bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of tyrosine hydroxylase by intermittent hypoxia: involvement of serine phosphorylation
Authors: Kumar Ganesh K. , Kim Dong-Kyu , Lee Myeong-Seon , Ramachandran Remya , Prabhakar Nanduri R.
Published: March 2015

Regulation of tyrosine hydroxylase (TH) by intermittent hypoxia (IH) was investigated in rat pheochromocytoma 12 (PC-12) cells by exposing them to alternating cycles of hypoxia (1% O2, 15 s) and normoxia (21% O2, 3 min) for up to 60 cycles; controls were exposed to normoxia for a similar duration. IH exposure increased dopamine content and TH activity by ∼42 and ∼56%, respectively. Immunoblot analysis revealed that comparable levels of TH protein were expressed in normoxic and IH cells. Removal of TH-bound catecholamines and in vitro phosphorylation of TH in cell-free extracts by the catalytic subunit of protein kinase A (PKA) increased TH activity in normoxic but not in IH cells, suggesting possible induction of TH phosphorylation and removal of endogenous inhibition of TH by IH. To assess the role of serine phosphorylation in IH-induced TH activation, TH immunoprecipitates and extracts derived from normoxic and IH cells were probed with anti-phosphoserine and anti-phospho-TH (Ser-40) antibody, respectively. Compared with normoxic cells, total serine and Ser-40-specific phosphorylation of TH were increased in IH cells. IH-induced activation of TH and the increase in total serine and Ser-40-specific phosphorylation of TH were inhibited by Ca2+/calmodulin-dependent protein kinase (CaMK) and PKA-specific inhibitors but not by inhibitors of the extracellular signal-regulated protein kinase pathway, suggesting that IH activates TH in PC-12 cells via phosphorylation of serine residues including Ser-40, in part, by CaMK and PKA. Our results also suggest that IH-induced phosphorylation of TH facilitates the removal of endogenous inhibition of TH, leading to increased synthesis of dopamine.
Exercise throughout 6° head-down tilt bed rest preserves thermoregulatory responses
Authors: Shibasaki Manabu , Wilson Thad E. , Cui Jian , Levine Benjamin D. , Crandall Craig G.
Published: March 2015

Spaceflight and its bed rest analog [6° head-down tilt (HDT)] decrease plasma and blood volume and aerobic capacity. These responses may be associated with impaired thermoregulatory responses observed during exercise and passive heating after HDT exposure. This project tested the hypothesis that dynamic exercise during 13 days of HDT bed rest preserves thermoregulatory responses. Throughout HDT bed rest, 10 subjects exercised for 90 min/day (75% of pre-HDT maximum heart rate; supine). Before and after HDT bed rest, each subject exercised in the supine position at the same workload in a 28°C room. The internal temperature (Tcore) threshold for the onset of sweating and cutaneous vasodilation, as well as the slope of the relationship between the elevation in Tcore relative to the elevation in sweat rate (SR) and cutaneous vascular conductance (CVC; normalized to local heating maximum), were quantified pre- and post-HDT. Tcore thresholds for the onset of cutaneous vasodilation on the chest and forearm (chest: 36.79 ± 0.12 to 36.94 ± 0.13°C, P = 0.28; forearm: 36.76 ± 0.12 to 36.91 ± 0.11°C, P = 0.16) and slope of the elevation in CVC relative to Tcore (chest: 77.9 ± 14.2 to 80.6 ± 17.2%max/°C; P = 0.75; forearm: 76.3 ± 11.8 to 67.5 ± 14.3%max/°C, P = 0.39) were preserved post-HDT. Moreover, the Tcore threshold for the onset of SR (36.66 ± 0.12 to 36.74 ± 0.10°C; P = 0.36) and the slope of the relationship between the elevation in SR and the elevation in Tcore (1.23 ± 0.19 to 1.01 ± 0.14 mg · cm-2 · min-1 · °C-1; P = 0.16) were also maintained. Finally, after HDT bed rest, peak oxygen uptake and plasma and blood volumes were not different relative to pre-HDT bed rest values. These data suggest that dynamic exercise during this short period of HDT bed rest preserves thermoregulatory responses.
Skeletal muscle basal AMP-activated protein kinase activity is chronically elevated in alloxan-diabetic dogs: impact of exercise
Authors: Christopher Michael J. , Chen Zhi-Ping , Rantzau Christian , Kemp Bruce E. , Alford Frank P.
Published: March 2015

The effect of diabetes and exercise on skeletal muscle (SkM) AMP-activated protein kinase (AMPK)α1 and -α2 activities and site-specific phosphorylation of acetyl-CoA carboxylase was examined in the same six dogs before alloxan (35 mg/kg)-induced diabetes (C) and after 4-5 wk of suboptimally controlled hyperglycemic and hypoinsulinemic diabetes (DHG) in the presence and absence of 300-min phlorizin (50 μg·kg-1·min-1)-induced “normoglycemia” (DNG). In each study, the dog underwent a 150-min [3-3H]glucose infusion period, followed by a 30-min treadmill exercise test (60-70% maximal oxygen capacity) to measure the rate of glucose disposal into peripheral tissues (Rdtissue). SkM biopsies were taken from the thigh (vastus lateralis) before and immediately after exercise. In the C and DHG states, the rise in plasma free fatty acids (FFA) with exercise (∼40%) was similar. In the DNG group, preexercise FFA were significantly higher, but the absolute rise in FFA with exercise was similar. However, the exercise-induced increment in Rdtissue was significantly blunted (by ∼40-50%) in the DNG group compared with the other states. In SkM, preexercise AMPKα1 and -α2 activities were significantly elevated (by ∼60-125%) in both diabetic states, but unlike the C group these activities did not rise further with exercise. Additionally, preexercise acetyl-CoA carboxylase phosphorylation in both diabetic states was elevated by ∼70-80%, but the increases with exercise were similar to the C group. Preexercise AMPKα1 and -α2 activities were negatively correlated with Rdtissue during exercise for the combined groups (both P < 0.02). In conclusion, the elevated preexercise SkM AMPKα1 and -α2 activities contribute to the ongoing basal supply of glucose and fatty acid metabolism in suboptimally controlled hypoinsulinemic diabetic dogs; but whether they also play a permissive role in the metabolic stress response to exercise remains uncertain.
V˙o 2 kinetics in heavy exercise is not altered by prior exercise with a different muscle group
Authors: Fukuba Yoshiyuki , Hayashi Naoyuki , Koga Shunsaku , Yoshida Takayoshi
Published: March 2015

We examined whether lactic acidemia-induced hyperemia at the onset of high-intensity leg exercise contributed to the speeding of pulmonary O2 uptake (V˙o 2) after prior heavy exercise of the same muscle group or a different muscle group (i.e., arm). Six healthy male subjects performed two protocols that consisted of two consecutive 6-min exercise bouts separated by a 6-min baseline at 0 W: 1) both bouts of heavy (work rate: 50% of lactate threshold to maximal V˙o 2) leg cycling (L1-ex to L2-ex) and 2) heavy arm cranking followed by identical heavy leg cycling bout (A1-ex to A2-ex). Blood lactate concentrations before L1-ex, L2-ex, and A2-ex averaged 1.7 ± 0.3, 5.6 ± 0.9, and 6.7 ± 1.4 meq/l, respectively. An “effective” time constant (τ) of V˙o 2 with the use of the monoexponential model in L2-ex (τ: 36.8 ± 4.3 s) was significantly faster than that in L1-ex (τ: 52.3 ± 8.2 s). Warm-up arm cranking did not facilitate theV˙o 2 kinetics for the following A2-ex [τ: 51.7 ± 9.7 s]. The double-exponential model revealed no significant change of primary τ (phase II)V˙o 2 kinetics. Instead, the speeding seen in the effective τ during L2-ex was mainly due to a reduction of theV˙o 2 slow component. Near-infrared spectroscopy indicated that the degree of hyperemia in working leg muscles was significantly higher at the onset of L2-ex than A2-ex. In conclusion, facilitation of V˙o 2 kinetics during heavy exercise preceded by an intense warm-up exercise was caused principally by a reduction in the slow component, and it appears unlikely that this could be ascribed exclusively to systemic lactic acidosis.
Compositional changes in lipid microdomains of air-blood barrier plasma membranes in pulmonary interstitial edema
Authors: Palestini Paola , Calvi Chiara , Conforti Elena , Daffara Rossella , Botto Laura , Miserocchi Giuseppe
Published: March 2015

We evaluated in anesthetized rabbits the compositional changes of plasmalemmal lipid microdomains from lung tissue samples after inducing pulmonary interstitial edema (0.5 ml/kg for 3 h, leading to ∼5% increase in extravascular water). Lipid microdomains (lipid rafts and caveolae) were present in the detergent-resistant fraction (DRF) obtained after discontinuous sucrose density gradient. DRF was enriched in caveolin-1, flotillin, aquaporin-1, GM1, cholesterol, sphingomyelin, and phosphatidylserine, and their contents significantly increased in interstitial edema. The higher DRF content in caveolin, flotillin, and aquaporin-1 and of the ganglioside GM1 suggests an increase both in caveolar domains and in lipid rafts, respectively. Compositional changes could be ascribed to endothelial and epithelial cells that provide most of plasma membrane surface area in the air-blood barrier. Alterations in lipid components in the plasma membrane may reflect rearrangement of floating lipid platforms within the membrane and/or lipid translocation from intracellular stores. Lipid traffic could be stimulated by the marked increase in hydraulic interstitial pressure after initial water accumulation, from approximately -10 to 5 cmH2O, due to the low compliance of the pulmonary tissue, in particular in the basement membranes and in the interfibrillar substance. Compositional changes in lipid microdomains represent a sign of cellular activation and suggest the potential role of mechanotransduction in response to developing interstitial edema.
Invited Review: Functional genomics in the mouse: powerful techniques for unraveling the basis of human development and disease
Authors: Bogue Clifford W.
Published: March 2015

Now that near-complete DNA sequences of both the mouse and human genomes are available, the next major challenge will be to determine how each of these genes functions, both alone and in combination with other genes in the genome. The mouse has a long and rich history in biological research, and many consider it a model organism for the study of human development and disease. Over the past few years, exciting progress has been made in developing techniques for chromosome engineering, mutagenesis, mapping and maintenance of mutations, and identification of mutant genes in the mouse. In this mini-review, many of these powerful techniques will be presented along with their application to the study of development, physiology, and disease.
Postural changes in capillary pressure in the hallux of healthy volunteers
Authors: de Graaff Jurgen C. , Ubbink Dirk T. , Lagarde Sjoerd M. , Jacobs Michael J. H. M.
Published: March 2015

Capillary circulation is delicately regulated by microvascular constriction mechanisms, thereby controlling capillary perfusion and transmural pressure. The influence of posture on capillary flow has been investigated in both diseased and healthy people. However, its influence on capillary pressure has rarely been investigated. We measured capillary pressures in the supine and sitting positions in the hallux of healthy volunteers. The capillaries in the eponychium of the hallux were punctured by using a micropipette connected to a micropressure system (900A, WPI). Also, peripheral arterial and venous pressures were measured in both positions. The rise in systolic capillary pressure from supine to sitting position (32 mmHg; from 39 to 71 mmHg, respectively) was significantly ( P < 0.001) smaller than the rise in systolic arterial toe pressure (57 mmHg, from 87 to 144 mmHg, respectively) and venous pressure (41 mmHg, from 26 mmHg to 67 mmHg, respectively). This study shows that the postural rise in precapillary arteriolar pressure is not completely transmitted to the capillaries, probably because of activation of peripheral vasoconstriction mechanisms.
High tidal volume upregulates intrapulmonary cytokines in an in vivo mouse model of ventilator-induced lung injury
Authors: Wilson Michael R. , Choudhury Sharmila , Goddard Michael E. , O'Dea Kieran P. , Nicholson Andrew G. , Takata Masao
Published: March 2015

Mechanical ventilation has been demonstrated to exacerbate lung injury, and a sufficiently high tidal volume can induce injury in otherwise healthy lungs. However, it remains controversial whether injurious ventilation per se, without preceding lung injury, can initiate cytokine-mediated pulmonary inflammation. To address this, we developed an in vivo mouse model of acute lung injury produced by high tidal volume (Vt) ventilation. Anesthetized C57BL6 mice were ventilated at high Vt (34.5 ± 2.9 ml/kg, mean ± SD) for a duration of 156 ± 17 min until mean blood pressure fell below 45 mmHg ( series 1); high Vt for 120 min ( series 2); or low Vt (8.8 ± 0.5 ml/kg) for 120 or 180 min ( series 3). High Vt produced progressive lung injury with a decrease in respiratory system compliance, increase in protein concentration in lung lavage fluid, and lung pathology showing hyaline membrane formation. High-Vt ventilation was associated with increased TNF-α in lung lavage fluid at the early stage of injury ( series 2) but not the later stage ( series 1). In contrast, lavage fluid macrophage inflammatory protein-2 (MIP-2) was increased in all high-Vt animals. Lavage fluid from high-Vt animals contained bioactive TNF-α by WEHI bioassay. Low-Vt ventilation induced minimal changes in physiology and pathology with negligible TNF-α and MIP-2 proteins and TNF-α bioactivity. These results demonstrate that high-Vt ventilation in the absence of underlying injury induces intrapulmonary TNF-α and MIP-2 expression in mice. The apparently transient nature of TNF-α upregulation may help explain previous controversy regarding the involvement of cytokines in ventilator-induced lung injury.
Anion channels influence ECC by modulating L-type Ca2+ channel in ventricular myocytes
Authors: Zhou Shi-Sheng , Gao Zhan , Dong Ling , Ding Yan-Feng , Zhang Xiao-Dong , Wang Yue-Min , Pei Jian-Ming , Gao Feng , Ma Xin-Liang
Published: March 2015

Anion channels are extensively expressed in the heart, but their roles in cardiac excitation-contraction coupling (ECC) are poorly understood. We, therefore, investigated the effects of anion channels on cardiac ventricular ECC. Edge detection, fura 2 fluorescence measurements, and whole cell patch-clamp techniques were used to measure cell shortening, the intracellular Ca2+ transient, and the L-type Ca2+ current ( I Ca,L) in single rat ventricular myocytes. The anion channel blockers 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) and niflumic acid reversibly inhibited the Ca2+ transients and cell shortening in a dose-dependent manner. Comparable results were observed when the majority of the extracellular Cl− was replaced with the relatively impermeant anions glutamate (Glt−) and aspartate (Asp−). NPPB and niflumic acid or the Cl− substitutes did not affect the resting intracellular Ca2+ concentration but significantly inhibited I Ca,L. In contrast, replacement of extracellular Cl− with the permeant anions NO[Formula: see text], SCN−, and Br− supported the ECC and I Ca,L, which were still sensitive to blockade by NPPB. Exposure of cardiac ventricular myocytes to a hypotonic bath solution enhanced the amplitude of cell shortening and supported I Ca,L, whereas hypertonic stress depressed the contraction and I Ca,L. Moreover, cardiac contraction was completely abolished by NPPB (50 μM) under hypotonic conditions. It is concluded that a swelling-activated anion channel may be involved in the regulation of cardiac ECC through modulating L-type Ca2+ channel activity.
Myofascial force transmission between a single muscle head and adjacent tissues: length effects of head III of rat EDL
Authors: Maas Huub , Jaspers Richard T. , Baan Guus C. , Huijing Peter A.
Published: March 2015

Force transmission from muscle fibers via the connective tissue network (i.e., myofascial force transmission) is an important determinant of muscle function. This study investigates the role of myofascial pathways for force transmission from multitendoned extensor digitorum longus (EDL) muscle within an intact anterior crural compartment. Effects of length changes exclusively of head III of rat EDL muscle (EDL III) on myofascial force transmission were assessed. EDL III was lengthened at the distal tendon. For different lengths of EDL III, isometric forces were measured at the distal tendon of EDL III, as well as at the proximal tendon of whole EDL and at the distal tendons of tibialis anterior and extensor hallucis longus (TA+EHL) muscles. Lengthening of EDL III caused high changes in force exerted at the distal tendon of EDL III (from 0 to 1.03 ± 0.07 N). In contrast, only minor changes were found in force exerted at the proximal EDL tendon (from 2.37 ± 0.09 to 2.53 ± 0.10 N). Increasing the length of EDL III decreased TA+EHL force significantly (by 7%, i.e., from 5.62 ± 0.27 to 5.22 ± 0.32 N). These results show that force is transmitted between EDL III and adjacent tissues via myofascial pathways. Optimal force exerted at the distal tendon of EDL III (1.03 ± 0.07 N) was more than twice the force expected on the basis of the physiological cross-sectional area of EDL III muscle fibers (0.42 N). Therefore, a substantial fraction of this force must originate from sources other than EDL III. It is concluded that myofascial pathways play an important role in force transmission from multitendoned muscles.
Decreased nitric oxide- and axon reflex-mediated cutaneous vasodilation with age during local heating
Authors: Minson Christopher T. , Holowatz Lacy A. , Wong Brett J. , Kenney W. Larry , Wilkins Brad W.
Published: March 2015

Cutaneous vasodilation is reduced in healthy older vs. young subjects; however, the mechanisms that underlie these age-related changes are unclear. Our goal in the present study was to determine the role of nitric oxide (NO) and the axon reflexes in the skin blood flow (SkBF) response to local heating with advanced age. We placed two microdialysis fibers in the forearm skin of 10 young (Y; 22 ± 2 yr) and 10 older (O; 77 ± 5 yr) men and women. SkBF over each site was measured by laser-Doppler flowmetry (LDF; Moor DRT4). Both sites were heated to 42°C for ∼60 min while 10 mM N G-nitro-l-arginine methyl ester (l-NAME) was infused throughout the protocol to inhibit NO synthase (NOS) in one site and 10 mM l-NAME was infused after 40 min of local heating in the second site. Data were expressed as a percentage of maximal vasodilation (%CVCmax; 28 mM nitroprusside infusion). Local heating beforel-NAME infusion resulted in a significantly reduced initial peak (Y: 61 ± 2%CVCmax vs. O: 46 ± 4%CVCmax) and plateau (Y: 93 ± 2%CVCmaxvs. O: 82 ± 5%CVCmax) CVC values in older subjects ( P < 0.05). When NOS was inhibited after 40 min of heating, CVC declined to the same value in the young and older groups. Thus the overall contribution of NO to the plateau phase of the SkBF response to local heating was less in the older subjects. The initial peak response was significantly lower in the older subjects in both microdialysis sites (Y: 52 ± 4%CVCmax vs. O: 38 ± 5%CVCmax; P < 0.05). These data suggest that age-related changes in both axon reflex-mediated and NO-mediated vasodilation contribute to attenuated cutaneous vasodilator responses in the elderly.
Mild obesity does not limit change in end-expiratory lung volume during cycling in young women
Authors: Babb T. G. , DeLorey D. S. , Wyrick B. L. , Gardner P. P.
Published: March 2015

To investigate the effects of obesity on the regulation of end-expiratory lung volume (EELV) during exercise we studied nine obese (41 ± 6% body fat and 35 ± 7 yr, mean ± SD) and eight lean (18 ± 3% body fat and 34 ± 4 yr) women. We hypothesized that the simple mass loading of obesity would constrain the decrease in EELV in the supine position and during exercise. All subjects underwent respiratory mechanics measurements in the supine and seated positions, and during graded cycle ergometry to exhaustion. Data were analyzed between groups by independent t-test in the supine and seated postures, and during exercise at ventilatory threshold and peak. Total lung capacity (TLC) was reduced in the obese women ( P < 0.05). EELV was significantly lower in the obese subjects in the supine (37 ± 6 vs. 45 ± 5% TLC) and seated (45 ± 6 vs. 53 ± 5% TLC) positions and at ventilatory threshold (41 ± 4 vs. 49 ± 5% TLC) ( P < 0.01). In conclusion, despite reduced resting lung volumes and alterations in respiratory mechanics during exercise, mild obesity in women does not appear to constrain EELV during cycling nor does it limit exercise capacity. Also, these data suggest that other nonmechanical factors also regulate the level of EELV during exercise.
Interactive effect of hypoxia and otolith organ engagement on cardiovascular regulation in humans
Authors: Monahan Kevin D. , Ray Chester A.
Published: March 2015

We determined the interaction between the vestibulosympathetic reflex and the arterial chemoreflex in 12 healthy subjects. Subjects performed three trials in which continuous recordings of muscle sympathetic nerve activity (MSNA), mean arterial blood pressure (MAP), heart rate (HR), and arterial oxygen saturation were obtained. First, in prone subjects the otolith organs were engaged by use of head-down rotation (HDR). Second, the arterial chemoreflex was activated by inspiration of hypoxic gas (10% O2 and 90% N2) for 7 min with HDR being performed during minute 6. Third, hypoxia was repeated (15 min) with HDR being performed during minute 14. HDR [means ± SE; increase (Δ)7 ± 1 bursts/min and Δ50 ± 11% for burst frequency and total MSNA, respectively; P < 0.05] and hypoxia (Δ6 ± 2 bursts/min and Δ62 ± 29%; P < 0.05) increased MSNA. Additionally, MSNA increased when HDR was performed during hypoxia (Δ11 ± 2 bursts/min and Δ127 ± 57% change from normoxia; P < 0.05). These increases in MSNA were similar to the algebraic sum of the individual increase in MSNA elicited by HDR and hypoxia (Δ13 ± 1 bursts/min and Δ115 ± 36%). Increases in MAP (Δ3 ± 1 mmHg) and HR (Δ19 ± 1 beats/min) during combined HDR and hypoxia generally were smaller ( P < 0.05) than the algebraic sum of the individual responses (Δ5 ± 1 mmHg and Δ24 ± 2 beats/min for MAP and HR, respectively; P < 0.05). These findings indicate an additive interaction between the vestibulosympathetic reflex and arterial chemoreflex for MSNA. Therefore, it appears that MSNA outputs between the vestibulosympathetic reflex and arterial chemoreflex are independent of one another in humans.
Hemodynamic and ventilatory effects of manual respiratory physiotherapy techniques of chest clapping, vibration, and shaking in an animal model
Authors: Wong W. P. , Paratz J. D. , Wilson K. , Burns Y. R.
Published: March 2015

Chest clapping, vibration, and shaking were studied in 10 physiotherapists who applied these techniques on an anesthetized animal model. Hemodynamic variables (such as heart rate, blood pressure, pulmonary artery pressure, and right atrial pressure) were measured during the application of these techniques to verify claims of adverse events. In addition, expired tidal volume and peak expiratory flow rate were measured to ascertain effects of these techniques. Physiotherapists in this study applied chest clapping at a rate of 6.2 ± 0.9 Hz, vibration at 10.5 ± 2.3 Hz, and shaking at 6.2 ± 2.3 Hz. With the use of these rates, esophageal pressure swings of 8.8 ± 5.0, 0.7 ± 0.3, and 1.4 ± 0.7 mmHg resulted from clapping, vibration, and shaking respectively. Variability in rates and “forces” generated by these techniques was <20% in average coefficients of variation. In addition, clinical experience accounted for 76% of the variance in vibration rate ( P = 0.001). Cardiopulmonary physiotherapy experience and layers of towel used explained ∼79% of the variance in clapping force ( P = 0.004), whereas age and clinical experience explained >80% of variance in shaking force ( P = 0.003). Application of these techniques by physiotherapists was found to have no significant effects on hemodynamic and most ventilatory variables in this study. From this study, we conclude that chest clapping, vibration, and shaking 1) can be consistently performed by physiotherapists; 2) are significantly related to physiotherapists' characteristics, particularly clinical experience; and 3) caused no significant hemodynamic effects.
Opposite actions of caffeine and creatine on muscle relaxation time in humans
Authors: Hespel P. , ‘t Eijnde B. Op , Van Leemputte M.
Published: March 2015

The effect of creatine and caffeine supplementation on muscle torque generation and relaxation was investigated in healthy male volunteers. Maximal torque (Tmax), contraction time (CT) from 0.25 to 0.75 of Tmax, and relaxation time (RT) from 0.75 to 0.25 of Tmax were measured during an exercise test consisting of 30 intermittent contractions of musculus quadriceps (2 s stimulation, 2 s rest) that were induced by electrical stimulation. According to a double-blind randomized crossover design, subjects ( n = 10) performed the exercise test before (pretest) and after (posttest) creatine supplementation (Cr, 4 × 5 g/day, 4 days), short-term caffeine intake (Caf, 5 mg · kg−1 · day−1, 3 days), creatine supplementation + short-term caffeine intake (Cr+Caf), acute caffeine intake (ACaf, 5 mg/kg) or placebo. Compared with placebo, Cr shortened RT by ∼5% ( P < 0.05). Conversely, Caf increased RT (+∼10%, P < 0.05), in particular as RT increased because of fatigue. RT was not significantly changed by either Cr+Caf or ACaf. Tmax and CT were similar during all experimental conditions. Initial Tmax was ∼20% of voluntary maximal isometric contraction force, which was not different between treatments. It is concluded that Caf intake (3 days) prolongs muscle RT and by this action overrides the shortening of RT due to creatine supplementation.
Effect of high-intensity training on exercise-induced gene expression specific to ion homeostasis and metabolism
Authors: Nordsborg Nikolai , Bangsbo Jens , Pilegaard Henriette
Published: March 2015

Changes in gene expression during recovery from high-intensity, intermittent, one-legged exercise were studied before and after 5.5 wk of training. Genes related to metabolism, as well as Na+, K+, and pH homeostasis, were selected for analyses. After the same work was performed before and after the training period, several muscle biopsies were obtained from vastus lateralis muscle. In the untrained state, the Na+-K+-ATPase α1-subunit mRNA level was approximately threefold higher ( P < 0.01) at 0, 1, and 3 h after exercise, relative to the preexercise resting level. After 3-5 h of recovery in the untrained state, pyruvate dehydrogenase kinase 4 and hexokinase II mRNA levels were elevated 13-fold ( P < 0.001) and 6-fold ( P < 0.01), respectively. However, after the training period, only pyruvate dehydrogenase kinase 4 mRNA levels were elevated ( P < 0.05) during the recovery period. No changes in resting mRNA levels were observed as a result of training. In conclusion, cellular adaptations to high-intensity exercise training may, in part, be induced by transcriptional regulation. After training, the transcriptional response to an exercise bout at a given workload is diminished.
Cardiovascular effects of the respiratory muscle metaboreflexes in dogs: rest and exercise
Authors: Rodman Joshua R. , Henderson Kathleen S. , Smith Curtis A. , Dempsey Jerome A.
Published: March 2015

In awake dogs, lactic acid was injected into the phrenic and deep circumflex iliac arteries to elicit the diaphragm and abdominal muscle metaboreflexes, respectively. At rest, injections into the phrenic or deep circumflex iliac arteries significantly increased mean arterial blood pressure 21 ± 7% and reduced cardiac output 6 ± 2% and blood flow to the hindlimbs 20 ± 9%. Simultaneously, total systemic, hindlimb, and abdominal expiratory muscle vascular conductances were reduced. These cardiovascular responses were not accompanied by significant changes in the amplitude or timing of the diaphragm electromyogram. During treadmill exercise that increased cardiac output, hindlimb blood flow, and vascular conductance 159 ± 106, 276 ± 309, and 299 ± 90% above resting values, lactic acid injected into the phrenic or deep circumflex iliac arteries also elicited pressor responses and reduced hindlimb blood flow and vascular conductance. Adrenergic receptor blockade at rest eliminated the cardiovascular effects of the respiratory muscle metaboreflex. We conclude that the cardiovascular effects of respiratory muscle metaboreflex activation are similar to those previously reported for limb muscles. When activated via metabolite production, the respiratory muscle metaboreflex may contribute to the increased sympathetic tone and redistribution of blood flow during exercise.
Expression of angiotensin II type 1 (AT1) receptor in the rostral ventrolateral medulla in rats
Authors: Hu Lian , Zhu Da-Nian , Yu Zhang , Wang John Q. , Sun Zhong-Jie , Yao Tai
Published: March 2015

In the present study, the changes of amino acids release in the spinal cord after the application of angiotensin II (ANG II) in the rostral ventrolateral medulla (RVLM) and the distribution of ANG receptors on neurons of the RVLM were investigated. A microdialysis experiment showed that microinjection of angiotensin II into the RVLM significantly ( P < 0.01) increased the release of aspartate and glutamate in the intermediolateral column of the spinal cord. Immunofluorescence technique combined with confocal microscopy demonstrated that most of the glutamatergic and GABAergic neurons in the RVLM of both Wistar and spontaneously hypertensive rats (SHR) were double labeled with ANG type 1 (AT1) receptor. Immunocytochemical studies demonstrated that the mean optic density of AT1 receptor of the cell surface as well as the whole cell was higher ( P < 0.05) in SHR than that in Wistar rats, indicating that the higher expression of AT1 receptors in the RVLM may contribute to the higher responsiveness of SHR to ANG II stimulation. Immunogold staining and electronmicroscopic study demonstrated that AT1 receptor in the RVLM was distributed on the rough endoplasmic reticulum, cell membrane, and nerve processes. The results suggest that effects evoked by ANG II in the RVLM are closely related to glutamatergic and GABAergic pathways. These results indirectly support the hypothesis that ANG II in the RVLM may activate vasomotor sympathetic glutamatergic neurons, leading to an increase in sympathetic nerve activity and arterial blood pressure.
Comparative responses to α,β-methylene-ATP in cat pulmonary, mesenteric, and hindquarter vascular beds
Authors: Bivalacqua Trinity J. , Champion Hunter C. , Shah Mrugeshkumar K. , De Witt Bracken J. , Inscho Edward W. , Kadowitz Philip J.
Published: March 2015

Responses to the P2X-purinoceptor agonist α,β-methylene-ATP (α,β-MeATP) were investigated in the pulmonary, hindquarter, and mesenteric vascular beds in the cat. Under constant-flow conditions, injections of α,β-MeATP caused dose-related increases in perfusion pressure in the pulmonary and hindquarter beds and a biphasic response in the mesenteric circulation. In the pulmonary vascular bed, the order of potency was α,β-MeATP > U-46619 > angiotensin II, whereas, in the hindquarters, the order of potency was angiotensin II > U-46619 > α,β-MeATP. The order of potency was similar in the hindquarter and mesenteric beds when the pressor component of the response to α,β-MeATP was compared with responses to angiotensin II and U-46619. The P2X-receptor antagonist pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid attenuated the pressor response to α,β-MeATP in the hindquarter circulation and the pressor component in the mesenteric vascular bed. Pressor responses to α,β-MeATP were not altered by cyclooxygenase, α-adrenergic, or angiotensin AT1 antagonists. These data show that α,β-MeATP has potent pressor activity in the pulmonary circulation, where it was 100-fold more potent than angiotensin II. In contrast, α,β-MeATP had modest pressor activity in the systemic bed, where it was 1,000-fold less potent than angiotensin II. These data suggest that responses to α,β-MeATP are dependent on the vascular bed studied and may be dependent on the density of P2X receptors in the vascular bed.
Bone resorption is induced on the second day of bed rest: results of a controlled crossover trial
Authors: Baecker Natalie , Tomic Aleksandra , Mika Claudia , Gotzmann Andrea , Platen Petra , Gerzer Rupert , Heer Martina
Published: March 2015

The aim of the study was to analyze the kinetics of short-term changes in bone turnover. We studied in a randomized crossover design the effects of 6 days of bed rest on eight healthy male subjects (mean body wt: 70.1 ± 5.7 kg; mean age: 25.5 ± 2.9 yr). The metabolic ward period was divided into three parts: 4 ambulatory days, 6 days of either bed rest or non-bed rest periods, and 1 recovery day. The diet was identical in both bed rest and non-bed rest phases. Continuous urine collection started on the first day in the metabolic ward to analyze excretion of bone resorption markers, namely C-telopeptide (CTX) and N-telopeptide (NTX), creatinine, urea, and 3-methylhistidine. On the second ambulatory day and on the fifth day of bed rest or during the non-bed rest phase, blood was drawn to analyze bone formation markers and amino acid concentrations. Urinary calcium excretion was increased as early as the first day of bed rest ( P < 0.01). CTX and NTX excretion stayed unchanged during the first 24 h of bed rest compared with the non-bed rest period. However, already on the second day, both resorption markers had increased significantly. NTX excretion increased by 28.7 ± 14.0% ( P < 0.01), whereas CTX excretion rose by 17.8 ± 8.3% ( P < 0.001). Creatinine, urea, and 3-methylhistidine excretion did not change. We conclude that 24 h of bed rest are sufficient to induce a significant rise in osteoclast activity in healthy subjects.
Selected Contribution: Airway contractility and smooth muscle Ca2+ signaling in lung slices from different mouse strains
Authors: Bergner Albrecht , Sanderson Michael J.
Published: March 2015

To investigate the hypothesis that altered Ca2+ signaling in airway smooth muscle cells (SMCs) is responsible for airway hyperreactivity, we compared, with the use of confocal and phase-contrast microscopy, the airway contractility and Ca2+ changes in SMCs induced by acetylcholine (ACh) in lung slices from different mouse strains (A/J, Balb/C, and C3H/ HeJ). The airways from each mouse strain displayed a concentration-dependent contraction to ACh. The contractile response of the airways of the C3H/HeJ mice was found, in contrast to earlier studies, to be much greater and faster than that of A/J and Balb/C mice. This difference in airway reactivity can be, in part, attributable to halothane, a volatile anesthetic that was previously used during in vivo measurements of airway reactivity but found here to significantly alter the ACh contractile response of airways in lung slices. The ACh-induced Ca2+ response of the airway SMCs in all of the various mouse strains was also concentration dependent. The magnitude of the initial Ca2+ increase and the frequency of the subsequent Ca2+ oscillations induced by ACh increased with ACh concentration. However, no differences in the Ca2+ responses to ACh could be distinguished between the mouse strains. These results suggest that the mechanism responsible for airway hyperreactivity in different mouse strains resides with the Ca2+ sensitivity of the contractile apparatus of the SMCs rather than with the Ca2+ signaling itself.
A model for integrative study of human gastric acid secretion
Authors: Joseph Ian M. P. , Zavros Yana , Merchant Juanita L. , Kirschner Denise
Published: March 2015

We have developed a unique virtual human model of gastric acid secretion and its regulation in which food provides a driving force. Food stimulus triggers neural activity in central and enteric nervous systems and G cells to release gastrin, a critical stimulatory hormone. Gastrin stimulates enterochromaffin-like cells to release histamine, which, together with acetylcholine, stimulates acid secretion from parietal cells. Secretion of somatostatin from antral and corpus D cells comprises a negative-feedback loop. We demonstrate that although acid levels are most sensitive to food and nervous system inputs, somatostatin-associated interactions are also important in governing acidity. The importance of gastrin in acid secretion is greatest at the level of transport between the antral and corpus regions. Our model can be applied to study conditions that are not yet experimentally reproducible. For example, we are able to preferentially deplete antral or corpus somatostatin. Depletion of antral somatostatin exhibits a more significant elevation of acid release than depletion of corpus somatostatin. This increase in acid release is likely due to elevated gastrin levels. Prolonged hypergastrinemia has significant effects in the long term (5 days) by promoting enterochromaffin-like cell overgrowth. Our results may be useful in the design of therapeutic strategies for acid secretory dysfunctions such as hyper- and hypochlorhydria.
Increased rate of force development and neural drive of human skeletal muscle following resistance training
Authors: Aagaard Per , Simonsen Erik B. , Andersen Jesper L. , Magnusson Peter , Dyhre-Poulsen Poul
Published: March 2015

The maximal rate of rise in muscle force [rate of force development (RFD)] has important functional consequences as it determines the force that can be generated in the early phase of muscle contraction (0–200 ms). The present study examined the effect of resistance training on contractile RFD and efferent motor outflow (“neural drive”) during maximal muscle contraction. Contractile RFD (slope of force-time curve), impulse (time-integrated force), electromyography (EMG) signal amplitude (mean average voltage), and rate of EMG rise (slope of EMG-time curve) were determined (1-kHz sampling rate) during maximal isometric muscle contraction (quadriceps femoris) in 15 male subjects before and after 14 wk of heavy-resistance strength training (38 sessions). Maximal isometric muscle strength [maximal voluntary contraction (MVC)] increased from 291.1 ± 9.8 to 339.0 ± 10.2 N · m after training. Contractile RFD determined within time intervals of 30, 50, 100, and 200 ms relative to onset of contraction increased from 1,601 ± 117 to 2,020 ± 119 ( P < 0.05), 1,802 ± 121 to 2,201 ± 106 ( P < 0.01), 1,543 ± 83 to 1,806 ± 69 ( P < 0.01), and 1,141 ± 45 to 1,363 ± 44 N · m · s−1( P < 0.01), respectively. Corresponding increases were observed in contractile impulse ( P < 0.01–0.05). When normalized relative to MVC, contractile RFD increased 15% after training (at zero to one-sixth MVC; P < 0.05). Furthermore, muscle EMG increased ( P < 0.01–0.05) 22–143% (mean average voltage) and 41–106% (rate of EMG rise) in the early contraction phase (0–200 ms). In conclusion, increases in explosive muscle strength (contractile RFD and impulse) were observed after heavy-resistance strength training. These findings could be explained by an enhanced neural drive, as evidenced by marked increases in EMG signal amplitude and rate of EMG rise in the early phase of muscle contraction.
Sleep-disordered breathing, pharyngeal size and soft tissue anatomy in children
Authors: Fregosi R. F. , Quan S. F. , Kaemingk K. L. , Morgan W. J. , Goodwin J. L. , Cabrera R. , Gmitro A.
Published: March 2015

We tested the hypothesis that pharyngeal geometry and soft tissue dimensions correlate with the severity of sleep-disordered breathing. Magnetic resonance images of the pharynx were obtained in 18 awake children, 7-12 yr of age, with obstructive apnea-hypopnea index (OAHI) values ranging from 1.81 to 24.2 events/h. Subjects were divided into low-OAHI ( n = 9) and high-OAHI ( n = 9) groups [2.8 ± 0.7 and 13.5 ± 4.9 (SD) P < 0.001]. The OAHI correlated positively with the size of the tonsils ( r2 = 0.42, P = 0.024) and soft palate ( r2 = 0.33, P = 0.049) and inversely with the volume of the oropharyx ( r2 = 0.42, P = 0.038). The narrowest point in the pharyngeal airway was smaller in the high-compared with the low-OAHI group (4.4 ± 1.2 vs. 6.0 ± 1.3 mm; P = 0.024), and this point was in the retropalatal airway in all but two subjects. The airway cross-sectional area (CSA)-airway length relation showed that the high-OAHI group had a narrower retropapatal airway than the low-OAHI group, particularly in the retropalatal region where the soft palate, adenoids, and tonsils overlap ( P = 0.001). The “retropalatal air space,” which we defined as the ratio of the retropalatal airway CSA to the CSA of the soft palate, correlated inversely with the OAHI ( r2 = 0.49, P = 0.001). We conclude that 7- to 12-yr-old children with a narrow retropalatal air space have significantly more apneas and hypopneas during sleep compared with children with relatively unobstructed retropalatal airways.
Effects of rapid saline infusion on lung mechanics and airway responsiveness in humans
Authors: Pellegrino Riccardo , Dellacà Raffaele , Macklem Peter T. , Aliverti Andrea , Bertini Stefania , Lotti Pamela , Agostoni PierGiuseppe , Locatelli Alessandro , Brusasco Vito
Published: March 2015

Lung mechanics and airway responsiveness to methacholine (MCh) were studied in seven volunteers before and after a 20-min intravenous infusion of saline. Data were compared with those of a time point-matched control study. The following parameters were measured: 1-s forced expiratory volume, forced vital capacity, flows at 40% of control forced vital capacity on maximal (V̇m40) and partial (V̇p40) forced expiratory maneuvers, lung volumes, lung elastic recoil, lung resistance (Rl), dynamic elastance (Edyn), and within-breath resistance of respiratory system (Rrs). Rl and Edyn were measured during tidal breathing before and for 2 min after a deep inhalation and also at different lung volumes above and below functional residual capacity. Rrs was measured at functional residual capacity and at total lung capacity. Before MCh, saline infusion caused significant decrements of forced expiratory volume in 1 s, V̇m40, and V̇p40, but insignificantly affected lung volumes, elastic recoil, Rl, Edyn, and Rrs at any lung volume. Furthermore, saline infusion was associated with an increased response to MCh, which was not associated with significant changes in the ratio of V̇m40to V̇p40. In conclusion, mild airflow obstruction and enhanced airway responsiveness were observed after saline, but this was not apparently due to altered elastic properties of the lung or inability of the airways to dilate with deep inhalation. It is speculated that it was likely the result of airway wall edema encroaching on the bronchial lumen.
Nonlinear surface EMG analysis to detect changes of motor unit conduction velocity and synchronization
Authors: Farina Dario , Fattorini Luigi , Felici Francesco , Filligoi Giancarlo
Published: March 2015

Amplitude and frequency content of the surface electromyographic (EMG) signal reflect central and peripheral modifications of the neuromuscular system. Classic surface EMG spectral variables applied to assess muscle functions are the centroid and median power spectral frequencies. More recently, nonlinear tools have been introduced to analyze the surface EMG; among them, the recurrence quantification analysis (RQA) was shown to be particularly promising for the detection of muscle status changes. The purpose of this work was to analyze the effect of motor unit short-term synchronization and conduction velocity (CV) on EMG spectral variables and two variables extracted by RQA, the percentage of recurrence (%Rec) and determinism (%Det). The study was performed on the basis of a simulation model, which allowed changing the degree of synchronization and mean CV of a number of motor units, and of an experimental investigation of the surface EMG signal properties detected during high-force-level isometric fatiguing contractions of the biceps brachii muscle. Simulations and experimental results were largely in agreement and show that 1) spectral variables, %Rec, and %Det are influenced by CV and degree of synchronization; 2) spectral variables are highly correlated with %Det ( R = −0.95 in the simulations and −0.78 and −0.75 for the initial values and normalized slopes, respectively, in the experimental signals), and thus the information they provide on muscle properties is basically the same; and 3) variations of %Det and %Rec in response to changes in muscle properties are significantly larger than the variations of spectral variables. This study validates RQA as a means for fatigue assessment with potential advantages (such as the higher sensitivity to changes of muscle status) with respect to the classic spectral analysis.
Acute pathophysiological effects of muscle-expressed Dp71 transgene on normal and dystrophic mouse muscle
Authors: Wieneke Sascha , Heimann Peter , Leibovitz Sigalit , Nudel Uri , Jockusch Harald
Published: March 2015

products of the dystrophin gene range from the 427-kDa full-length dystrophin to the 70.8-kDa Dp71. Dp427 is expressed in skeletal muscle, where it links the actin cytoskeleton with the extracellular matrix via a complex of dystrophin-associated proteins (DAPs). Dystrophin deficiency disrupts the DAP complex and causes muscular dystrophy in humans and the mdx mouse. Dp71, the major nonmuscle product, consists of the COOH-terminal part of dystrophin, including the binding site for the DAP complex but lacks binding sites for microfilaments. Dp71 transgene (Dp71tg) expressed in mdx muscle restores the DAP complex but does not prevent muscle degeneration. In wild-type (WT) mouse muscle, Dp71tg causes a mild muscular dystrophy. In this study, we tested, using isolated extensor digitorum longus muscles, whether Dp71tg exerts acute influences on force generation and sarcolemmal stress resistance. In WT muscles, there was no effect on isometric twitch and tetanic force generation, but with a cytomegalovirus promotor-driven transgene, contraction with stretch led to sarcolemmal ruptures and irreversible loss of tension. In MDX muscle, Dp71tg reduced twitch and tetanic tension but did not aggravate sarcolemmal fragility. The adverse effects of Dp71 in muscle are probably due to its competition with dystrophin and utrophin (in MDX muscle) for binding to the DAP complex.
Cutaneous active vasodilation in humans during passive heating postexercise
Authors: Kenny Glen P. , Périard Julien , Journeay W. Shane , Sigal Ronald J. , Reardon Francis D.
Published: March 2015

The hypothesis that exercise causes an increase in the postexercise esophageal temperature threshold for onset of cutaneous vasodilation through an alteration of active vasodilator activity was tested in nine subjects. Increases in forearm skin blood flow and arterial blood pressure were measured and used to calculate cutaneous vascular conductance at two superficial forearm sites: one with intact α-adrenergic vasoconstrictor activity (untreated) and one infused with bretylium tosylate (bretylium treated). Subjects remained seated resting for 15 min (no-exercise) or performed 15 min of treadmill running at either 55, 70, or 85% of peak oxygen consumption followed by 20 min of seated recovery. A liquid-conditioned suit was used to increase mean skin temperature (∼4.0°C/h), while local forearm temperature was clamped at 34°C, until cutaneous vasodilation. No differences in the postexercise threshold for cutaneous vasodilation between untreated and bretylium-treated sites were observed for either the no-exercise or exercise trials. Exercise resulted in an increase in the postexercise threshold for cutaneous vasodilation of 0.19 ± 0.01, 0.39 ± 0.02, and 0.53 ± 0.02°C above those of the no-exercise resting values for the untreated site ( P < 0.05). Similarly, there was an increase of 0.20 ± 0.01, 0.37 ± 0.02, and 0.53 ± 0.02°C for the treated site for the 55, 70, and 85% exercise trials, respectively ( P < 0.05). It is concluded that reflex activity associated with the postexercise increase in the onset threshold for cutaneous vasodilation is more likely mediated through an alteration of active vasodilator activity rather than through adrenergic vasoconstrictor activity.