vs. 20 ± 8 s) and slowed in the remainder (32 ± 11 vs. 44 ± 16 s), the latter group having worse New York Heart Association scores (P = 0.042) and slower Vo(2) kinetics (P = 0.001). These data indicate that prior moderate-intensity exercise improves muscle oxygenation and speeds Vo(2) kinetics in CHF. The most severely limited patients, however, appear to have an intramuscular pathology that limits Vo(2) kinetics during moderate exercise.     

Older type 2 diabetic males do not exhibit abnormal pulmonary oxygen uptake and muscle oxygen utilization dynamics during submaximal cycling exercise

There are reports of abnormal pulmonary oxygen uptake (Vo(2)) and deoxygenated hemoglobin ([HHb]) kinetics in individuals with Type 2 diabetes (T2D) below 50 yr of age with disease durations of <5 yr. We examined the Vo(2) and muscle [HHb] kinetics in 12 older T2D patients with extended disease durations (age: 65 ± 5 years; disease duration 9.3 ± 3.8 years) and 12 healthy age-matched control participants (CON; age: 62 ± 6 years). Maximal oxygen uptake (Vo(2max)) was determined via a ramp incremental cycle test and Vo(2) and [HHb] kinetics were determined during subsequent submaximal step exercise. The Vo(2max) was significantly reduced (P < 0.05) in individuals with T2D compared with CON (1.98 ± 0.43 vs. 2.72 ± 0.40 l/min, respectively) but, surprisingly, Vo(2) kinetics was not different in T2D compared with CON (phase II time constant: 43 ± 17 vs. 41 ± 12 s, respectively). The Δ[HHb]/ΔVo(2) was significantly higher in T2D compared with CON (235 ± 99 vs. 135 ± 33 AU·l(-1)·min(-1); P < 0.05). Despite a lower Vo(2max), Vo(2) kinetics is not different in older T2D compared with healthy age-matched control participants. The elevated Δ[HHb]/ΔVo(2) in T2D individuals possibly indicates a compromised muscle blood flow that mandates a greater O(2) extraction during exercise. Longer disease duration may result in adaptations in the O(2) extraction capabilities of individuals with T2D, thereby mitigating the expected age-related slowing of Vo(2) kinetics.     

Baroreceptor unloading in postural tachycardia syndrome augments peripheral chemoreceptor sensitivity and decreases central chemoreceptor sensitivity

While orthostatic tachycardia is the hallmark of postural tachycardia syndrome (POTS), orthostasis also initiates increased minute ventilation (Ve) and decreased end-tidal CO(2) in many patients. We hypothesized that chemoreflex sensitivity would be increased in patients with POTS. We therefore measured chemoreceptor sensitivity in 20 POTS (16 women and 4 men) and 14 healthy controls (10 women and 4 men), 16-35 yr old by exposing them to eucapneic hyperoxia (30% O(2)), eucapneic hypoxia (10% O(2)), and hypercapnic hyperoxia (30% O(2) + 5% CO(2)) while supine and during 70° head-upright tilt. Heart rate, mean arterial pressure, O(2) saturation, end-tidal CO(2), and Ve were measured. Peripheral chemoreflex sensitivity was calculated as the difference in Ve during hypoxia compared with room air divided by the change in O(2) saturation. Central chemoreflex sensitivity was determined by the difference in Ve during hypercapnia divided by the change in CO(2). POTS subjects had an increased peripheral chemoreflex sensitivity (in l·min(-1)·%oxygen(-1)) in response to hypoxia (0.42 ± 0.38 vs. 0.19 ± 0.17) but a decreased central chemoreflex sensitivity (l·min(-1)·Torr(-1)) CO(2) response (0.49 ± 0.38 vs. 1.04 ± 0.18) compared with controls. CO(2) sensitivity was also reduced in POTS subjects when supine. POTS patients are markedly sensitized to hypoxia when upright but desensitized to CO(2) while upright or supine. The interactions between orthostatic baroreflex unloading and altered chemoreflex sensitivities may explain the hyperventilation in POTS patients.     

Pulmonary O2 uptake kinetics as a determinant of high-intensity exercise tolerance in humans

Tolerance to high-intensity constant-power (P) exercise is well described by a hyperbola with two parameters: a curvature constant (W') and power asymptote termed "critical power" (CP). Since the ability to sustain exercise is closely related to the ability to meet the ATP demand in a steady state, we reasoned that pulmonary O(2) uptake (Vo(2)) kinetics would relate to the P-tolerable duration (t(lim)) parameters. We hypothesized that 1) the fundamental time constant (τVo(2)) would relate inversely to CP; and 2) the slow-component magnitude (ΔVo(2sc)) would relate directly to W'. Fourteen healthy men performed cycle ergometry protocols to the limit of tolerance: 1) an incremental ramp test; 2) a series of constant-P tests to determine Vo(2max), CP, and W'; and 3) repeated constant-P tests (WR(6)) normalized to a 6 min t(lim) for τVo(2) and ΔVo(2sc) estimation. The WR(6) t(lim) averaged 365 ± 16 s, and Vo(2max) (4.18 ± 0.49 l/min) was achieved in every case. CP (range: 171-294 W) was inversely correlated with τVo(2) (18-38 s; R(2) = 0.90), and W' (12.8-29.9 kJ) was directly correlated with ΔVo(2sc) (0.42-0.96 l/min; R(2) = 0.76). These findings support the notions that 1) rapid Vo(2) adaptation at exercise onset allows a steady state to be achieved at higher work rates compared with when Vo(2) kinetics are slower; and 2) exercise exceeding this limit initiates a "fatigue cascade" linking W' to a progressive increase in the O(2) cost of power production (Vo(2sc)), which, if continued, results in attainment of Vo(2max) and exercise intolerance. Collectively, these data implicate Vo(2) kinetics as a key determinant of high-intensity exercise tolerance in humans.     

Cardiac resynchronization therapy modulation of exercise left ventricular function and pulmonary O₂ uptake in heart failure

To better understand the mechanisms contributing to improved exercise capacity with cardiac resynchronization therapy (CRT), we studied the effects of 6 mo of CRT on pulmonary O(2) uptake (Vo(2)) kinetics, exercise left ventricular (LV) function, and peak Vo(2) in 12 subjects (age: 56 ± 15 yr, peak Vo(2): 12.9 ± 3.2 ml·kg(-1)·min(-1), ejection fraction: 18 ± 3%) with heart failure. We hypothesized that CRT would speed Vo(2) kinetics due to an increase in stroke volume secondary to a reduction in LV end-systolic volume (ESV) and that the increase in peak Vo(2) would be related to an increase in cardiac output reserve. We found that Vo(2) kinetics were faster during the transition to moderate-intensity exercise after CRT (pre-CRT: 69 ± 21 s vs. post-CRT: 54 ± 17 s, P < 0.05). During moderate-intensity exercise, LV ESV reserve (exercise - resting) increased 9 ± 7 ml (vs. a 3 ± 9-ml decrease pre-CRT, P < 0.05), and steady-state stroke volume increased (pre-CRT: 42 ± 8 ml vs. post-CRT: 61 ± 12 ml, P < 0.05). LV end-diastolic volume did not change from rest to steady-state exercise post-CRT (P > 0.05). CRT improved heart rate, measured as a lower resting and steady-state exercise heart rate and as faster heart rate kinetics after CRT (pre-CRT: 89 ± 12 s vs. post-CRT: 69 ± 21 s, P < 0.05). For peak exercise, cardiac output reserve increased significantly post-CRT and was 22% higher at peak exercise post-CRT (both P < 0.05). The increase in cardiac output was due to both a significant increase in peak and reserve stroke volume and to a nonsignificant increase in heart rate reserve. Similar patterns in LV volumes as moderate-intensity exercise were observed at peak exercise. Cardiac output reserve was related to peak Vo(2) (r = 0.48, P < 0.05). These findings demonstrate the chronic CRT-mediated cardiac factors that contribute, in part, to the speeding in Vo(2) kinetics and increase in peak Vo(2) in clinically stable heart failure patients.     

The 10-20-30 training concept improves performance and health profile in moderately trained runners

The effect of an alteration from regular endurance to interval (10-20-30) training on the health profile, muscular adaptations, maximum oxygen uptake (Vo(2max)), and performance of runners was examined. Eighteen moderately trained individuals (6 females and 12 males; Vo(2max): 52.2 ± 1.5 ml·kg(-1)·min(-1)) (means ± SE) were divided into a high-intensity training (10-20-30; 3 women and 7 men) and a control (CON; 3 women and 5 men) group. For a 7-wk intervention period the 10-20-30 replaced all training sessions with 10-20-30 training consisting of low-, moderate-, and high-speed running (<30%, <60%, and >90% of maximal intensity) for 30, 20, and 10 s, respectively, in three or four 5-min intervals interspersed by 2 min of recovery, reducing training volume by 54% (14.0 ± 0.9 vs. 30.4 ± 2.3 km/wk) while CON continued the normal training. After the intervention period Vo(2max) in 10-20-30 was 4% higher, and performance in a 1,500-m and a 5-km run improved (P < 0.05) by 21 and 48 s, respectively. In 10-20-30, systolic blood pressure was reduced (P < 0.05) by 5 ± 2 mmHg, and total and low-density lipoprotein (LDL) cholesterol was lowered (P < 0.05) by 0.5 ± 0.2 and 0.4 ± 0.1 mmol/l, respectively. No alterations were observed in CON. Muscle membrane proteins and enzyme activity did not change in either of the groups. The present study shows that interval training with short 10-s near-maximal bouts can improve performance and Vo(2max) despite a ～50% reduction in training volume. In addition, the 10-20-30 training regime lowers resting systolic blood pressure and blood cholesterol, suggesting a beneficial effect on the health profile of already trained individuals.     

Muscle fiber recruitment and the slow component of O2 uptake: constant work rate vs. all-out sprint exercise

The slow component of pulmonary O(2) uptake (Vo(2)) during constant work rate (CWR) high-intensity exercise has been attributed to the progressive recruitment of (type II) muscle fibers. We tested the following hypotheses: 1) the Vo(2) slow component gain would be greater in a 3-min all-out cycle test than in a work-matched CWR test, and 2) the all-out test would be associated with a progressive decline, and the CWR test with a progressive increase, in muscle activation, as estimated from the electromyogram (EMG) of the vastus lateralis muscle. Eight men (aged 21-39 yr) completed a ramp incremental test, a 3-min all-out test, and a work- and time-matched CWR test to exhaustion. The maximum Vo(2) attained in an initial ramp incremental test (3.97 ± 0.83 l/min) was reached in both experimental tests (3.99 ± 0.84 and 4.03 ± 0.76 l/min for all-out and CWR, respectively). The Vo(2) slow component was greater (P < 0.05) in the all-out test (1.21 ± 0.31 l/min, 4.2 ± 2.2 ml·min(-1)·W(-1)) than in the CWR test (0.59 ± 0.22 l/min, 1.70 ± 0.5 ml·min(-1)·W(-1)). The integrated EMG declined by 26% (P < 0.001) during the all-out test and increased by 60% (P < 0.05) during the CWR test from the first 30 s to the last 30 s of exercise. The considerable reduction in muscle efficiency in the all-out test in the face of a progressively falling integrated EMG indicates that progressive fiber recruitment is not requisite for development of the Vo(2) slow component during voluntary exercise in humans.     

A novel cardiopulmonary exercise test protocol and criterion to determine maximal oxygen uptake in chronic heart failure

Cardiopulmonary exercise testing for peak oxygen uptake (Vo(2peak)) can evaluate prognosis in chronic heart failure (CHF) patients, with the peak respiratory exchange ratio (RER(peak)) commonly used to confirm maximal effort and maximal oxygen uptake (Vo(2max)). We determined the precision of RER(peak) in confirming Vo(2max), and whether a novel ramp-incremental (RI) step-exercise (SE) (RISE) test could better determine Vo(2max) in CHF. Male CHF patients (n = 24; NYHA class I-III) performed a symptom-limited RISE-95 cycle ergometer test in the format: RI (4-18 W/min; ～10 min); 5 min recovery (10 W); SE (95% peak RI work rate). Patients (n = 18) then performed RISE-95 tests using slow (3-8 W/min; ～15 min) and fast (10-30 W/min; ～6 min) ramp rates. Pulmonary gas exchange was measured breath-by-breath. Vo(2peak) was compared within patients by unpaired t-test of the highest 12 breaths during RI and SE phases to confirm Vo(2max) and its 95% confidence limits (CI(95)). RER(peak) was significantly influenced by ramp rate (fast, medium, slow: 1.21 ± 0.1 vs. 1.15 ± 0.1 vs. 1.09 ± 0.1; P = 0.001), unlike Vo(2peak) (mean n = 18; 14.4 ± 2.6 ml·kg(-1)·min(-1); P = 0.476). Group Vo(2peak) was similar between RI and SE (n = 24; 14.5 ± 3.0 vs. 14.7 ± 3.1 ml·kg(-1)·min(-1); P = 0.407); however, within-subject comparisons confirmed Vo(2max) in only 14 of 24 patients (CI(95) for Vo(2max) estimation averaged 1.4 ± 0.8 ml·kg(-1)·min(-1)). The RER(peak) in CHF was significantly influenced by ramp rate, suggesting its use to determine maximal effort and Vo(2max) be abandoned. In contrast, the RISE-95 test had high precision for Vo(2max) confirmation with patient-specific CI(95) (without secondary criteria), and showed that Vo(2max) is commonly underestimated in CHF. The RISE-95 test was well tolerated by CHF patients, supporting its use for Vo(2max) confirmation.     

Effect of contractile duration on intracellular PO2 kinetics in Xenopus single skeletal myocytes.

It has been suggested that skeletal muscle O(2) uptake (Vo(2)) kinetics follow a first-order control model. Consistent with that, Vo(2) should show both 1) similar onset kinetics and 2) an on-off symmetry across submaximal work intensities regardless of the metabolic perturbation. To date, consensus on this issue has not been reached in whole body studies due to numerous confounding factors associated with O(2) availability and fiber-type recruitment. To test whether single myocytes demonstrate similar intracellular Po(2) (Pi(O(2))) on- and off-transient kinetics at varying work intensities, we studied Xenopus laevis single myocyte (n = 8) Pi(O(2)) via phosphorescence quenching during two bouts of electrically induced isometric muscle contractions of 200 (low)- and 400 (high)-ms contraction duration (1 contraction every 4 s, 15 min between trials, order randomized). The fall in Pi(O(2)), which is inversely proportional to the net increase in Vo(2), was significantly greater (P < 0.05) during the high (24.1 +/- 3.2 Torr) vs. low (17.4 +/- 1.6 Torr) contraction bout. However, the mean response time (MRT; time to 63% of the overall change) for the fall in Pi(O(2)) from resting baseline to end contractions was not different (high, 77.8 +/- 11.5 vs. low, 76.1 +/- 13.6 s; P > 0.05) between trials. The initial rate of change at contraction onset, defined as DeltaPi(O(2))/MRT, was significantly greater (P < 0.05) in high compared with low. Pi(O(2)) off-transient MRT from the end of the contraction bout to initial baseline was unchanged (high, 83.3 +/- 18.3 vs. low, 80.4 +/- 21.6 s; P > 0.05) between high and low trials. These data revealed that Pi(O(2)) dynamics in frog isolated skeletal myocytes were invariant despite differing contraction durations and, by inference, metabolic demands. Thus these findings demonstrate that mitochondria can respond more rapidly at the initial onset of contractions when challenged with an augmented metabolic stimulus in accordance with an apparent first-order rate law.     

Influence of phase I duration on phase II VO2 kinetics parameter estimates in older and young adults

Older adults (O) may have a longer phase I pulmonary O(2) uptake kinetics (Vo(2)(p)) than young adults (Y); this may affect parameter estimates of phase II Vo(2)(p). Therefore, we sought to: 1) experimentally estimate the duration of phase I Vo(2)(p) (EE phase I) in O and Y subjects during moderate-intensity exercise transitions; 2) examine the effects of selected phase I durations (i.e., different start times for modeling phase II) on parameter estimates of the phase II Vo(2)(p) response; and 3) thereby determine whether slower phase II kinetics in O subjects represent a physiological difference or a by-product of fitting strategy. Vo(2)(p) was measured breath-by-breath in 19 O (68 ± 6 yr; mean ± SD) and 19 Y (24 ± 5 yr) using a volume turbine and mass spectrometer. Phase I Vo(2)(p) was longer in O (31 ± 4 s) than Y (20 ± 7 s) (P < 0.05). In O, phase II τVo(2)(p) was larger (P < 0.05) when fitting started at 15 s (49 ± 12 s) compared with fits starting at the individual EE phase I (43 ± 12 s), 25 s (42 ± 10 s), 35 s (42 ± 12 s), and 45 s (45 ± 15 s). In Y, τVo(2)(p) was not affected by the time at which phase II Vo(2)(p) fitting started (τVo(2)(p) = 31 ± 7 s, 29 ± 9 s, 30 ± 10 s, 32 ± 11 s, and 30 ± 8 s for fittings starting at 15 s, 25 s, 35 s, 45 s, and EE phase I, respectively). Fitting from EE phase I, 25 s, or 35 s resulted in the smallest CI τVo(2)(p) in both O and Y. Thus, fitting phase II Vo(2)(p) from (but not constrained to) 25 s or 35 s provides consistent estimates of Vo(2)(p) kinetics parameters in Y and O, despite the longer phase I Vo(2)(p) in O.     

Impaired pulmonary oxygen uptake kinetics and reduced peak aerobic power during small muscle mass exercise in heart transplant recipients.

We examined peak and reserve cardiovascular function and skeletal muscle oxygenation during unilateral knee extension (ULKE) exercise in five heart transplant recipients (HTR, mean +/- SE; age: 53 +/- 3 years; years posttransplant: 6 +/- 4) and five age- and body mass-matched healthy controls (CON). Pulmonary oxygen uptake (Vo(2)(p)), heart rate (HR), stroke volume (SV), cardiac output (Q), and skeletal muscle deoxygenation (HHb) kinetics were assessed during moderate-intensity ULKE exercise. Peak exercise and reserve Vo(2)(p), Q, and systemic arterial-venous oxygen difference (a-vO(2diff)) were 23-52% lower (P < 0.05) in HTR. The reduced Q and a-vO(2diff) reserves were associated with lower HR and HHb reserves, respectively. The phase II Vo(2)(p) time delay was greater (HTR: 38 +/- 2 vs. CON: 25 +/- 1 s, P < 0.05), while time constants for phase II Vo(2)(p) (HTR: 54 +/- 8 vs. CON: 31 +/- 3 s), Q (HTR: 66 +/- 8 vs. CON: 28 +/- 4 s), and HHb (HTR: 27 +/- 5 vs. CON: 13 +/- 3 s) were significantly slower in HTR. The HR half-time was slower in HTR (113 +/- 21 s) vs. CON (21 +/- 2 s, P < 0.05); however, no significant difference was found between groups for SV kinetics (HTR: 39 +/- 8 s vs. CON 31 +/- 6 s). The lower peak Vo(2)(p) and prolonged Vo(2)(p) kinetics in HTR were secondary to impairments in both cardiovascular and skeletal muscle function that result in reduced oxygen delivery and utilization by the active muscles.     

Exercise training and muscle microvascular oxygenation: functional role of nitric oxide

Exercise training induces multiple adaptations within skeletal muscle that may improve local O(2) delivery-utilization matching (i.e., Po(2)mv). We tested the hypothesis that increased nitric oxide (NO) function is intrinsic to improved muscle Po(2)mv kinetics from rest to contractions after exercise training. Healthy young Sprague-Dawley rats were assigned to sedentary (n = 18) or progressive treadmill exercise training (n = 10; 5 days/wk, 6-8 wk, final workload of 60 min/day at 35 m/min, -14% grade) groups. Po(2)mv was measured via phosphorescence quenching in the spinotrapezius muscle at rest and during 1-Hz twitch contractions under control (Krebs-Henseleit solution), sodium nitroprusside (SNP, NO donor; 300 μM), and N(G)-nitro-l-arginine methyl ester (l-NAME, nonspecific NO synthase blockade; 1.5 mM) superfusion conditions. Exercise-trained rats had greater peak oxygen uptake (Vo(2peak)) than their sedentary counterparts (81 ± 1 vs. 72 ± 2 ml·kg(-1)·min(-1), respectively; P < 0.05). Exercise-trained rats had significantly slower Po(2)mv fall throughout contractions (τ(1); time constant for the first component) during control (sedentary: 8.1 ± 0.6; trained: 15.2 ± 2.8 s). Compared with control, SNP slowed τ(1) to a greater extent in sedentary rats (sedentary: 38.7 ± 5.6; trained: 26.8 ± 4.1 s; P > 0.05) whereas l-NAME abolished the differences in τ(1) between sedentary and trained rats (sedentary: 12.0 ± 1.7; trained: 11.2 ± 1.4 s; P < 0.05). Our results indicate that endurance exercise training leads to greater muscle microvascular oxygenation across the metabolic transient following the onset of contractions (i.e., slower Po(2)mv kinetics) partly via increased NO-mediated function, which likely constitutes an important mechanism for training-induced metabolic adaptations.     

VO(2) on-kinetics in isolated canine muscle in situ during slowed convective O(2) delivery

The purpose of this study was to examine O(2) uptake (Vo(2)) on-kinetics when the spontaneous blood flow (and therefore O(2) delivery) on-response was slowed by 25 and 50 s. The isolated gastrocnemius muscle complex (GS) in situ was studied in six anesthetized dogs during transitions from rest to a submaximal metabolic rate (≈50-70% of peak Vo(2)). Four trials were performed: 1) a pretrial in which resting and steady-state blood flows were established, 2) a control trial in which the blood flow on-kinetics mean response time (MRT) was set at 20 s (CT20), 3) an experimental trial in which the blood flow on-kinetics MRT was set at 45 s (EX45), and 4) an experimental trial in which the blood flow on-kinetics MRT was set at 70 s (EX70). Slowing O(2) delivery via slowing blood flow on-kinetics resulted in a linear slowing of the Vo(2) on-kinetics response (R = 0.96). Average MRT values for CT20, EX45, and EX70 Vo(2) on-kinetics were (means ± SD) 17 ± 2, 23 ± 4, and 26 ± 3 s, respectively (P < 0.05 among all). During these transitions, slowing blood flow resulted in greater muscle deoxygenation (as indicated by near-infrared spectroscopy), suggesting that lower intracellular Po(2) values were reached. In this oxidative muscle, Vo(2) and O(2) delivery were closely matched during the transition period from rest to steady-state contractions. In conjunction with our previous work showing that speeding O(2) delivery did not alter Vo(2) on-kinetics under similar conditions, it appears that spontaneously perfused skeletal muscle operates at the nexus of sufficient and insufficient O(2) delivery in the transition from rest to contractions.     

Muscle capillary blood flow kinetics estimated from pulmonary O2 uptake and near-infrared spectroscopy.

The near-infrared spectroscopy (NIRS) signal (deoxyhemoglobin concentration; [HHb]) reflects the dynamic balance between muscle capillary blood flow (Q(cap)) and muscle O(2) uptake (Vo(2)(m)) in the microcirculation. The purposes of the present study were to estimate the time course of Q(cap) from the kinetics of the primary component of pulmonary O(2) uptake (Vo(2)(p)) and [HHb] throughout exercise, and compare the Q(cap) kinetics with the Vo(2)(p) kinetics. Nine subjects performed moderate- (M; below lactate threshold) and heavy-intensity (H, above lactate threshold) constant-work-rate tests. Vo(2)(p) (l/min) was measured breath by breath, and [HHb] (muM) was measured by NIRS during the tests. The time course of Q(cap) was estimated from the rearrangement of the Fick equation [Q(cap) = Vo(2)(m)/(a-v)O(2), where (a-v)O(2) is arteriovenous O(2) difference] using Vo(2)(p) (primary component) and [HHb] as proxies of Vo(2)(m) and (a-v)O(2), respectively. The kinetics of [HHb] [time constant (tau) + time delay [HHb]; M = 17.8 +/- 2.3 s and H = 13.7 +/- 1.4 s] were significantly (P < 0.001) faster than the kinetics of Vo(2) [tau of primary component (tau(P)); M = 25.5 +/- 8.8 s and H = 25.6 +/- 7.2 s] and Q(cap) [mean response time (MRT); M = 25.4 +/- 9.1 s and H = 25.7 +/- 7.7 s]. However, there was no significant difference between MRT of Q(cap) and tau(P)-Vo(2) for both intensities (P = 0.99), and these parameters were significantly correlated (M and H; r = 0.99; P < 0.001). In conclusion, we have proposed a new method to noninvasively approximate Q(cap) kinetics in humans during exercise. The resulting overall Q(cap) kinetics appeared to be tightly coupled to the temporal profile of Vo(2)(m).     

Glucokinase activation repairs defective bioenergetics of islets of Langerhans isolated from type 2 diabetics

It was reported previously that isolated human islets from individuals with type 2 diabetes mellitus (T2DM) show reduced glucose-stimulated insulin release. To assess the possibility that impaired bioenergetics may contribute to this defect, glucose-stimulated respiration (Vo(2)), glucose usage and oxidation, intracellular Ca(2+), and insulin secretion (IS) were measured in pancreatic islets isolated from three healthy and three type 2 diabetic organ donors. Isolated mouse and rat islets were studied for comparison. Islets were exposed to a "staircase" glucose stimulus, whereas IR and Vo(2) were measured. Vo(2) of human islets from normals and diabetics increased sigmoidally from equal baselines of 0.25 nmol/100 islets/min as a function of glucose concentration. Maximal Vo(2) of normal islets at 24 mM glucose was 0.40 ± 0.02 nmol·min(-1)·100 islets(-1), and the glucose S(0.5) was 4.39 ± 0.10 mM. The glucose stimulation of respiration of islets from diabetics was lower, V(max) of 0.32 ± 0.01 nmol·min(-1)·100 islets(-1), and the S(0.5) shifted to 5.43 ± 0.13 mM. Glucose-stimulated IS and the rise of intracellular Ca(2+) were also reduced in diabetic islets. A clinically effective glucokinase activator normalized the defective Vo(2), IR, and free calcium responses during glucose stimulation in islets from type 2 diabetics. The body of data shows that there is a clear relationship between the pancreatic islet energy (ATP) production rate and IS. This relationship was similar for normal human, mouse, and rat islets and the data for all species fitted a single sigmoidal curve. The shared threshold rate for IS was ～13 pmol·min(-1)·islet(-1). Exendin-4, a GLP-1 analog, shifted the ATP production-IS curve to the left and greatly potentiated IS with an ATP production rate threshold of ～10 pmol·min(-1)·islet(-1). Our data suggest that impaired β-cell bioenergetics resulting in greatly reduced ATP production is critical in the molecular pathogenesis of type 2 diabetes mellitus.     

Aerobic exercise reduces neuronal responses in food reward brain regions

Acute exercise suppresses ad libitum energy intake, but little is known about the effects of exercise on food reward brain regions. After an overnight fast, 30 (17 men, 13 women), healthy, habitually active (age = 22.2 ± 0.7 yr, body mass index = 23.6 ± 0.4 kg/m(2), Vo(2peak) = 44.2 ± 1.5 ml·kg(-1)·min(-1)) individuals completed 60 min of exercise on a cycle ergometer or 60 min of rest (no-exercise) in a counterbalanced, crossover fashion. After each condition, blood oxygen level-dependent responses to high-energy food, low-energy food, and control visual cues, were measured by functional magnetic resonance imaging. Exercise, compared with no-exercise, significantly (P < 0.005) reduced the neuronal response to food (high and low food) cues vs. control cues in the insula (-0.37 ± 0.13 vs. +0.07 ± 0.18%), putamen (-0.39 ± 0.10 vs. -0.10 ± 0.09%), and rolandic operculum (-0.37 ± 0.17 vs. 0.17 ± 0.12%). Exercise alone significantly (P < 0.005) reduced the neuronal response to high food vs. control and low food vs. control cues in the inferior orbitofrontal cortex (-0.94 ± 0.33%), insula (-0.37 ± 0.13%), and putamen (-0.41 ± 0.10%). No-exercise alone significantly (P < 0.005) reduced the neuronal response to high vs. control and low vs. control cues in the middle (-0.47 ± 0.15%) and inferior occipital gyrus (-1.00 ± 0.23%). Exercise reduced neuronal responses in brain regions consistent with reduced pleasure of food, reduced incentive motivation to eat, and reduced anticipation and consumption of food. Reduced neuronal response in these food reward brain regions after exercise is in line with the paradigm that acute exercise suppresses subsequent energy intake.     

Sex differences in thermoeffector responses during exercise at fixed requirements for heat loss

To assess potential mechanisms responsible for the lower sudomotor thermosensitivity in women during exercise, we examined sex differences in sudomotor function and skin blood flow (SkBF) during exercise performed at progressive increases in the requirement for heat loss. Eight men and eight women cycled at rates of metabolic heat production of 200, 250, and 300 W/m(2) of body surface area, with each rate being performed sequentially for 30 min. The protocol was performed in a direct calorimeter to measure evaporative heat loss (EHL) and in a thermal chamber to measure local sweat rate (LSR) (ventilated capsule), SkBF (laser-Doppler), sweat gland activation (modified iodine-paper technique), and sweat gland output (SGO) on the back, chest, and forearm. Despite a similar requirement for heat loss between the sexes, significantly lower increases in EHL and LSR were observed in women (P ≤ 0.001). Sex differences in EHL and LSR were not consistently observed during the first and second exercise periods, whereas EHL (348 ± 13 vs. 307 ± 9 W/m(2)) and LSR on the back (1.61 ± 0.07 vs. 1.20 ± 0.09 mg·min(-1)·cm(-2)), chest (1.33 ± 0.06 vs. 1.08 ± 0.09 mg·min(-1)·cm(-2)), and forearm (1.53 ± 0.07 vs. 1.20 ± 0.06 mg·min(-1)·cm(-2), men vs. women) became significantly greater in men during the last exercise period (P < 0.05). At each site, differences in LSR were solely due to a greater SGO in men, as opposed to differences in sweat gland activation. In contrast, no sex differences in SkBF were observed throughout the exercise period. The present study demonstrates that sex differences in sudomotor function are only evidenced beyond a certain requirement for heat loss, solely through differences in SGO. In contrast, the lower EHL and LSR in women are not paralleled by a lower SkBF response.     

Sex differences in salt sensitivity to nitric oxide dependent vasodilation in healthy young adults

Dietary sodium and blood pressure regulation differs between normotensive men and women, an effect which may involve endothelial production of nitric oxide (NO). Therefore, we tested the hypothesis that differences in the NO component of endothelium-dependent vasodilation between low and high dietary sodium intake depend on sex. For 5 days prior to study, healthy adults consumed a controlled low-sodium diet (10 mmol/day, n = 30, mean age ± SE: 30 ± 1 yr, 16 men) or high-sodium diet (400 mmol/day, n = 36, age 23 ± 1 yr, 13 men). Forearm blood flow (FBF, plethysmography) responses to brachial artery administration of acetylcholine (ACh, 4 μg·100 ml tissue(-1)·min(-1)) were measured before and after endothelial NO synthase inhibition with N(G)-monomethyl-l-arginine (l-NMMA, 50 mg bolus + 1 mg/min infusion). The NO component of endothelium-dependent dilation was calculated as the response to ACh before and after l-NMMA accounting for changes in baseline FBF: [(FBF ACh - FBF baseline) - (FBF ACh(L-NMMA) - FBF baseline(L-NMMA))]. This value was 5.7 ± 1.3 and 2.5 ± 0.8 ml·100 ml forearm tissue(-1)·min(-1) for the low- and high-sodium diets, respectively (main effect of sodium, P = 0.019). The sodium effect was larger for the men, with values of 7.9 ± 2.0 and 2.2 ± 1.4 for men vs. 3.1 ± 1.3 and 2.7 ± 1.0 ml·100 ml forearm tissue(-1)·min(-1) for the women (P = 0.034, sex-by-sodium interaction). We conclude that the NO component of endothelium-dependent vasodilation is altered by dietary sodium intake based on sex, suggesting that endothelial NO production is sensitive to dietary sodium in healthy young men but not women.     

Oxygen uptake kinetics during two bouts of heavy cycling separated by fatiguing sprint exercise in humans.

We tested the hypothesis that O(2) uptake (Vo(2)) kinetics at the onset of heavy exercise would be altered in a state of muscle fatigue and prior metabolic acidosis. Eight well-trained cyclists completed two identical bouts of 6-min cycling exercise at >85% of peak Vo(2) separated by three successive bouts of 30 s of sprint cycling. Not only was baseline Vo(2) elevated after prior sprint exercises but also the time constant of phase II Vo(2) kinetics was faster (28.9 +/- 2.4 vs. 22.2 +/- 1.7 s; P < 0.05). CO(2) output (Vco(2)) was significantly reduced throughout the second exercise bout. Subsequently Vo(2) was greater at 3 min and increased less after this after prior sprint exercise. Cardiac output, estimated by impedance cardiography, was significantly higher in the first 2 min of the second heavy exercise bout. Normalized integrated surface electromyography of four leg muscles and normalized mean power frequency were not different between exercise bouts. Vo(2) and Vco(2) kinetic responses to heavy exercise were markedly altered by prior multiple sprint exercises.