Journal of Applied Physiology current issue

Noninvasive ventilation in neonates: the lungs don't like it!

Andrade, F. H. — 2008-11-04

Found in translation: the dependence of oxygen uptake kinetics on O2 delivery and O2 utilization

Burnley, M. — 2008-11-04

Role of respiratory control mechanisms in the pathogenesis of obstructive sleep disorders

Younes, M. — 2008-11-04

Obstructive sleep disorders develop when the normal reduction in pharyngeal dilator activity at sleep onset occurs in an individual whose pharynx requires a relatively high level of dilator activity to remain sufficiently open. They range from steady snoring, to slowly evolving hypopneas, to fast-recurring obstructive hypopneas and apneas. A fundamental observation is that the polysomnographic picture differs substantially among subjects with the same pharyngeal collapsibility, and even in the same subject at different times, indicating that the type and severity of the disorder is determined to a large extent by the individual's response to the obstruction. The present report reviews the various mechanisms involved in the response to sleep-induced obstructive events. When the obstructive event takes the form of mild-moderate flow limitation, compensation can take place through an increase in the fraction of time spent in inspiration (Ti/Ttot) without any increase in maximum flow (V_MAX). With more severe obstructions, V_MAX must increase. Recent data indicate that the obstructed upper airway can reopen reflexly, without arousal, if chemical drive is allowed to reach a threshold (T_ER) but that this is often preempted by a low arousal threshold. The relation between T_ER and arousal threshold, as well as the lung-to-carotid circulation time and the rate of rise of chemical drive during the obstructive event, determine the magnitude of ventilatory overshoot at the end of an event and, by extension, whether initial obstructive events will be followed by stable breathing, slow evolving hypopneas with occasional arousals, or repetitive events.

Mechanisms of active laryngeal closure during noninvasive intermittent positive pressure ventilation in nonsedated lambs

2008-11-04

The present study stems from our recent demonstration (Moreau-Bussiere F, Samson N, St-Hilaire M, Reix P, Lafond JR, Nsegbe E, Praud JP. J Appl Physiol 102: 2149–2157, 2007) that a progressive increase in nasal intermittent positive pressure ventilation (nIPPV) leads to active glottal closure in nonsedated, newborn lambs. The aim of the study was to determine whether the mechanisms involved in this glottal narrowing during nIPPV originate from upper airway receptors and/or from bronchopulmonary receptors. Two groups of newborn lambs were chronically instrumented for polysomnographic recording: the first group of five lambs underwent a two-step bilateral thoracic vagotomy using video-assisted thoracoscopic surgery (bilateral vagotomy group), while the second group, composed of six lambs, underwent chronic laryngotracheal separation (isolated upper airway group). A few days later, polysomnographic recordings were performed to assess glottal muscle electromyography during step increases in nIPPV (volume control mode). Results show that active glottal narrowing does not develop when nIPPV is applied on the upper airways only, and that this narrowing is prevented by bilateral vagotomy when nIPPV is applied on intact airways. In conclusion, active glottal narrowing in response to increasing nIPPV originates from bronchopulmonary receptors.

Effect of eccentric exercise-induced muscle damage on the dynamics of muscle oxygenation and pulmonary oxygen uptake

2008-11-04

Unaccustomed eccentric exercise has a profound impact on muscle structure and function. However, it is not known whether associated microvascular dysfunction disrupts the matching of O₂ delivery (Qo₂) to O₂ utilization (Vo₂). Near-infrared spectroscopy (NIRS) was used to test the hypothesis that eccentric exercise-induced muscle damage would elevate the muscle Qo₂:Vo₂ ratio during severe-intensity exercise while preserving the speed of the Vo₂ kinetics at exercise onset. Nine physically active men completed "step" tests to severe-intensity exercise from an unloaded baseline on a cycle ergometer before (Pre) and 48 h after (Post) eccentric exercise (100 squats with a load corresponding to 70% of body mass). NIRS and breath-by-breath pulmonary Vo₂ were measured continuously during the exercise tests and subsequently modeled using standard nonlinear regression techniques. There were no changes in phase II pulmonary Vo₂ kinetics following the onset of exercise (time constant: Pre, 25 ± 4 s; Post, 24 ± 2 s; amplitude: Pre, 2.36 ± 0.23 l/min; Post, 2.37 ± 0.23 l/min; all P > 0.05). However, the primary (Pre, 14 ± 3 s; Post, 19 ± 3 s) and overall (Pre, 16 ± 4 s; Post, 21 ± 4 s) mean response time of the [HHb] response was significantly slower following eccentric exercise (P < 0.05). The slower [HHb] kinetics observed following eccentric exercise is consistent with an increased Qo₂:Vo₂ ratio during transitions to severe-intensity exercise. We propose that unchanged primary phase Vo₂ kinetics are associated with an elevated Qo₂:Vo₂ ratio that preserves blood-myocyte O₂ flux.

Differential attenuation of AMPK activation during acute exercise following exercise training or AICAR treatment

2008-11-04

Short-term exercise training in humans attenuates AMP-activated protein kinase (AMPK) activation during subsequent exercise conducted at the same absolute workload. Short-term 5-aminoimidazole-4-carboxyamide- ribonucleoside (AICAR) administration in rats mimics exercise training on skeletal muscle in terms of increasing insulin sensitivity, mitochondrial enzymes, and GLUT4 content, but it is not known whether these adaptations are accompanied by reduced AMPK activation during subsequent exercise. We compared the effect of 10 days of treadmill training (60 min/day) with 10 days of AICAR administration (0.5 mg/g body weight ip) on subsequent AMPK activation during 45 min of treadmill exercise in male Sprague-Dawley rats. Compared with nonexercised control rats, acute exercise significantly (P < 0.05) increased AMPK Thr¹⁷² phosphorylation (p-AMPK; 1.6-fold) and ACCβ Ser²¹⁸ phosphorylation (p-ACCβ; 4.9-fold) in the soleus and p-ACCβ 2.2-fold in the extensor digitorum longus. Ten days of exercise training abolished the increase in soleus p-AMPK and attenuated the increase in p-ACCβ (nonsignificant 2-fold increase). Ten days of AICAR administration also attenuated the exercise-induced increases in AMPK signaling in the soleus although not as effectively as 10 days of exercise training (nonsignificant 1.3-fold increase in p-AMPK; significant 3-fold increase in p-ACCβ). The increase in skeletal muscle 2-deoxyglucose uptake during exercise was greater after either 10 days of exercise training or AICAR administration. In conclusion, 10 days of AICAR administration substantially mimics the effect of 10 days training on attenuating skeletal muscle AMPK activation in response to subsequent exercise.

Humans adjust control to initial squat depth in vertical squat jumping

Bobbert, M. F., Casius, L. J. R., Sijpkens, I. W. T., Jaspers, R. T. — 2008-11-04

The purpose of this study was to gain insight into the control strategy that humans use in jumping. Eight male gymnasts performed vertical squat jumps from five initial postures that differed in squat depth (P1–P5) while kinematic data, ground reaction forces, and electromyograms (EMGs) of leg muscles were collected; the latter were rectified and smoothed to obtain SREMGs. P3 was the preferred initial posture; in P1, P2, P4, and P5 height of the mass center was +13, +7, –7 and –14 cm, respectively, relative to that in P3. Furthermore, maximum-height jumps from the initial postures observed in the subjects were simulated with a model comprising four body segments and six Hill-type muscles. The only input was the onset of stimulation of each of the muscles (Stim). The subjects were able to perform well-coordinated squat jumps from all postures. Peak SREMG levels did not vary among P1–P5, but SREMG onset of plantarflexors occurred before that of gluteus maximus in P1 and >90 ms after that in P5 (P < 0.05). In the simulation study, similar systematic shifts occurred in Stim onsets across the optimal control solutions for jumps from P1–P5. Because the adjustments in SREMG onsets to initial posture observed in the subjects were very similar to the adjustments in optimal Stim onsets of the model, it was concluded that the SREMG adjustments were functional, in the sense that they contributed to achieving the greatest jump height possible from each initial posture. For the model, we were able to develop a mapping from initial posture to Stim onsets that generated successful jumps from P1–P5. It appears that to explain how subjects adjust their control to initial posture there is no need to assume that the brain contains an internal dynamics model of the musculoskeletal system.

Predicting diffusive alveolar oxygen transfer from carbon monoxide-diffusing capacity in exercising foxhounds

Hsia, C. C. W., Wagner, P. D., Dane, D. M., Wagner, H. E., Johnson, R. L. — 2008-11-04

Although lung diffusing capacity for carbon monoxide (Dl_CO) is a widely used test of diffusive O₂ transfer, few studies have directly related Dl_CO to O₂-diffusing capacity (Dl_O₂); none has used the components of Dl_CO, i.e., conductance of alveolar membrane and capillary blood, to predict Dl_O₂ from rest to exercise. To understand the relationship between Dl_CO and Dl_O₂ at matched levels of cardiac output, we analyzed cumulative data from rest to heavy exercise in 43 adult dogs, with normal lungs or reduced lung capacity following lung resection, that were studied by two techniques. 1) A rebreathing (RB) technique was used to measure Dl_CO and pulmonary blood flow at two O₂ tensions, independent of O₂ exchange. Dl_CO was partitioned into CO-diffusing capacity of alveolar membrane and pulmonary capillary blood volume using the Roughton-Forster equation and converted into an equivalent Dl_O₂, [Dl_O₂(RB)]. 2) A multiple inert-gas elimination technique (MIGET) was used to measure ventilation-perfusion distributions, O₂ and CO₂ exchange under hypoxia, to derive Dl_O₂ [Dl_O₂(MIGET)] by the Lilienthal-Riley technique and Bohr integration. For direct comparisons, Dl_O₂(RB) was interpolated to the cardiac output measured by the Fick principle corresponding to Dl_O₂(MIGET). The Dl_O₂-to-Dl_CO ratio averaged 1.61. Correlation between Dl_O₂(RB) and Dl_O₂(MIGET) was similar in normal and post-resection groups. Overall, Dl_O₂(MIGET) = 0.975 Dl_O₂(RB); mean difference between the two techniques was under 5% for both animal groups. We conclude that, despite various uncertainties inherent in these two disparate methods, the Roughton-Forster equation adequately predicts diffusive O₂ transfer from rest to heavy exercise in canines with normal, as well as reduced, lung capacities.

Cardiovascular dynamics in healthy subjects with differing heart rate responses to tilt

2008-11-04

Orthostatic stress such as head-up tilt (HUT) elicits a wide range of heart rate (HR) and arterial pressure (AP) responses among healthy individuals. In this study, we evaluated cardiovascular dynamics in healthy subjects with different HR responses to HUT, but without autonomic dysfunction. We measured AP (brachial artery) and HR (ECG) during 5 min of 60° HUT in 76 healthy normotensive individuals. We then chose individuals on the basis of the extremes of HR responses to HUT (high = HR ≥ 20 beats/min, and low = HR ≤ 10 beats/min; n = 15 per group). Peak HR during HUT was 87 ± 10 beats/min in the high and 69 ± 14 beats/min in the low group (P < 0.05). High HR responders had lower systolic pressure at baseline (121 ± 9 vs. 129 ± 11 mmHg, P < 0.05) and during HUT (120 ± 10 vs. 131 ± 13 mmHg, P < 0.05), and higher plasma norepinephrine (NE) response to HUT (NE: 156.9 ± 17.8 vs. 89.0 ± 17.2 pg/ml; P < 0.05). NE during HUT was also significantly correlated with HR when all 76 subjects were included in a regression analysis (r = 0.39; P < 0.001). Pulse pressure was lower during HUT in high HR responders compared with low HR responders (45 ± 1 vs. 55 ± 2 mmHg, P < 0.05). High HR responders also had larger fluctuations in systolic and pulse pressure during HUT (coefficient of variation = 10.7 ± 0.7 vs. 5.7 ± 0.3%; 7.9 ± 0.5 vs. 4.1 ± 0.4%, respectively, P < 0.05). Sex distribution was different between groups (high: 5 women, 10 men; low: 10 women, 5 men). Higher HR with lower AP during HUT is consistent with normal baroreflex mechanisms of integration. Although interindividual variability appears to be a fundamental part of cardiovascular regulation, the mechanisms of these differences and the sex discrepancy requires further investigation.

Changes in muscle size and MHC composition in response to resistance exercise with heavy and light loading intensity

2008-11-04

Muscle mass accretion is accomplished by heavy-load resistance training. The effect of light-load resistance exercise has been far more sparsely investigated with regard to potential effect on muscle size and contractile strength. We applied a resistance exercise protocol in which the same individual trained one leg at 70% of one-repetition maximum (1RM) (heavy load, HL) while training the other leg at 15.5% 1RM (light load, LL). Eleven sedentary men (age 25 ± 1 yr) trained for 12 wk at three times/week. Before and after the intervention muscle hypertrophy was determined by magnetic resonance imaging, muscle biopsies were obtained bilaterally from vastus lateralis for determination of myosin heavy chain (MHC) composition, and maximal muscle strength was assessed by 1RM testing and in an isokinetic dynamometer at 60°/s. Quadriceps muscle cross-sectional area increased (P < 0.05) 8 ± 1% and 3 ± 1% in HL and LL legs, respectively, with a greater gain in HL than LL (P < 0.05). Likewise, 1RM strength increased (P < 0.001) in both legs (HL: 36 ± 5%, LL: 19 ± 2%), albeit more so with HL (P < 0.01). Isokinetic 60°/s muscle strength improved by 13 ± 5% (P < 0.05) in HL but remained unchanged in LL (4 ± 5%, not significant). Finally, MHC IIX protein expression was decreased with HL but not LL, despite identical total workload in HL and LL. Our main finding was that LL resistance training was sufficient to induce a small but significant muscle hypertrophy in healthy young men. However, LL resistance training was inferior to HL training in evoking adaptive changes in muscle size and contractile strength and was insufficient to induce changes in MHC composition.

Skeletal muscle adaptation and performance responses to once a day versus twice every second day endurance training regimens

2008-11-04

We determined the effects of a cycle training program in which selected sessions were performed with low muscle glycogen content on training capacity and subsequent endurance performance, whole body substrate oxidation during submaximal exercise, and several mitochondrial enzymes and signaling proteins with putative roles in promoting training adaptation. Seven endurance-trained cyclists/triathletes trained daily (High) alternating between 100-min steady-state aerobic rides (AT) one day, followed by a high-intensity interval training session (HIT; 8 x 5 min at maximum self-selected effort) the next day. Another seven subjects trained twice every second day (Low), first undertaking AT, then 1–2 h later, the HIT. These training schedules were maintained for 3 wk. Forty-eight hours before and after the first and last training sessions, all subjects completed a 60-min steady-state ride (60SS) followed by a 60-min performance trial. Muscle biopsies were taken before and after 60SS, and rates of substrate oxidation were determined throughout this ride. Resting muscle glycogen concentration (412 ± 51 vs. 577 ± 34 µmol/g dry wt), rates of whole body fat oxidation during 60SS (1,261 ± 247 vs. 1,698 ± 174 µmol·kg^–1·60 min^–1), the maximal activities of citrate synthase (45 ± 2 vs. 54 ± 1 mmol·kg dry wt^–1·min^–1), and β-hydroxyacyl-CoA-dehydrogenase (18 ± 2 vs. 23 ± 2 mmol·kg dry wt^–1·min^–1) along with the total protein content of cytochrome c oxidase subunit IV were increased only in Low (all P < 0.05). Mitochondrial DNA content and peroxisome proliferator-activated receptor- coactivator-1 protein levels were unchanged in both groups after training. Cycling performance improved by ~10% in both Low and High. We conclude that compared with training daily, training twice every second day compromised high-intensity training capacity. While selected markers of training adaptation were enhanced with twice a day training, the performance of a 1-h time trial undertaken after a 60-min steady-state ride was similar after once daily or twice every second day training programs.

Aging increases upper airway collapsibility in Fischer 344 rats

Ray, A. D., Ogasa, T., Magalang, U. J., Krasney, J. A., Farkas, G. A. — 2008-11-04

The upper airway muscles play an important role in maintaining upper airway collapsibility, and the incidence of sleep-disordered breathing increases with age. We hypothesize that the increase in airway collapsibility with increasing age can be linked to changes in upper airway muscle mechanics and structure. Eight young (Y: 6 mo) and eight old (O: 30 mo) Fischer 344 rats were anesthetized and mechanically ventilated, and the pharyngeal pressure associated with flow limitation (Pcrit) was measured 1) with the hypoglossal (cnXII) nerve intact, 2) following bilateral cnXII denervation, and 3) during cnXII stimulation. With the cnXII intact, the upper airways of older rats were more collapsible compared with their younger counterparts [Pcrit = –7.1 ± 0.6 (SE) vs. –9.5 ± 0.7 cmH₂O, respectively; P = 0.033]. CnXII denervation resulted in an increase in Pcrit such that Pcrit became similar in both groups (O: –4.2 ± 0.5 cmH₂O; Y: –5.4 ± 0.5 cmH₂O). In all rats, cnXII stimulation decreased Pcrit (less collapsible) in both groups (O: –11.3 ± 1.0 cmH₂O; Y: –10.2 ± 1.0 cmH₂O). The myosin heavy chain composition of the genioglossus muscle demonstrated a decrease in the percentage of the IIb isoform (38.3 ± 2.5 vs. 21.7 ± 1.7%; P < 0.001); in contrast, the sternohyoid muscle demonstrated an increase in the percentage of the IIb isoform (72.2 ± 2.5 vs. 58.4 ± 2.3%; P = 0.001) with age. We conclude that the upper airway becomes more collapsible with age and that the increase in upper airway collapsibility with age is likely related to altered neural control rather than to primary alterations in upper airway muscle structure and function.

Pulmonary gas exchange response to exercise- and mannitol-induced bronchoconstriction in mild asthma

2008-11-04

Both exercise (EIB) and mannitol challenges were performed in asthmatic patients to assess and compare their pulmonary gas exchange responses for an equivalent degree of bronchoconstriction. In 11 subjects with EIB [27 ± 4 (SD) yr; forced expiratory volume in 1 s (FEV₁), 86 ± 8% predicted], ventilation-perfusion (Va/Q) distributions (using multiple inert gas elimination technique) were measured 5, 15, and 45 min after cycling exercise (FEV₁ fall, 35 ± 12%) and after mannitol (33 ± 10%), 1 wk apart. Five minutes after EIB, minute ventilation (Ve; by 123 ± 60%), cardiac output (Qt, by 48 ± 29%), and oxygen uptake (Vo₂; by 54 ± 25%) increased, whereas arterial Po₂ (Pa_O₂; by 14 ± 11 Torr) decreased due to moderate Va/Q imbalance, assessed by increases in dispersions of pulmonary blood flow (log SD_Q; by 0.53 ± 0.16) and alveolar ventilation (log SD_V; by 0.28 ± 0.15) (dimensionless) (P < 0.01 each). In contrast, for an equivalent degree of bronchoconstriction and minor increases in Ve, Qt, and Vo₂, mannitol decreased Pa_O₂ more intensely (by 24 ± 9 Torr) despite fewer disturbances in log SDQ (by 0.27 ± 0.12). Notwithstanding, mannitol-induced increase in log SDV at 5 min (by 0.35 ± 0.15) was similar to that observed during EIB, as was the slow recovery in log SD_V and high Va/Q ratio areas, at variance with the faster recovery of log SD_Q and low Va/Q ratio areas. In asthmatic individuals, EIB provokes more Va/Q imbalance but less hypoxemia than mannitol, primarily due to postexercise increases in Ve and Qt benefiting Pa_O₂. Va/Q inequalities during both challenges most likely reflect uneven airway narrowing and blood flow redistribution generating distinctive Va/Q patterns, including the development of areas with low and high Va/Q ratios.

ACTN3 genotype is associated with muscle phenotypes in women across the adult age span

Walsh, S., Liu, D., Metter, E. J., Ferrucci, L., Roth, S. M. — 2008-11-04

The R577X polymorphism in the -actinin-3 encoding gene (ACTN3) has been associated with elite athletic performance, and recently with differences in isometric and dynamic muscle strength and power in the general population. In this study we sought to determine the association of ACTN3 R577X genotype with muscle strength and mass phenotypes in men and women across the adult age span. Eight hundred forty-eight (n = 848) adult volunteers (454 men and 394 women) aged 22–90 yr were genotyped for ACTN3 R577X. Knee extensor (KE) shortening and lengthening peak torque values were determined using isokinetic dynamometry and fat-free mass (FFM) by dual-energy X-ray absorptiometry. Women deficient in -actinin-3 (X/X; n = 53) displayed lower KE shortening peak torque (30°/s: 89.5 ± 3.5 vs. 99.3 ± 1.4 N·m, P = 0.011; 180°/s: 60.3 ± 2.6 vs. 67.0 ± 1.0 N·m, P = 0.019) and KE lengthening peak torque (30°/s: 122.8 ± 5.7 vs. 137.0 ± 2.2 N·m, P = 0.022; 180°/s: 121.8 ± 5.8 vs. 138.5 ± 2.2 N·m, P = 0.008) compared with R/X + R/R women (n = 341). Women X/X homozygotes also displayed lower levels of both total body FFM (38.9 ± 0.5 vs. 40.1 ± 0.2 kg, P = 0.040) and lower limb FFM (11.9 ± 0.2 vs. 12.5 ± 0.1 kg, P = 0.044) compared with R/X + R/R women. No genotype-related differences were observed in men. In conclusion, our results indicate that the absence of -actinin-3 protein (i.e., ACTN3 X/X genotype) influences KE peak torque and FFM in women but not men.

Effect of oxygen and heliox breathing on air bubbles in adipose tissue during 25-kPa altitude exposures

Randsoe, T., Kvist, T. M., Hyldegaard, O. — 2008-11-04

At altitude, bubbles are known to form and grow in blood and tissues causing altitude decompression sickness. Previous reports indicate that treatment of decompression sickness by means of oxygen breathing at altitude may cause unwanted bubble growth. In this report we visually followed the in vivo changes of micro air bubbles injected into adipose tissue of anesthetized rats at 101.3 kPa (sea level) after which they were decompressed from 101.3 kPa to and held at 25 kPa (10,350 m), during breathing of oxygen or a heliox(34:66) mixture (34% helium and 66% oxygen). Furthermore, bubbles were studied during oxygen breathing preceded by a 3-h period of preoxygenation to eliminate tissue nitrogen before decompression. During oxygen breathing, bubbles grew from 11 to 198 min (mean: 121 min, ±SD 53.4) after which they remained stable or began to shrink slowly. During heliox breathing bubbles grew from 30 to 130 min (mean: 67 min, ±SD 31.0) from which point they stabilized or shrank slowly. No bubbles disappeared during either oxygen or heliox breathing. Preoxygenation followed by continuous oxygen breathing at altitude caused most bubbles to grow from 19 to 179 min (mean: 51 min, ±SD 47.7) after which they started shrinking or remained stable throughout the observation period. Bubble growth time was significantly longer during oxygen breathing compared with heliox breathing and preoxygenated animals. Significantly more bubbles disappeared in preoxygenated animals compared with oxygen and heliox breathing. Preoxygenation enhanced bubble disappearance compared with oxygen and heliox breathing but did not prevent bubble growth. The results indicate that oxygen breathing at 25 kPa promotes air bubble growth in adipose tissue regardless of the tissue nitrogen pressure.

Effects of physical activity on strength and skeletal muscle fat infiltration in older adults: a randomized controlled trial

2008-11-04

Considerable evidence suggests that the loss of strength and muscle mass appear to be inevitable consequences of aging. Moreover, aging is associated with an increase in body fat. This study examined whether increased physical activity could prevent or reverse the losses of strength and skeletal muscle mass as well as the gain in fat in older adults. Eleven men and 31 women completed a randomized trial consisting of either a physical activity (PA; n = 22) or successful aging health educational control (SA; n = 20) group. Isokinetic knee extensor strength and computed tomography-derived midthigh skeletal muscle and adipose tissue cross-sectional areas (CSA) were assessed at baseline and at 12 mo following randomization. Total body weight and muscle CSA decreased in both groups, but these losses were not different between groups. Strength adjusted for muscle mass decreased (–20.1 ± 9.3%, P < 0.05) in SA. The loss of strength was completely prevented in PA (+2.5 ± 8.3%). In addition, there was a significant increase (18.4 ± 6.0%) in muscle fat infiltration in SA, but this gain was nearly completely prevented in PA (2.3 ± 5.7%). In conclusion, regular physical activity prevents both the age-associated loss of muscle strength and increase in muscle fat infiltration in older adults with moderate functional limitations.

Nitric oxide inhibits cutaneous vasoconstriction to exogenous norepinephrine

Shibasaki, M., Low, D. A., Davis, S. L., Crandall, C. G. — 2008-11-04

Previously, we found that nitric oxide (NO) inhibits cutaneous vasoconstrictor responsiveness evoked by whole body cooling, as well as an orthostatic stress in the heat-stressed human (Shibasaki M, Durand S, Davis SL, Cui J, Low DA, Keller DM, Crandall CG. J Physiol 585: 627–634, 2007). However, it remains unknown whether this response occurs via NO acting through presynaptic or postsynaptic mechanisms. The aim of this study was to test the hypothesis that NO is capable of impairing cutaneous vasoconstriction via postsynaptic mechanisms. Skin blood flow was monitored over two forearm sites where intradermal microdialysis membranes were previously placed. Skin blood flow was elevated four- to fivefold through perfusion of the NO donor sodium nitroprusside at one site and through perfusion of adenosine (primarily non-NO mechanisms) at a second site. Once a plateau in vasodilation was evident, increasing concentrations of norepinephrine (1 x 10^–8 to 1 x 10^–2 M) were administrated through both microdialysis probes, while the aforementioned vasodilator agents continued to be perfused. Cutaneous vascular conductance was calculated by dividing skin blood flow by mean arterial blood pressure. The administration of norepinephrine decreased cutaneous vascular conductance at both sites. However, the dose of norepinephrine at the onset of vasoconstriction (–5.9 ± 1.3 vs. –7.2 ± 0.7 log M norepinephrine, P = 0.021) and the concentration of norepinephrine resulting in 50% of the maximal vasoconstrictor response (–4.9 ± 1.2 vs. –6.1 ± 0.2 log M norepinephrine dose; P = 0.012) occurred at significantly higher norepinephrine concentrations for the sodium nitroprusside site relative to the adenosine site, respectively. These results suggested that NO is capable of attenuating cutaneous vasoconstrictor responsiveness to norepinephrine via postsynaptic mechanisms.

Effect of hypohydration on hyperthermic hyperpnea and cutaneous vasodilation during exercise in men

Fujii, N., Honda, Y., Hayashi, K., Kondo, N., Nishiyasu, T. — 2008-11-04

We tested the hypothesis that, in humans, hypohydration attenuates hyperthermic hyperpnea during exercise in the heat. On two separate occasions, thirteen male subjects performed a fluid replacement (FR) and a no-fluid replacement (NFR) trial in random order. The subjects performed two bouts of cycle exercise (Ex1 and Ex2, 30–60 min) at 50% peak oxygen uptake (Vo_{2 peak}) in 35°C separated by a 70- to 80-min rest period, during which they drank water containing 25 mosmol/l sodium in the FR trial but not the NFR trial. The drinking in the FR trial nearly restored the body fluid to the euhydrated condition, so that the body fluid status differed between the trials before Ex2 (the difference in plasma osmolality before Ex2 was 9.4 mosmol/kgH₂O; plasma volume was 7.6%, and body weight was 2.5%). The slopes of the linear relationships between ventilatory variables (minute ventilation, ventilatory equivalents for oxygen uptake and carbon dioxide output, tidal volume, respiratory frequency, and end-tidal CO₂ pressure) and esophageal temperature (T_es) did not significantly differ between Ex1 and Ex2, or between the FR and NFR trials. On the other hand, during Ex2 in the NFR trial, the T_es threshold for the onset of increased forearm vascular conductance (FVC) was higher, and the slope and peak values of the relationship between FVC and T_es were lower than during Ex1 in the NFR trial and during Ex2 in the FR trial. These findings suggest that hypohydration does not affect the hyperthermic hyperpnea during exercise, although it markedly attenuates the cutaneous vasodilatory response.

Fat adaptation followed by carbohydrate restoration increases AMPK activity in skeletal muscle from trained humans

2008-11-04

We have previously reported that 5 days of a high-fat diet followed by 1 day of high-carbohydrate intake (Fat-adapt) increased rates of fat oxidation and decreased rates of muscle glycogenolysis during submaximal cycling compared with consumption of an isoenergetic high-carbohydrate diet (HCHO) for 6 days (Burke et al. J Appl Physiol 89: 2413–2421, 2000; Stellingwerff et al. Am J Physiol Endocrinol Metab 290: E380–E388, 2006). To determine potential mechanisms underlying shifts in substrate selection, eight trained subjects performed Fat-adapt and HCHO. On day 7, subjects performed 1-h cycling at 70% peak O₂ uptake. Muscle biopsies were taken immediately before and after exercise. Resting muscle glycogen content was similar between treatments, but muscle triglyceride levels were higher after Fat-adapt (P < 0.05). Resting AMPK-₁ and -₂ activity was higher after Fat-adapt (P = 0.02 and P = 0.05, respectively), while the phosphorylation of AMPK's downstream target, acetyl-CoA carboxylase (pACC at Ser²²¹), tended to be elevated after Fat-adapt (P = 0.09). Both the respiratory exchange ratio (P < 0.01) and muscle glycogen utilization (P < 0.05) were lower during exercise after Fat-adapt. Exercise increased AMPK-₁ activity after HCHO (P = 0.03) but not Fat-adapt. Exercise was associated with an increase in pACC at Ser²²¹ for both dietary treatments (P < 0.05), with postexercise pACC Ser²²¹ higher after Fat-adapt (P = 0.02). In conclusion, compared with HCHO, Fat-adapt increased resting muscle triglyceride stores and resting AMPK-₁ and -₂ activity. Fat-adapt also resulted in higher rates of whole body fat oxidation, reduced muscle glycogenolysis, and attenuated the exercise-induced rise in AMPK-₁ and AMPK-₂ activity compared with HCHO. Our results demonstrate that AMPK-₁ and AMPK-₂ activity and fuel selection in skeletal muscle in response to exercise can be manipulated by diet and/or the interactive effects of diet and exercise training.

Corticospinal-evoked responses in lower limb muscles during voluntary contractions at varying strengths

Oya, T., Hoffman, B. W., Cresswell, A. G. — 2008-11-04

This study investigated corticospinal-evoked responses in lower limb muscles during voluntary contractions at varying strengths. Similar investigations have been made on upper limb muscles, where evoked responses have been shown to increase up to ~50% of maximal force and then decline. We elicited motor-evoked potentials (MEPs) and cervicomedullary motor-evoked potentials (CMEPs) in the soleus (Sol) and medial gastrocnemius (MG) muscles using magnetic stimulation over the motor cortex and cervicomedullary junction during voluntary plantar flexions with the torque ranging from 0 to 100% of a maximal voluntary contraction. Differences between the MEP and CMEP were also investigated to assess whether any changes were occurring at the cortical or spinal levels. In both Sol and MG, MEP and CMEP amplitudes [normalized to maximal M wave (M_max)] showed an increase, followed by a plateau, over the greater part of the contraction range with responses increasing from ~0.2 to ~6% of M_max for Sol and from ~0.3 to ~10% of M_max for MG. Because both MEPs and CMEPs changed in a similar manner, the observed increase and lack of decrease at high force levels are likely related to underlying changes occurring at the spinal level. The evoked responses in the Sol and MG increase over a greater range of contraction strengths than for upper limb muscles, probably due to differences in the pattern of motor unit recruitment and rate coding for these muscles and the strength of the corticospinal input.

Observations on the physiological interactions between obesity and asthma

2008-11-04

To explore whether asthma and obesity share overlapping pathogenic features, we examined the impact of each alone, and in combination, on multiple aspects of lung function. We reasoned that if they influenced the lungs through similar mechanisms, the individual physiological manifestations in the comorbid state should interact in a complex fashion. If not, then the abnormalities should simply add. We measured specific conductance, spirometry, lung volumes, and airway responsiveness to adrenergic and cholinergic agonists in 52 normal, 53 asthmatic, 52 obese, and 53 asthmatic and obese patients using standard techniques. Six-minute walks were performed in subsets from each group. Asthma significantly lowered specific conductance and the spirometric variables while increasing airway reactivity and residual volume. Obesity also reduced the spirometric variables as well as total lung capacity and functional residual capacity. Residual volume, specific conductance, and airway responsivity were unaltered. With comorbidity, the disease-specific derangements added algebraically. Features that existed in isolation appeared unchanged in the combination, whereas shared ones either added or subtracted depending on the individual directional changes. Synergistic interactions were not observed. Body mass index weakly correlated with spirometry and lung volumes in asthma, but not with specific conductance or bronchial reactivity. Exercise performance did not aid in differentiation. Our findings indicate asthma and obesity appear to influence the respiratory system through different processes.

Eccentric contractions do not induce rhabdomyolysis in malignant hyperthermia susceptible mice

Corona, B. T., Rouviere, C., Hamilton, S. L., Ingalls, C. P. — 2008-11-04

Recent studies suggest a link between exercise-induced rhabdomyolysis and mutations of the ryanodine receptor (RYR1) associated with malignant hyperthermia (MH). We hypothesized that MH-susceptible mice (RYR1^Y522S/wt) would exhibit greater anterior crural muscle [tibialis anterior (TA) and extensor digitorum longus (EDL) muscles] damage and strength deficits following the performance of a single or repeated bouts of eccentric contractions compared with wild-type (WT) mice. After a single injury bout, RYR1^Y522S/wt mice produced more isometric torque than WT mice immediately and 3 and 7 days postinjury. Moreover, EDL muscle isometric specific force deficits were fully recovered for RYR1^Y522S/wt but not WT mice 14 days postinjury. The percentage of fibers in TA muscle exhibiting signs of muscle damage 7 and 14 days postinjury were at least three times less in RYR1^Y522S/wt than in WT mice. Uninjured and injured EDL muscle from RYR1^Y522S/wt mice also displayed greater S-glutathionylation of RYR1 than that from WT mice. During the weekly injury bouts, torque production by RYR1^Y522S/wt mice was fully recovered before the third and fourth injury bouts, whereas torque was still reduced for WT mice. Three days after multiple injury bouts, there were ~50% fewer fibers exhibiting signs of muscle damage in RYR1^Y522S/wt than in WT TA muscle. These findings indicate that the RYR1^Y522S/wt mutation protects skeletal muscle from exercise-induced muscle injury and do not support a direct association between MH susceptibility and contraction-induced rhabdomyolysis when core temperature is maintained at lower physiological temperatures during exercise.

Carbonic anhydrase III and four-and-a-half LIM protein 1 are preferentially oxidized with muscle unloading

Chen, C.-n., Ferrington, D. A., Thompson, L. V. — 2008-11-04

The identities of proteins that show disuse-related changes in the content of oxidative modification are unknown. Furthermore, it is unknown whether the global accumulation of oxidized proteins is greater in aged animals with muscle disuse. The purposes of this study are 1) to identify the exact proteins that show disuse-related changes in oxidation levels and 2) to test the hypothesis that the global accumulation of oxidized proteins with muscle disuse would be greater in aged animals. Adult and old rats were randomized into four groups: weight bearing and 3, 7, or 14 days of hindlimb unloading. Soleus muscles were harvested to investigate the protein oxidation with unloading. Slot blot, SDS-PAGE, and Western blot analyses were used to detect the accumulation of 4-hydroxy-2-nonenol (HNE)- and nitrotyrosine (NT)-modified proteins. Matrix-assisted laser desorption ionization-time of flight and tandem mass spectroscopy were used to identify modified proteins. We found that global HNE- and NT-modified proteins accumulated significantly with aging but not with muscle unloading. Two HNE and NT target proteins, four-and-a-half LIM protein 1 (FHL1) and carbonic anhydrase III (CAIII), showed changes in the oxidation levels with muscle unloading. The changes in the oxidation levels happened to adult rats but not old rats. However, old rats had higher baseline levels of HNE-modified FHL1. In summary, the data suggest that the muscle unloading-related changes of protein oxidation are more significant in specific proteins and that the changes are age related.

Changes in vascular and cardiac function after prolonged strenuous exercise in humans

2008-11-04

Prolonged exercise has been shown to result in an acute depression in cardiac function. However, little is known about the effect of this type of exercise on vascular function. Therefore, the purpose of the present study was to investigate the impact of an acute bout of prolonged strenuous exercise on vascular and cardiac function and the appearance of biomarkers of cardiomyocyte damage in 15 male (32 ± 10 yr) nonelite runners. The subjects were tested on two occasions, the day before and within an hour of finishing the London marathon (229 ± 38 min). Function of the brachial and femoral arteries was determined using flow-mediated dilatation (FMD). Echocardiographic assessment of cardiac strain, strain rate, tissue velocities, and flow velocities during diastole and systole were also obtained. Venous blood samples were taken for later assessment of cardiac troponin I (cTnI), a biomarker of cardiomyocyte damage. Completion of the marathon resulted in a depression in femoral (P = 0.04), but not brachial (P = 0.96), artery FMD. There was no change, pre- vs. postmarathon, in vascular shear, indicating that the impaired femoral artery function was not related to hemodynamic changes. The ratio of peak early to atrial radial strain rate, a measure of left ventricular diastolic function, was reduced postmarathon (P = 0.006). Postrace cTnI was elevated in 12 of 13 runners, with levels above the recognized clinical threshold for damage in 7 of these. In conclusion, when taken together, these data suggest a transient depression in cardiac and leg vascular function following prolonged intensive exercise.

Dynamic adaptation of cardiac baroreflex sensitivity to prolonged exposure to microgravity: data from a 16-day spaceflight

2008-11-04

This study explored the process of arterial baroreflex adaptation to microgravity, starting from the first day of flight, during the 16-day STS-107 Columbia Space Shuttle mission. Continuous blood pressure (BP), ECG, and respiratory frequency were collected in four astronauts on ground (baseline) and during flight at days 0–1, 6–7, and 12–13, both at rest and during moderate exercise (75 W) on a cycle ergometer. Sensitivity of the baroreflex heart rate control (BRS) was assessed by sequence and spectral alpha methods. Baroreflex effectiveness index (BEI); low-frequency (LF) power and high-frequency (HF) power of systolic BP (SBP), diastolic BP (DBP), and R-R interval (RRI); the RRI LF/HF ratio; and the RRI root mean square of successive differences (RMSSD) index were also estimated. We found that, at rest, BRS increased in early flight phase, compared with baseline (means ± SE: 18.3 ± 3.4 vs. 10.4 ± 1.2 ms/mmHg; P < 0.05), and it tended to return to baseline in subsequent days. During exercise, BRS was lower than at rest, without differences between preflight and in-flight values. At rest, in the early flight phase, RMSSD and RRI HF power increased (P < 0.05) compared with baseline, whereas LF powers of SBP and DBP decreased. No statistical difference was found in these parameters during exercise before vs. during flight. These findings demonstrate that heart rate baroreflex sensitivity and markers of cardiac vagal modulation are enhanced during early exposure to microgravity, likely because of the blood centralization, and return to baseline values in subsequent flight phases, possibly because of the fluid loss. No deconditioning seems to occur in the baroreflex control of the heart.

Hypoglossal premotor neurons of the intermediate medullary reticular region express cholinergic markers

Volgin, D. V., Rukhadze, I., Kubin, L. — 2008-11-04

The inspiratory drive to hypoglossal (XII) motoneurons originates in the caudal medullary intermediate reticular (IRt) region. This drive is mainly glutamatergic, but little is known about the neurochemical features of IRt XII premotor neurons. Prompted by the evidence that XII motoneuronal activity is controlled by both muscarinic (M) and nicotinic cholinergic inputs and that the IRt region contains cells that express choline acetyltransferase (ChAT), a marker of cholinergic neurons, we investigated whether some IRt XII premotor neurons are cholinergic. In seven rats, we applied single-cell reverse transcription-polymerase chain reaction to acutely dissociated IRt neurons retrogradely labeled from the XII nucleus. We found that over half (21/37) of such neurons expressed mRNA for ChAT and one-third (13/37) also had M2 receptor mRNA. In contrast, among the IRt neurons not retrogradely labeled, only 4 of 29 expressed ChAT mRNA (P < 0.0008) and only 3 of 29 expressed M2 receptor mRNA (P < 0.04). The distributions of other cholinergic receptor mRNAs (M1, M3, M4, M5, and nicotinic ₄-subunit) did not differ between IRt XII premotor neurons and unlabeled IRt neurons. In an additional three rats with retrograde tracers injected into the XII nucleus and ChAT immunohistochemistry, 5–11% of IRt XII premotor neurons located at, and caudal to, the area postrema were ChAT positive, and 27–48% of ChAT-positive caudal IRt neurons were retrogradely labeled from the XII nucleus. Thus the pre- and postsynaptic cholinergic effects previously described in XII motoneurons may originate, at least in part, in medullary IRt neurons.

Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice

2008-11-04

Aging is an important determinant of adult hippocampal neurogenesis as the proliferation of neural stem/precursor cells (NSCs) declines dramatically before middle age. Contrary to this, physical exercise is known to promote adult hippocampal neurogenesis. The objective of this study is to investigate the effects of mandatory treadmill running (TR) on neurogenesis, including 1) NSCs proliferation, 2) neurite outgrowth of neuronal progenitor cells, and 3) the survival of newborn neurons in dentate area of middle-aged animals. Compared with 3-mo-old mice, numbers of mitotic cells and neuronal progenitor cells decreased dramatically by middle age and remained at low levels after middle age. Five weeks of TR not only increased NSC proliferation and the number of immature neurons but also promoted the maturation and survival of immature neurons in middle-aged mice. The neurogenic and neurotrophic effects of TR were not due to the reduction of the age-related elevation of serum corticosterone. Significantly, 5 wk of TR restored the age-dependent decline of brain-derived neurotrophic factor and its receptor, TrkB, which are known to promote neuronal differentiation and survival. Taken together, mandatory running exercise alters the brain chemistries of middle-aged animals toward an environment that is favorable to NSC proliferation, survival, and maturation.

Head-down tilt posture elicits transient lymphocyte mobilization from the iliac, but not mesenteric, lymph nodes of rats

Suzuki, S., Mizuno, R., Ikomi, F., Ohhashi, T. — 2008-11-04

The effects of short-term simulated microgravity on the lymph dynamics of rat lymph nodes were investigated using a combination of Bollman's cage and head-down tilt (HDT). Efferent lymphatics of the iliac and mesenteric lymph nodes were cannulated for the collection of lymph. There was no significant difference in lymph flow rate from the iliac lymph nodes between non-HDT (control) and HDT rats. Lymph flow rate from the mesenteric lymph nodes in HDT rats was slightly higher than that obtained with the control. The cell count obtained from the iliac lymph nodes in HDT rats was significantly larger than those of the controls, while no significant difference in the number of cells from the mesenteric lymph nodes was observed between the control and HDT groups. The cells from the iliac lymph nodes in the control and HDT rats were mostly lymphocytes. The distribution of subsets of lymphocytes (CD3+, CD4+, CD8a+, and CD45R+) from the iliac lymph nodes in HDT rats was not significantly different from the subsets of lymphocytes in the control. Immunization did not affect the distribution of lymphocyte subsets from the iliac lymph nodes in the control and HDT groups. There was no significant difference in the concentrations of lymph albumin in iliac afferent or efferent lymphatics between the control and HDT groups. These findings suggest that HDT posture in Bollman's cage induces transient output of lymphocytes from the iliac lymph nodes of rats in vivo without changing the flow rate, lymphocyte subsets, or concentration of albumin.

Upper airway loading induces growth retardation and change in local chondrocyte IGF-I expression is reversed by stimulation of GH release in juvenile rats

Segev, Y., Berdugo-Boura, N., Porati, O., Tarasiuk, A. — 2008-11-04

Chronic resistive airway loading (CAL) impairs growth in juvenile rats. The effects of CAL on epiphyseal growth plate (EGP) structure and insulin-like growth factor (IGF)-I gene expression have not been explored. Little is known about whether stimulants of endogenous growth hormone (GH) secretion can normalize this growth impairment. This study explored the effect of CAL on circulating and EGP GH/IGF-I pathway GH and the effect of ritanserin (endogenous GH stimulant) on somatic growth and the GH/IGF-I axis. We hypothesized that CAL would lead to a decrease in body temperature (T_b) and alterations of GH/IGF-I pathways, consequently leading to growth retardation. The tracheae of 22-day-old male rats were obstructed by tracheal banding (38 sham-operated control, 42 CAL). Tibial EGP morphometry, liver and EGP IGF mRNA, and serum GH and IGF-I levels were analyzed with quantitative real-time PCR and ELISA. T_b and locomotion activity (MA) were measured with telemetric transmitters inserted into the abdominal cavity. CAL animals had lower T_b and MA despite preserved food consumption. CAL impaired both tibial and tail length gains. Tail and tibial length gains inversely correlated with tracheal resistance. Circulating GH and IGF-I, liver and EGP IGF-I mRNA, and EGP width were decreased in the CAL group. Ritanserin administration to CAL animals normalized circulating and local EGP GH and IGF-I levels and minimized the longitudinal growth impairment. We conclude that CAL causes growth delay associated with alterations in the GH/IGF-I axis. Stimulation of GH release by ritanserin restored both global and local GH/IGF-I pathways, yet growth parameters were only partially restored.

Elastin insufficiency predisposes to elevated pulmonary circulatory pressures through changes in elastic artery structure

Shifren, A., Durmowicz, A. G., Knutsen, R. H., Faury, G., Mecham, R. P. — 2008-11-04

Elastin is a major structural component of large elastic arteries and a principal determinant of arterial biomechanical properties. Elastin loss-of-function mutations in humans have been linked to the autosomal-dominant disease supravalvular aortic stenosis, which is characterized by stenotic lesions in both the systemic and pulmonary circulations. To better understand how elastin insufficiency influences the pulmonary circulation, we evaluated pulmonary cardiovascular physiology in a unique set of transgenic and knockout mice with graded vascular elastin dosage (range 45–120% of wild type). The central pulmonary arteries of elastin-insufficient mice had smaller internal diameters (P < 0.0001), thinner walls (P = 0.002), and increased opening angles (P = 0.002) compared with wild-type controls. Pulmonary circulatory pressures, measured by right ventricular catheterization, were significantly elevated in elastin-insufficient mice (P < 0.0001) and showed an inverse correlation with elastin level. Although elastin-insufficient animals exhibited mild to moderate right ventricular hypertrophy (P = 0.0001) and intrapulmonary vascular remodeling, the changes were less than expected, given the high right ventricular pressures, and were attenuated compared with those seen in hypoxia-induced models of pulmonary arterial hypertension. The absence of extensive pathological cardiac remodeling at the high pressures in these animals suggests a developmental adaptation designed to maintain right-sided cardiac output in a vascular system with altered elastin content.

Evidence of skeletal muscle damage following electrically stimulated isometric muscle contractions in humans

2008-11-04

It is unknown whether muscle damage at the level of the sarcomere can be induced without lengthening contractions. To investigate this, we designed a study where seven young, healthy men underwent 30 min of repeated electrical stimulated contraction of m. gastrocnemius medialis, with the ankle and leg locked in a fixed position. Two muscle biopsies were collected 48 h later: one from the stimulated muscle and one from the contralateral leg as a control. The biopsies were analyzed immunohistochemically for inflammatory cell infiltration and intermediate filament disruption. Ultrastructural changes at the level of the z-lines were investigated by transmission electron microscopy. Blood samples were collected for measurement of creatine kinase activity, and muscle soreness was assessed in the days following stimulation. The biopsies from the stimulated muscle revealed macrophage infiltration and desmin-negative staining in a small percentage of myofibers in five and four individuals, respectively. z-Line disruption was evident at varying magnitudes in all subjects and displayed a trend toward a positive correlation (r = 0.73, P = 0.0663) with the force produced by stimulation. Increased muscle soreness in all subjects, combined with a significant increase in creatine kinase activity (P < 0.05), is indirectly suggestive of muscle damage, and the novel findings of the present study, i.e., 1) macrophages infiltration, 2) lack of desmin staining, and 3) z-line disruption, provide direct evidence of damage at the myofiber and sarcomere levels. These data support the hypothesis that muscle damage at the level of the sarcomere can be induced without lengthening muscle contractions.

The role of p66Shc deletion in age-associated arterial dysfunction and disease states

Camici, G. G., Cosentino, F., Tanner, F. C., Luscher, T. F. — 2008-11-04

Accumulation of oxidative stress with age is hypothesized to be the primary causative mediator of age-associated diseases. Among different tissues, aging vessels are known to accumulate oxidative damage and undergo functional impairment. Oxidative stress affects the availability and/or balance of key regulators of vascular homeostasis and favors the development of cardiovascular disease. Reactive oxygen species are generated by different intracellular molecular pathways principally located in the cytoplasm and in the mitochondria. The mitochondrial enzyme p66^Shc is an adaptor protein and plays an important role as a redox enzyme implicated in mitochondrial eactive oxygen species generation and translation of oxidative signals into apoptosis. Mice lacking p66^Shc–/– gene display reduced production of intracellular oxidants and a 30% prolonged life span. For this reasons, a series of studies conceived to elucidate the function of p66^Shc and its possible implication in age-associated cardiovascular diseases have been carried out. Indeed, p66^Shc–/– mice have been shown to be protected from age-dependent endothelial dysfunction as well as age-related risk factors such as diabetes and hypercholesterolemia. This review focuses on delineating the role of the p66^Shc adaptor protein and its potential implication in the pathophysiology of aging and age-related cardiovascular disease.

Arginase and vascular aging

Santhanam, L., Christianson, D. W., Nyhan, D., Berkowitz, D. E. — 2008-11-04

Vascular and associated ventricular stiffness is one of the hallmarks of the aging cardiovascular system. Both an increase in reactive oxygen species production and a decrease in nitric oxide (NO) bioavailability contribute to the endothelial dysfunction that underlies this vascular stiffness, independent of other age-related vascular pathologies such as atherosclerosis. The activation/upregulation of arginase appears to be an important contributor to age-related endothelial dysfunction by a mechanism that involves substrate (l-arginine) limitation for NO synthase (NOS) 3 and therefore NO synthesis. Not only does this lead to impaired NO production but also it contributes to the enhanced production of reactive oxygen species by NOS. Although arginase abundance is increased in vascular aging models, it appears that posttranslational modification by S-nitrosylation of the enzyme enhances its activity as well. The S-nitrosylation is mediated by the induction of NOS2 in the endothelium. Furthermore, arginase activation contributes to aging-related vascular changes by mechanisms that are not directly related to changes in NO signaling, including polyamine-dependent vascular smooth muscle proliferation and collagen synthesis. Taken together, arginase may represent an as yet elusive target for the modification of age-related vascular and ventricular stiffness contributing to cardiovascular morbidity and mortality.

Age-related medial elastocalcinosis in arteries: mechanisms, animal models, and physiological consequences

Atkinson, J. — 2008-11-04

With age, the calcium content of the arterial wall increases. Calcification occurs at two main levels: intimal plaques and the medial elastic fiber network. The latter has been referred to as medial elastocalcinosis and is the subject of this review. The mechanisms involved in elastocalcinosis are complex and involve polar, apolar, and active processes. Vascular calcification may be species specific to humans. As laboratory animals, such as the rat, grow old, they suffer from only very mild arterial calcification. Different animal models of induction of massive arterial calcification by pharmacological and other means exist. Although extrapolation from such models to the clinical situation in terms of etiology is difficult, such models could be useful in the nonclinical study of the pathophysiological consequences of vascular calcification. Vascular calcification modifies arterial wall stiffness, and this could have clinically significant consequences on cardiac function and downstream circulatory control.

Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage

Mitchell, G. F. — 2008-11-04

Over the past decade, numerous studies have shown that increased aortic stiffness is associated with major cardiovascular disease end points, including heart disease, stroke, and kidney disease. Cardiac abnormalities and enhanced atherogenesis in the setting of increased pulsatile load on heart and arteries have been well described. However, recent studies have shown a further association between excessive pressure pulsatility and a number of afflictions of aging that share a predominant microvascular etiology, including many forms of kidney disease and cognitive impairment. In these disorders, microvascular remodeling and impaired regulation of local blood flow, which are related to large artery stiffness and pressure pulsatility, are associated with evidence of diffuse microscopic tissue damage. This brief review will summarize age-related changes in aortic and peripheral vascular function and will discuss potential mechanisms leading from changes in properties of large arteries to excessive pressure pulsatility, abnormal microvascular structure and function, and end-organ dysfunction and damage.

Aging affects vascular structure and function in a limb-specific manner

Nishiyama, S. K., Wray, D. W., Richardson, R. S. — 2008-11-04

The limb-specific effects of aging upon vessel structure and function are not well understood. Consequently, in 12 young (26 ± 2 yr) and 12 old (72 ± 1 yr) healthy subjects, we utilized ultrasound Doppler to evaluate intima-media thickness (IMT), ischemic reperfusion, and flow-mediated dilation (FMD) following (5 min) suprasystolic cuff occlusion in both the arm [brachial artery (BA)] and the leg [popliteal artery (PA)]. Structural measurements, whether normalized for vessel size or not, revealed a greater IMT in both the BA and PA with age (young: BA 0.028 ± 0.001 and PA 0.046 ± 0.003 cm, old: BA 0.039 ± 0.002 and PA 0.073 ± 0.005 cm; P < 0.05). Ischemic reperfusion revealed a similar pattern as IMT in terms of limb and age-related differences. There was an age-related attenuation in both BA FMD (old: 38% smaller BA FMD compared with young) and PA FMD (old: 71% smaller PA FMD compared with young). However, when this percent change was normalized for shear rate, only the PA FMD of the old group was still significantly attenuated (old: 41% smaller PA FMD/shear rate compared with young). Together, the finding of differential structural and functional parameters in the arms and legs of healthy young people, and the somewhat negative findings that are specific to the legs of otherwise healthy older people (greater IMT and attenuated FMD), support and may help to better understand the increased propensity to develop a vascular pathology in the legs with age.

Point:Counterpoint: Spectral properties of the surface EMG can characterize/do not provide information about motor unit recruitment strategies and muscle fiber type

von Tscharner, V., Nigg, B. M. — 2008-11-04

Counterpoint: Spectral properties of the surface emg do not provide information about motor unit recruitment and muscle fiber type

Farina, D. — 2008-11-04

Rebuttal from von Tscharner and Nigg

2008-11-04

Rebuttal from Farina

2008-11-04

Comments on Point:Counterpoint: Spectral properties of the surface EMG can characterize/do not provide information about motor unit recruitment strategies and muscle fiber type

2008-11-04

Last Word on Point:Counterpoint: Spectral properties of the surface EMG can characterize/do not provide information about motor unit recruitment strategies and muscle fiber type

von Tscharner, V., Nigg, B. M. — 2008-11-04

Last Word on Point:Counterpoint: Spectral properties of the surface EMG can characterize/do not provide information about motor unit recruitment and muscle fiber type

Farina, D. — 2008-11-04

Effect of altitude on leptin levels, does it go up or down?

Sierra-Johnson, J., Romero-Corral, A., Somers, V. K., Johnson, B. D. — 2008-11-04

Commentaries on Viewpoint: Effect of altitude on leptin levels, does it go up or down? Control of leptin with altitude exposure

Raff, H., Molthen, R., Pan, W., Kastin, A. J. — 2008-11-04

Commentary on Viewpoint: Regulation of leptin by hypoxia

2008-11-04

Last Word on Viewpoint: Effect of altitude on leptin levels, does it go up or down?

Sierra-Johnson, J., Romero-Corral, A., Somers, V. K., Johnson, B. D. — 2008-11-04

Comments on Baker et al.'s "Quantitative analysis of serum sodium concentration after prolonged running in the heat"

Weschler, L. B. — 2008-11-04

Reply to Weschler

Baker, L. B. — 2008-11-04