bluuebunny/crossref_metadata_2025 huggingface dataset:
Invited Review: Mechanisms of ventilator-induced lung injury: a perspective
Authors: Dos Santos C. C. , Slutsky A. S.
Published: December 2017

Despite advances in critical care, the mortality rate in patients with acute lung injury remains high. Furthermore, most patients who die do so from multisystem organ failure. It has been postulated that ventilator-induced lung injury plays a key role in determining the negative clinical outcome of patients exposed to mechanical ventilation. How mechanical ventilation exerts its detrimental effect is as of yet unknown, but it appears that overdistension of lung units or shear forces generated during repetitive opening and closing of atelectatic lung units exacerbates, or even initiates, significant lung injury and inflammation. The term “biotrauma” has recently been elaborated to describe the process by which stress produced by mechanical ventilation leads to the upregulation of an inflammatory response. For mechanical ventilation to exert its deleterious effect, cells are required to sense mechanical forces and activate intracellular signaling pathways able to communicate the information to its interior. This information must then be integrated in the nucleus, and an appropriate response must be generated to implement and/or modulate its response and that of neighboring cells. In this review, we present a perspective on ventilator-induced lung injury with a focus on mechanisms and clinical implications. We highlight some of the most recent findings, which we believe contribute to the generation and propagation of ventilator-induced lung injury, placing a special emphasis on their implication for future research and clinical therapies.
Caffeine potentiates low frequency skeletal muscle force in habitual and nonhabitual caffeine consumers
Authors: Tarnopolsky Mark , Cupido Cynthia
Published: December 2017

The mechanism of action underlying the ergogenic effect of caffeine is still unclear. Caffeine increases the force of muscular contraction during low-frequency stimulation by potentiating calcium release from the sarcoplasmic reticulum. Studies have also suggested an enhancement of lipid oxidation and glycogen sparing as potential mechanisms. Given that several studies have found an ergogenic effect of caffeine with no apparent metabolic effects, it is likely that a direct effect upon muscle is important. Twelve healthy male subjects were classified as habitual ( n = 6) or nonhabitual ( n = 6) caffeine consumers based on a 4-day diet record analysis, with a mean caffeine consumption of 771 and 14 mg/day for each group, respectively. Subjects were randomly allocated to receive caffeine (6 mg/kg) and placebo (citrate) in a double-blind, cross-over fashion ∼100 min before a 2-min tetanic stimulation of the common peroneal nerve in a custom-made dynamometer (2 trials each of 20 and 40 Hz). Tetanic torque was measured every 30 s during and at 1, 5, and 15 min after the stimulation protocol. Maximal voluntary contraction strength and peak twitch torque were measured before and after the stimulation protocol. Caffeine potentiated the force of contraction during the final minute of the 20-Hz stimulation ( P < 0.05) with no effect of habituation. There was no effect of caffeine on 40-Hz stimulation strength nor was there an effect on maximal voluntary contraction or peak twitch torque. These data support the hypothesis that some of the ergogenic effect of caffeine in endurance exercise performance occurs directly at the skeletal muscle level.
Effect of endurance training on oxygen uptake kinetics during treadmill running
Authors: Carter Helen , Jones Andrew M. , Barstow Thomas J. , Burnley Mark , Williams Craig , Doust Jonathan H.
Published: December 2017

The purpose of this study was to examine the effect of endurance training on oxygen uptake (V˙o 2) kinetics during moderate [below the lactate threshold (LT)] and heavy (above LT) treadmill running. Twenty-three healthy physical education students undertook 6 wk of endurance training that involved continuous and interval running training 3–5 days per week for 20–30 min per session. Before and after the training program, the subjects performed an incremental treadmill test to exhaustion for determination of the LT and the V˙o 2 max and a series of 6-min square-wave transitions from rest to running speeds calculated to require 80% of the LT and 50% of the difference between LT and maximal V˙o 2. The training program caused small (3–4%) but significant increases in LT and maximalV˙o 2 ( P < 0.05). TheV˙o 2 kinetics for moderate exercise were not significantly affected by training. For heavy exercise, the time constant and amplitude of the fast component were not significantly affected by training, but the amplitude of theV˙o 2 slow component was significantly reduced from 321 ± 32 to 217 ± 23 ml/min ( P< 0.05). The reduction in the slow component was not significantly correlated to the reduction in blood lactate concentration ( r = 0.39). Although the reduction in the slow component was significantly related to the reduction in minute ventilation ( r = 0.46; P < 0.05), it was calculated that only 9–14% of the slow component could be attributed to the change in minute ventilation. We conclude that theV˙o 2 slow component during treadmill running can be attenuated with a short-term program of endurance running training.
Bronchial reactivity of healthy subjects: 18–20 h postexposure to ozone
Authors: Foster W. Michael , Brown Robert H. , Macri Kristin , Mitchell Clifford S.
Published: December 2017

Exposure of humans to ambient levels of ozone (O3) causes inflammatory changes within lung tissues. These changes have been reported for the “initial” (1- to 3-h) and “late” (18- to 20-h) postexposure periods. We hypothesized that at the late period, when protein and cellular markers of inflammation at the airway surface remain abnormal and the integrity of the epithelial barrier is compromised, bronchial reactivity would be increased. To test this, we measured airway responsiveness to cumulative doses of methacholine (MCh) aerosol in healthy subjects 19 ± 1 h after a single exposure to O3 (130 min at ambient levels between 120 and 240 parts/billion and alternate periods of rest and moderate exercise) or filtered air. Exposures were conducted at two temperatures: mild (22°C) and moderate (30°C). At the late period, bronchial reactivity to MCh increased, i.e., interpolated dose of MCh leading to a 50% fall in specific airway conductance (PC50) was less after O3 than after filtered air. PC50 for O3 at 22°C was 27 mg/ml (20% less than the PC50 after filtered air), and for O3 at 30°C it was 19 mg/ml (70% less than the PC50 after filtered air). The forced expiratory volume in 1 s (FEV1) at the late time point after O3 was slightly but significantly reduced (2.3%) from the preexposure level. There was no relationship found between the functional changes observed early after exposure to O3 and subsequent changes in bronchial reactivity or FEV1 at the late time point. These results suggest that bronchial reactivity is significantly altered ∼1 day after O3; this injury may contribute to the respiratory morbidity that is observed 1–2 days after an episode of ambient air pollution.
Stability and change in genetic and environmental influences on hand-grip strength in older male twins
Authors: Carmelli Dorit , Reed Terry
Published: December 2017

The aim of this study was to investigate aging-related changes in the contribution of genetic and environmental influences to hand-grip strength in late adulthood. Subjects in this study are 152 intact twin pairs (77 monozygotic and 75 dizygotic pairs) from the National Heart, Lung, and Blood Institute Twin Study assessed repeatedly for hand-grip strength at mean ages of 63 and 73 yr. Structural equation genetic modeling was used to investigate stability and change in the genetic and environmental components of variance of hand-grip strength in late adulthood. Average decline in strength over the 10 yr of follow-up was −1.05 ± 6.8 (SD) kg and was highly significant ( P = 0.003). The test-retest correlation between baseline and follow-up grip strength was 0.62 ( P < 0.001). Bivariate genetic modeling found significant genetic and shared environmental stability in hand-grip strength over the 10 yr of follow-up, with genetic and shared environmental influences accounting for 35 and 48%, respectively, of the test-retest phenotypic correlation. We conclude from these results that stability in hand-grip strength in late adulthood is due primarily to continuity of genetic and familial influences.
Eicosanoid and muscarinic receptor blockade abolishes hyperventilation-induced bronchoconstriction
Authors: Freed Arthur N. , McCulloch Sharron , Wang Yongqiang
Published: December 2017

This study was designed to test the hypothesis that hyperventilation-induced bronchoconstriction (HIB) results from the combined effects of prostanoid and leukotriene metabolism. A bronchoscope was used in anesthetized dogs to record peripheral airway resistance and HIB before and after combined treatment with inhibitors of cyclooxygenase (indomethacin) and 5-lipoxygenase (MK-0591). Bronchoalveolar lavage fluid (BALF) cells and mediators from hyperventilated and control airways were also measured. Pretreatment with MK-0591 and indomethacin significantly attenuated, but did not abolish, HIB. However, addition of atropine nearly eliminated the residual response. Blockade of eicosanoid metabolism markedly reduced the concentrations of eicosanoids recovered in BALF after hyperventilation. Positive correlations between posthyperventilation BALF prostanoid and epithelial cell concentrations are suggestive of mucosal injury-induced mediator production and release. We conclude that HIB is prevented in the presence of eicosanoid and muscarinic-receptor blockade and that both classes of eicosanoids contribute similarly to the development of HIB.
Mutagenesis analysis of human SM22: characterization of actin binding
Authors: Fu Yiping , Liu Hong Wei , Forsythe Sean M. , Kogut Paul , McConville John F. , Halayko Andrew J. , Camoretti-Mercado Blanca , Solway Julian
Published: December 2017

SM22 is a 201-amino acid actin-binding protein expressed at high levels in smooth muscle cells. It has structural homology to calponin, but how SM22 binds to actin remains unknown. We performed site-directed mutagenesis to generate a series of NH2-terminal histidine (His)-tagged mutants of human SM22 in Escherichia coli and used these to analyze the functional importance of potential actin binding domains. Purified full-length recombinant SM22 bound to actin in vitro, as demonstrated by cosedimentation assay. Binding did not vary with calcium concentration. The COOH-terminal domain of SM22 is required for actin affinity, because COOH terminally truncated mutants [SM22-(1–186) and SM22-(1–166)] exhibited markedly reduced cosedimentation with actin, and no actin binding of SM22-(1–151) could be detected. Internal deletion of a putative actin binding site (154-KKAQEHKR-161) partially prevented actin binding, as did point mutation to neutralize either or both pairs of positively charged residues at the ends of this region (KK154LL and/or KR160LL). Internal deletion of amino acids 170–180 or 170–186 also partially or almost completely inhibited actin cosedimentation, respectively. Of the three consensus protein kinase C or casein kinase II phosphorylation sites in SM22, only Ser-181 was readily phosphorylated by protein kinase C in vitro, and such phosphorylation greatly decreased actin binding. Substitution of Ser-181 to aspartic acid (to mimic serine phosphorylation) also reduced actin binding. Immunostains of transiently transfected airway myocytes revealed that full-length NH2-terminal FLAG-tagged SM22 colocalizes with actin filaments, whereas FLAG-SM22-(1–151) does not. These data confirm that SM22 binds to actin in vitro and in vivo and, for the first time, demonstrate that multiple regions within the COOH-terminal domain are required for full actin affinity.
Faster top running speeds are achieved with greater ground forces not more rapid leg movements
Authors: Weyand Peter G. , Sternlight Deborah B. , Bellizzi Matthew J. , Wright Seth
Published: December 2017

We twice tested the hypothesis that top running speeds are determined by the amount of force applied to the ground rather than how rapidly limbs are repositioned in the air. First, we compared the mechanics of 33 subjects of different sprinting abilities running at their top speeds on a level treadmill. Second, we compared the mechanics of declined (−6°) and inclined (+9°) top-speed treadmill running in five subjects. For both tests, we used a treadmill-mounted force plate to measure the time between stance periods of the same foot (swing time, tsw) and the force applied to the running surface at top speed. To obtain the force relevant for speed, the force applied normal to the ground was divided by the weight of the body ( Wb) and averaged over the period of foot-ground contact (Favge/ Wb). The top speeds of the 33 subjects who completed the level treadmill protocol spanned a 1.8-fold range from 6.2 to 11.1 m/s. Among these subjects, the regression of Favge/ Wbon top speed indicated that this force was 1.26 times greater for a runner with a top speed of 11.1 vs. 6.2 m/s. In contrast, the time taken to swing the limb into position for the next step ( tsw) did not vary ( P = 0.18). Declined and inclined top speeds differed by 1.4-fold (9.96 ± 0.3 vs. 7.10 ± 0.3 m/s, respectively), with the faster declined top speeds being achieved with mass-specific support forces that were 1.3 times greater (2.30 ± 0.06 vs. 1.76 ± 0.04 Favge/ Wb) and minimum tswthat were similar (+8%). We conclude that human runners reach faster top speeds not by repositioning their limbs more rapidly in the air, but by applying greater support forces to the ground.
Kinetics of respiratory system elastance after airway challenge in dogs
Authors: Lauzon Anne-Marie , Bates Jason H. T.
Published: December 2017

We compared the time courses of lung mechanical changes with intravenous (iv) injection vs. aerosol administration of histamine, methacholine, and ACh in dogs. We interpret these results in terms of a spring-and-dashpot model of airway smooth muscle receiving activation via a tissue compartment when agonist is delivered by the iv route and through an additional airway wall compartment when it is delivered by the aerosol route. The model accurately accounts for the principal features of the respiratory system elastance response curves. It also accounts for the differences between iv and aerosol responses, supporting the notion that agonist delivered by aerosol has to traverse a longer pathway to the airway smooth muscle than does agonist delivered iv. The time constants representing diffusive exchange of agonist between compartments were not significantly different for the three agonists, suggesting that the three agonists shared a common principal means of clearance, which was presumably blood flow.
Size distribution of recruited alveolar volumes in airway reopening
Authors: Suki Béla , Alencar Adriano M. , Tolnai József , Asztalos Tibor , Peták Ferenc , Sujeer Mamatha K. , Patel Keena , Patel Jignish , Stanley H. Eugene , Hantos Zoltán
Published: December 2017

In 11 isolated dog lung lobes, we studied the size distribution of recruited alveolar volumes that become available for gas exchange during inflation from the collapsed state. Three catheters were wedged into 2-mm-diameter airways at total lung capacity. Small-amplitude pseudorandom pressure oscillations between 1 and 47 Hz were led into the catheters, and the input impedances of the regions subtended by the catheters were continuously recorded using a wave tube technique during inflation from −5 cmH2O transpulmonary pressure to total lung capacity. The impedance data were fit with a model to obtain regional tissue elastance (Eti) as a function of inflation. First, Eti was high and decreased in discrete jumps as more groups of alveoli were recruited. By assuming that the number of opened alveoli is inversely proportional to Eti, we calculated from the jumps in Eti the distribution of the discrete increments in the number of opened alveoli. This distribution was in good agreement with model simulations in which airways open in cascade or avalanches. Implications for mechanical ventilation may be found in these results.
Influence of dual ETA/ETB-receptor blockade on coronary responses to treadmill exercise in dogs
Authors: Takamura Masayuki , Parent Robert , Cernacek Peter , Lavallée Michel
Published: December 2017

We hypothesized that endothelin (ET) release during exercise may be triggered by α-adrenergic-receptor activation and thereby influence coronary hemodynamics and O2metabolism in dogs. Exercise resulted in coronary blood flow increases (to 1.88 ± 0.26 from 1.10 ± 0.12 ml · min−1· g−1) and in a fall ( P < 0.01) in coronary sinus O2saturation (17.4 ± 1.5 to 9.6 ± 0.7 vol%), whereas myocardial O2consumption (MV˙o2) increased (109 ± 13% from 145 ± 16 μl O2· min−1· g−1). Tezosentan, a dual ETA/ETB-receptor blocker, slightly reduced mean arterial pressure (MAP) and increased heart rate throughout exercise. The relationship between coronary sinus O2saturation and MV˙o2was shifted upward ( P < 0.05) after tezosentan administration; i.e., as MV˙o2increased during exercise, coronary sinus O2saturation was disproportionately higher after ET-receptor blockade. After propranolol, tezosentan resulted in significant decreases ( P < 0.05) in left ventricular pressure, the first derivative of left ventricular pressure over time, and MAP during exercise. As MV˙o2increased during exercise, coronary sinus O2saturation levels after tezosentan became superimposable over those observed before ET-receptor blockade. Thus dual blockade of ETA/ETBreceptors alters coronary hemodynamics and O2metabolism during exercise, but ET activity failed to increase beyond baseline levels.
Mixed-gas model for predicting decompression sickness in rats
Authors: Lillo R. S. , Parker E. C.
Published: December 2017

A mixed-gas model for rats was developed to further explore the role of different gases in decompression and to provide a global model for possible future evaluation of its usefulness for human prediction. A Hill-equation dose-response model was fitted to over 5,000 rat dives by using the technique of maximum likelihood. These dives used various mixtures of He, N2, Ar, and O2 and had times at depth up to 2 h and varied decompression profiles. Results supported past findings, including 1) differences among the gases in decompression risk (He < N2 < Ar) and exchange rate (He > Ar ≈ N2), 2) significant decompression risk of O2, and 3) increased risk of decompression sickness with heavier animals. New findings included asymmetrical gas exchange with gas washout often unexpectedly faster than uptake. Model success was demonstrated by the relatively small errors (and their random scatter) between model predictions and actual incidences. This mixed-gas model for prediction of decompression sickness in rats is the first such model for any animal species that covers such a broad range of gas mixtures and dive profiles.
Periodic breathing in heart failure patients: testing the hypothesis of instability of the chemoreflex loop
Authors: Pinna G. D. , Maestri R. , Mortara A. , Rovere M. T. La , Fanfulla F. , Sleight P.
Published: December 2017

In this study, we applied time- and frequency-domain signal processing techniques to the analysis of respiratory and arterial O2 saturation (SaO2 ) oscillations during nonapneic periodic breathing (PB) in 37 supine awake chronic heart failure patients. O2 was administered to eight of them at 3 l/min. Instantaneous tidal volume and instantaneous minute ventilation (IMV) signals were obtained from the lung volume signal. The main objectives were to verify 1) whether the timing relationship between IMV and SaO2 was consistent with modeling predictions derived from the instability hypothesis of PB and 2) whether O2 administration, by decreasing loop gain and increasing O2 stores, would have increased system stability reducing or abolishing the ventilatory oscillation. PB was centered around 0.021 Hz, whereas respiratory rate was centered around 0.33 Hz and was almost stable between hyperventilation and hypopnea. The average phase shift between IMV and SaO2 at the PB frequency was 205° (95% confidence interval 198–212°). In 12 of 37 patients in whom we measured the pure circulatory delay, the predicted lung-to-ear delay was 28.8 ± 5.2 s and the corresponding observed delay was 30.9 ± 8.8 s ( P = 0.13). In seven of eight patients, O2 administration abolished PB (in the eighth patient, SaO2 did not increase). These results show a remarkable consistency between theoretical expectations derived from the instability hypothesis and experimental observations and clearly indicate that a condition of loss of stability in the chemical feedback control of ventilation might play a determinant role in the genesis of PB in awake chronic heart failure patients.
Muscular reflexes elicited by electrical stimulation of the anterior cruciate ligament in humans
Authors: Dyhre-Poulsen Poul , Krogsgaard Michael R.
Published: December 2017

Anterior cruciate ligament (ACL)-deficient knees have impaired proprioception, and, although mechanoreceptors have been found in the ACL, the existence of a reflex elicited from these receptors has not been directly demonstrated in humans. In eight patients that underwent knee arthroscopy and had no sign of ACL disease, thin wire electrodes were inserted into the proximal and mid parts of the ACL. Postoperatively, the sensory nerve fibers inside the ACL were stimulated electrically while motor activity in the knee muscles was recorded using electromyography. In seven of the eight patients, a muscular contraction of the semitendinosus muscle could be elicited with stimulus trains consisting of at least two stimuli. The latency was 95 ± 35 ms. Stimulation during isometric contraction of either extensor or flexor muscles elicited a short, complete inhibition of the muscle activity in the contracting muscles. The latency of the inhibitory responses was 65 ± 20 ms in the semitendinosus muscle and 70 ± 15 ms in the rectus femoris muscle.
Power fatigue of the rat diaphragm muscle
Authors: Ameredes Bill T. , Zhan Wen-Zhi , Prakash Y. S. , Vandenboom Rene , Sieck Gary C.
Published: December 2017

We hypothesized that decrements in maximum power output (W˙max) of the rat diaphragm (Dia) muscle with repetitive activation are due to a disproportionate reduction in force (force fatigue) compared with a slowing of shortening velocity (velocity fatigue). Segments of midcostal Dia muscle were mounted in vitro (26°C) and stimulated directly at 75 Hz in 400-ms-duration trains repeated each second (duty cycle = 0.4) for 120 s. A novel technique was used to monitor instantaneous reductions in maximum specific force (Po) andW˙maxduring fatigue. During each stimulus train, activation was isometric for the initial 360 ms during which Powas measured; the muscle was then allowed to shorten at a constant velocity (30% Vmax) for the final 40 ms, and W˙maxwas determined. Compared with initial values, after 120 s of repetitive activation, PoandW˙maxdecreased by 75 and 73%, respectively. Maximum shortening velocity was measured in two ways: by extrapolation of the force-velocity relationship ( Vmax) and using the slack test [maximum unloaded shortening velocity ( Vo)]. After 120 s of repetitive activation, Vmaxslowed by 44%, whereas Voslowed by 22%. Thus the decrease inW˙maxwith repetitive activation was dominated by force fatigue, with velocity fatigue playing a secondary role. On the basis of a greater slowing of Vmaxvs. Vo, we also conclude that force and power fatigue cannot be attributed simply to the total inactivation of the most fatigable fiber types.
Effects of carbohydrate ingestion before and during exercise on glucose kinetics and performance
Authors: Febbraio Mark A. , Chiu Alison , Angus Damien J. , Arkinstall Melissa J. , Hawley John A.
Published: December 2017

We investigated the effect of carbohydrate (CHO) ingestion before and during exercise and in combination on glucose kinetics, metabolism and performance in seven trained men, who cycled for 120 min (SS) at ∼63% of peak power output, followed by a 7 kJ/kg body wt time trial (TT). On four separate occasions, subjects received either a placebo beverage before and during SS (PP); placebo 30 min before and 2 g/kg body wt of CHO in a 6.4% CHO solution throughout SS (PC); 2 g/kg body wt of CHO in a 25.7% CHO beverage 30 min before and placebo throughout SS (CP); or 2 g/kg body wt of CHO in a 25.7% CHO beverage 30 min before and 2 g/kg of CHO in a 6.4% CHO solution throughout SS (CC). Ingestion of CC and CP markedly (>8 mM) increased plasma glucose concentration ([glucose]) compared with PP and PC (5 mM). However, plasma [glucose] fell rapidly at the onset of SS so that after 80 min it was similar (6 mM) between all treatments. After this time, plasma [glucose] declined in both PP and CP ( P < 0.05) but was well maintained in both CC and PC. Ingestion of CC and CP increased rates of glucose appearance (Ra) and disappearance (Rd) compared with PP and PC at the onset of, and early during, SS ( P < 0.05). However, late in SS, both glucose Raand Rdwere higher in CC and PC compared with other trials ( P < 0.05). Although calculated rates of glucose oxidation were different when comparing the four trials ( P < 0.05), total CHO oxidation and total fat oxidation were similar. Despite this, TT was improved in CC and PC compared with PP ( P < 0.05). We conclude that 1) preexercise ingestion of CHO improves performance only when CHO ingestion is maintained throughout exercise, and 2) ingestion of CHO during 120 min of cycling improves subsequent TT performance.
Acute head-down tilt decreases the postexercise resting threshold for forearm cutaneous vasodilation
Authors: Kenny Glen P. , Jackson Dwayne N. , Reardon Francis D.
Published: December 2017

The purpose of this study was to evaluate the role of baroreceptor control on the postexercise threshold for forearm cutaneous vasodilation. On four separate days, six subjects (1 woman) were randomly exposed to 65° head-up tilt and to 15° head-down tilt during a No-Exercise and Exercise treatment protocol. Under each condition, a whole body water-perfused suit was used to regulate mean skin temperature (T̄sk) in the following sequence: 1) cooling until the threshold for vasoconstriction was evident; 2) heating (∼7.0°C/h) until vasodilation occurred; and 3) cooling until esophageal temperature (Tes) and T̄sk returned to baseline values. The Exercise treatment consisted of 15 min of cycling exercise at 70% maximal O2 uptake, followed by 15 min of recovery in the head-up tilt position. The No-Exercise treatment consisted of 30 min resting in the head-up tilt position. After the treatment protocols, subjects were returned to their pretreatment condition, then cooled and warmed again consecutively. The calculated Tes threshold for cutaneous vasodilation increased 0.24°C postexercise during head-up tilt ( P < 0.05), whereas no difference was measured during head-down tilt. In contrast, sequential measurements without exercise demonstrate a time-dependent decrease for head-up tilt (0.17°C) and no difference for head-down tilt. Pretreatment thresholds were significantly lower during head-down tilt compared with head-up tilt. We have shown that manipulating postexercise venous pooling by means of head-down tilt, in an effort to reverse its impact on baroreceptor unloading, resulted in a relative lowering of the resting postexercise elevation in the Tesfor forearm cutaneous vasodilation.
Effects of high fat provision on muscle PDH activation and malonyl-CoA content in moderate exercise
Authors: Odland L. Maureen , Heigenhauser George J. F. , Spriet Lawrence L.
Published: December 2017

This study examined the effects of elevated free fatty acid (FFA) provision on the regulation of pyruvate dehydrogenase (PDH) activity and malonyl-CoA (M-CoA) content in human skeletal muscle during moderate-intensity exercise. Seven men rested for 30 min and cycled for 10 min at 40% and 10 min at 65% of maximal O2uptake while being infused with either Intralipid and heparin (Int) or saline (control). Muscle biopsies were taken at 0, 1 (rest-to-exercise transition), 10, and 20 min. Exercise plasma FFA were elevated (0.99 ± 0.11 vs. 0.33 ± 0.03 mM), and the respiratory exchange ratio was reduced during Int (0.87 ± 0.02) vs. control (0.91 ± 0.01). PDH activation was lower during Int at 1 min (1.33 ± 0.19 vs. 2.07 ± 0.14 mmol · min−1· kg−1wet muscle) and throughout exercise. Muscle pyruvate was reduced during Int at rest [0.17 ± 0.03 vs. 0.25 ± 0.03 mmol/kg dry muscle (dm)] but increased above control during exercise. NADH was higher during Int vs. control at rest and 1 min of exercise (0.122 ± 0.016 vs. 0.102 ± 0.005 and 0.182 ± 0.016 vs. 0.150 ± 0.016 mmol/kg dm), but not at 10 and 20 min. M-CoA was lower during Int vs. control at rest and 20 min of exercise (1.12 ± 0.22 vs. 1.43 ± 0.17 and 1.33 ± 0.16 vs. 1.84 ± 0.17 μmol/kg dm). The reduced PDH activation with elevated FFA during the rest-to-exercise transition was related to higher mitochondrial NADH at rest and 1 min of exercise and lower muscle pyruvate at rest. The decreased M-CoA may have increased fat oxidation during exercise with elevated FFA by reducing carnitine palmitoyltransferase I inhibition and increasing mitochondrial FFA transport.
Role of mitogen-activated protein kinases in pulmonary endothelial cells exposed to cyclic strain
Authors: Kito Hiroyuki , Chen Emery L. , Wang Xiujie , Ikeda Masataka , Azuma Nobuyoshi , Nakajima Nobuyuki , Gahtan Vivian , Sumpio Bauer E.
Published: December 2017

The aim of this study was to examine the role of mitogen-activated protein kinases (MAPKs) activation in bovine pulmonary arterial endothelial cells (EC) exposed to cyclic strain. EC were subjected to 10% average strain at 60 cycles/min. Cyclic strain induced activation of extracellular signal-regulated kinase (ERK; 1.5-fold), c-Jun NH2-terminal protein kinase (JNK; 1.9-fold), and p38 (1.5-fold) with a peak at 30 min. To investigate the functional role of the activated MAPKs, we analyzed cells after treatment with PD-98059, a specific ERK kinase inhibitor, or SB-203580, a catalytic inhibitor for p38, and after transient transfection with JNK(K-R), and MEKK(K-M) the respective catalytically inactive mutants of JNK1 and MAPK kinase kinase-1. Cyclic strain increased activator protein-1 (AP-1) binding activity, which was blocked by PD-98059 and SB-203580. Activity of AP-1-dependent luciferase reporter driven by 12- O-tetradecanoyl-phorbol-13-acetate-responsive element (TRE) was induced by cyclic strain, and this was attenuated by PD-98059, MEKK(K-M), JNK(K-R), and SB-203580. PD-98059 and SB-203850 did not inhibit cell alignment and migration induced by cyclic strain. MEKK(K-M) and JNK(K-R) transfection did not block cyclic strain-induced cell alignment. In conclusion, cyclic strain activates ERK, JNK, and p38, and their activation plays a role in transcriptional activation of AP-1/TRE but not in cell alignment and migration changes in bovine pulmonary arterial EC.
Metabolic component of intestinal Pco2during dysoxia
Authors: Raza Ovais , Schlichtig Robert
Published: December 2017

The adequacy of intestinal perfusion during shock and resuscitation might be estimated from intestinal tissue acid-base balance. We examined this idea from the perspective of conventional blood acid-base physicochemistry. As the O2supply diminishes with failing blood flow, tissue acid-base changes are first “respiratory,” with CO2coming from combustion of fuel and stagnating in the decreasing blood flow. When the O2supply decreases to critical, the changes become “metabolic” due to lactic acid. In blood, the respiratory vs. metabolic distinction is conventionally made using the buffer base principle, in which buffer base is the sum of HCO3−and noncarbonate buffer anion (A−). During purely respiratory acidosis, buffer base stays constant because HCO3−cannot buffer its own progenitor, carbonic acid, so that the rise of HCO3−equals the fall of A−. During anaerobic “metabolism,” however, lactate's H+is buffered by both A−and HCO3−, causing buffer base to decrease. We quantified the partitioning of lactate's H+between HCO3−and A−buffer in anoxic intestine by compressing intestinal segments of anesthetized swine into a steel pipe and measuring Pco2and lactate at 5- to 10-min intervals. Their rises followed first-order kinetics, yielding k = 0.031 min−1and half time = ∼22 min. Pco2vs. lactate relations were linear. Over 3 h, lactate increased by 31 ± 3 mmol/l tissue fluid (mM) and Pco2by ∼17 mM, meaning that one-half of lactate's H+was buffered by tissue HCO3−and one-half by A−. The data were consistent with a lumped p Kavalue near 6.1 and total A−concentration of ∼30 mmol/kg. We conclude that the respiratory vs. metabolic distinction could be made in tissue by estimating tissue buffer base from measured pH and Pco2.
Influence of training on sweating responses during submaximal exercise in horses
Authors: McCutcheon L. J. , Geor R. J.
Published: December 2017

Sweating responses were examined in five horses during a standardized exercise test (SET) in hot conditions (32–34°C, 45–55% relative humidity) during 8 wk of exercise training (5 days/wk) in moderate conditions (19–21°C, 45–55% relative humidity). SETs consisting of 7 km at 50% maximal O2consumption, determined 1 wk before training day (TD) 0, were completed on a treadmill set at a 6° incline on TD0, 14, 28, 42, and 56. Mean maximal O2consumption, measured 2 days before each SET, increased 19% [TD0 to 42: 135 ± 5 (SE) to 161 ± 4 ml · kg−1· min−1]. Peak sweating rate (SR) during exercise increased on TD14, 28, 42, and 56 compared with TD0, whereas SRs and sweat losses in recovery decreased by TD28. By TD56, end-exercise rectal and pulmonary artery temperature decreased by 0.9 ± 0.1 and 1.2 ± 0.1°C, respectively, and mean change in body mass during the SET decreased by 23% (TD0: 10.1 ± 0.9; TD56: 7.7 ± 0.3 kg). Sweat Na+concentration during exercise decreased, whereas sweat K+concentration increased, and values for Cl−concentration in sweat were unchanged. Moderate-intensity training in cool conditions resulted in a 1.6-fold increase in sweating sensitivity evident by 4 wk and a 0.7 ± 0.1°C decrease in sweating threshold after 8 wk during exercise in hot, dry conditions. Altered sweating responses contributed to improved heat dissipation during exercise and a lower end-exercise core temperature. Despite higher SRs for a given core temperature during exercise, decreases in recovery SRs result in an overall reduction in sweat fluid losses but no change in total sweat ion losses after training.
Physical exercise and normobaric hypoxia: independent modulators of peripheral cholecystokinin metabolism in man
Authors: Bailey Damian M. , Davies Bruce , Castell Linda M. , Newsholme Eric A. , Calam John
Published: December 2017

The purpose of the present investigation was to determine the independent effects of hypoxia and physical exercise on peripheral cholecystokinin (CCK) metabolism in humans. Thirty-two physically active men were randomly assigned in a double-blind manner to either a normoxic (N; n = 14) or hypoxic (H; n = 18) group. During the acute study, subjects in the H group only participated in two tests, separated by 48 h, which involved a cycling test to exhaustion in normobaric normoxia and normobaric hypoxia (inspired O2 fraction = 0.21 and 0.16, respectively). In the intermittent study, N and H groups cycle-trained for 4 wk at the same relative exercise intensity in both normoxia and hypoxia. Acute normoxic exercise consistently raised plasma CCK during both studies by 290–723%, which correlated with increases in the plasma ratio of free tryptophan to branched chain amino acids ( r = 0.58–0.71, P < 0.05). In contrast, acute hypoxic exercise decreased CCK by 7.0 ± 5.5 pmol/l, which correlated with the decrease in arterial oxygen saturation ( r = 0.56, P < 0.05). In the intermittent study, plasma CCK response at rest and after normoxic exercise was not altered after physical training, despite a slight decrease in adiposity. We conclude that peripheral CCK metabolism 1) is more sensitive to acute changes than chronic changes in energy expenditure and 2) is potentially associated with acute changes in tissue Po 2 and metabolic precursors of cerebral serotoninergic activity.
Differences in skeletal muscle between men and women with chronic heart failure
Authors: Duscha Brian D , Annex Brian H , Keteyian Steven J , Green Howard J. , Sullivan Martin J. , Samsa Gregory P. , Brawner Clinton A. , Schachat Fred H. , Kraus William E.
Published: December 2017

Men with chronic heart failure (CHF) have alterations in their skeletal muscle that are partially responsible for a decreased exercise tolerance. The purpose of this study was to investigate whether skeletal muscle alterations in women with CHF are similar to those observed in men and if these alterations are related to exercise intolerance. Twenty-five men and thirteen women with CHF performed a maximal exercise test for evaluation of peak oxygen consumption (V˙o 2) and resting left ventricular ejection fraction, after which a biopsy of the vastus lateralis was performed. Twenty-one normal subjects (11 women, 10 men) were also studied. The relationship between muscle markers and peakV˙o 2 was consistent for CHF men and women. When controlling for gender, analysis showed that oxidative enzymes and capillary density are the best predictors of peakV˙o 2 . These results indicate that aerobically matched CHF men and women have no differences in skeletal muscle biochemistry and histology. However, when CHF groups were separated by peak exercise capacity of 4.5 metabolic equivalents (METs), CHF men with peak V˙o 2 >4.5 METs had increased citrate synthase and 3-hydroxyacyl-CoA dehydrogenase compared with CHF men with peak V˙o 2 <4.5 METs. CHF men with a lower peak V˙o 2 had increased capillary density compared with men with higher peakV˙o 2. These observations were not reproduced in CHF women. This suggests that differences may exist in how skeletal muscle adapts to decreasing peakV˙o 2 in patients with CHF.
Exercise-associated differences in an array of proteins involved in signal transduction and glucose transport
Authors: Yu Mei , Blomstrand Eva , Chibalin Alexander V. , Wallberg-Henriksson Harriet , Zierath Juleen R. , Krook Anna
Published: December 2017

Vastus lateralis muscle biopsies were obtained from endurance-trained (running ∼50 km/wk) and untrained (no regular physical exercise) men, and the expression of an array of insulin-signaling intermediates was determined. Expression of insulin receptor and insulin receptor substrate-1 and -2 was decreased 44% ( P < 0.05), 57% ( P < 0.001), and 77% ( P < 0.001), respectively, in trained vs. untrained muscle. The downstream signaling target, Akt kinase, was not altered in trained subjects. Components of the mitogenic signaling cascade were also assessed. Extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase expression was 190% greater ( P < 0.05), whereas p38 mitogen-activated protein kinase expression was 32% lower ( P < 0.05), in trained vs. untrained muscle. GLUT-4 protein expression was twofold higher ( P < 0.05), and the GLUT-4 vesicle-associated protein, the insulin-regulated aminopeptidase, was increased 4.7-fold ( P < 0.05) in trained muscle. In conclusion, the expression of proteins involved in signal transduction is altered in skeletal muscle from well-trained athletes. Downregulation of early components of the insulin-signaling cascade may occur in response to increased insulin sensitivity associated with endurance training.
Effects of human pregnancy on cardiac autonomic function above and below the ventilatory threshold
Authors: Avery N. D. , Wolfe L. A. , Amara C. E. , Davies G. A. L. , McGrath M. J.
Published: December 2017

This study examined the effects of human pregnancy on heart rate variability (HRV), spontaneous baroreflex (SBR) sensitivity, and plasma catecholamines at rest and during exercise. Subjects were 14 healthy, physically active pregnant women (PG; mean gestational age = 33.9 ± 1.0 wk). Results were compared with an age-matched nonpregnant control group (NPG; n = 14) with similar characteristics. The electrocardiographic R-wave-R-wave interval and systolic blood pressure (via finger plethysmograph) were measured on a beat-to-beat basis at rest and during upright cycling at 60 and 110% of the ventilatory threshold (Tvent). Parasympathetic nervous system (PNS) modulation (as reflected by HRV high-frequency/total power and SBR slope) was significantly reduced at rest in the PG vs. the NPG. During exercise, PNS modulation decreased significantly in both groups, but the magnitude of PNS withdrawal from rest to 110% Tvent was smaller in the PG vs. NPG. Sympathetic nervous system (SNS) modulation (reflected by the low-frequency power-to-high-frequency power ratio) increased above resting values at 60 and 110% Tvent in the NPG. SNS modulation at 110% Tvent was significantly lower in the PG compared with the NPG. Plasma norepinephrine and epinephrine levels were also lower at 110% Tvent in the PG. It was concluded that healthy pregnant women exhibit lower PNS modulation at rest and blunted SNS modulation during exercise above Tvent in late gestation.
Superoxide, hydroxyl radical, and hydrogen peroxide effects on single-diaphragm fiber contractile apparatus
Authors: Callahan L. A. , She Z. W. , Nosek T. M.
Published: December 2017

Reactive oxygen species contribute to diaphragm dysfunction in certain pathophysiological conditions (i.e., sepsis and fatigue). However, the precise alterations induced by reactive oxygen species or the specific species that are responsible for the derangements in skeletal muscle function are incompletely understood. In this study, we evaluated the effect of the superoxide anion radical (O2−·), hydroxyl radical (·OH), and hydrogen peroxide (H2O2) on maximum calcium-activated force (Fmax) and calcium sensitivity of the contractile apparatus in chemically skinned (Triton X-100) single rat diaphragm fibers. O2−· was generated using the xanthine/xanthine oxidase system; ·OH was generated using 1 mM FeCl2, 1 mM ascorbate, and 1 mM H2O2; and H2O2was added directly to the bathing medium. Exposure to O2−· or ·OH significantly decreased Fmaxby 14.5% ( P < 0.05) and 43.9% ( P < 0.005), respectively. ·OH had no effect on Ca2+sensitivity. Neither 10 nor 1,000 μM H2O2significantly altered Fmaxor Ca2+sensitivity. We conclude that the diaphragm is susceptible to alterations induced by a direct effect of ·OH and O2−·, but not H2O2, on the contractile proteins, which could, in part, be responsible for prolonged depression in contractility associated with respiratory muscle dysfunction in certain pathophysiological conditions.
Energetic driving forces are maintained in resting rat skeletal muscle after dietary creatine supplementation
Authors: McMillen J. , Donovan C. M. , Messer J. I. , Willis W. T.
Published: December 2017

The total creatine (TCr) pool of skeletal muscle is composed of creatine (Cr) and phosphocreatine (PCr). In resting skeletal muscle, the ratio of PCr to TCr (PCr/TCr; PCr energy charge) is ∼0.6–0.8, depending on the fiber type. PCr/TCr is linked to the cellular free energy of ATP hydrolysis by the Cr kinase equilibrium. Dietary Cr supplementation increases TCr in skeletal muscle. However, many previous studies have reported data indicating that PCr/TCr falls after supplementation, which would suggest that Cr supplementation alters the resting energetic state of myocytes. This study investigated the effect of Cr supplementation on the energy phosphates of resting skeletal muscle. Male rats were fed either rodent chow (control) or chow supplemented with 2% (wt/wt) Cr. After 2 wk on the diet, the gastrocnemius and soleus muscles were freeze clamped and removed from anesthetized animals. Cr supplementation increased TCr, PCr, and Cr levels in the gastrocnemius by 20, 22, and 17%, respectively ( P < 0.05). A numerical 6% higher mean soleus TCr in Cr-supplemented rats was not statistically significant. All other energy phosphate concentrations, free energy of ATP hydrolysis, and PCr/TCr were not different between the two groups in either muscle. We conclude that Cr supplementation simply increased TCr in fast-twitch rat skeletal muscle but did not otherwise alter resting cellular energetic state.
Reductions in visceral fat during weight loss and walking are associated with improvements inV˙o 2 max
Authors: Lynch Nicole A. , Nicklas Barbara J. , Berman Dora M. , Dennis Karen E. , Goldberg Andrew P.
Published: December 2017

The accumulation of visceral fat is independently associated with an increased risk for cardiovascular disease. The aim of this study was to determine whether the loss of visceral adipose tissue area (VAT; computed tomography) is related to improvements in maximal O2 uptake (V˙o 2 max) during a weight loss (250–350 kcal/day deficit) and walking (3 days/wk, 30–40 min) intervention. Forty obese [body fat 47 ± 1 (SE) %], sedentary (V˙o 2 max 19 ± 1 ml · kg−1 · min−1) postmenopausal women (age 62 ± 1 yr) participated in the study. The intervention resulted in significant declines in body weight (−8%), total fat mass (dual-energy X-ray absorptiometry; −17%), VAT (−17%), and subcutaneous adipose tissue area (−17%) with no change in lean body mass (all P < 0.001). Women with an average 10% increase in V˙o 2 max reduced VAT by an average of 20%, whereas those who did not increaseV˙o 2 max decreased VAT by only 10%, despite comparable reductions in body fat, fat mass, and subcutaneous adipose tissue area. The decrease in VAT was independently related to the change in V˙o 2 max( r 2 = 0.22; P < 0.01) and fat mass ( r 2 = 0.08; P = 0.05). These data indicate that greater improvements inV˙o 2 max with weight loss and walking are associated with greater reductions in visceral adiposity in obese postmenopausal women.
Effect of muscle mass on V˙o 2kinetics at the onset of work
Authors: Koga Shunsaku , Barstow Thomas J. , Shiojiri Tomoyuki , Takaishi Tetsuo , Fukuba Yoshiyuki , Kondo Narihiko , Shibasaki Manabu , Poole David C.
Published: December 2017

The dependence of O2 uptake (V˙o 2) kinetics on the muscle mass recruited under conditions when fiber and muscle recruitment patterns are similar following the onset of exercise has not been determined. We developed a motorized cycle ergometer that facilitated one-leg (1L) cycling in which the electromyographic (EMG) profile of the active muscles was not discernibly altered from that during two-leg (2L) cycling. Six subjects performed 1L and 2L exercise transitions from unloaded cycling to moderate [VT) exercise. The 1L condition yielded kinetics that was unchanged from the 2L condition [the phase 2 time constants (τ1, in s) for  0.05; for >VT: 1L = 26.8 ± 12.0; 2L = 27.8 ± 16.1, P > 0.05]. The overall V˙o 2 kinetics (mean response time) was not significantly different for the two exercise conditions. However, the gain of the fast component (the amplitude/work rate) during the 1L exercise was significantly higher than that for the 2L exercise for both moderate and heavy work rates. The slow-component responses evident for heavy exercise were temporally and quantitatively unaffected by the 1L condition. These data demonstrate that, when leg muscle recruitment patterns are unchanged as assessed by EMG analysis, on-transient V˙o 2 kinetics for both moderate and heavy exercise are not dependent on the muscle mass recruited.