Farup, J., De Lisio, M., Rahbek, S. K., Bjerre, J., Vendelbo, M. H., Boppart, M. D., Vissing, K., 2015-10-01 08:52:16 AM
Aim: Skeletal muscle satellite cells (SCs) are important for muscle repair and hypertrophy in response mechanical stimuli. Neuron-glial antigen 2 positive (NG2+) and alkaline phosphatase positive (ALP+) pericytes may provide an alternative source of myogenic progenitors and/or secrete paracrine factors to induce Pax7+ SC proliferation and differentiation. The purpose of this study was to investigate NG2+ and ALP+ cell quantity, as well as SC content and activation in human skeletal muscle following prolonged concentric (Conc) or eccentric (Ecc) resistance training. Methods: Male subjects engaged in unilateral resistance training utilizing isolated Ecc or Conc contractions. After 12 weeks, muscle biopsies were analyzed for NG2+ and ALP+ pericytes, total Pax7+ SCs, activated SCs (Pax7+MyoD+), and differentiating myogenic cells (Pax7- MyoD+). Results: NG2+ cells localized to CD31+ vessels and the majority co-expressed ALP. NG2+ pericyte quantity decreased following both Conc and Ecc training (p<0.05). ALP+ pericyte quantity declined following Conc (p<0.05), but not Ecc training. Conversely, total Pax7+ SC content was elevated following Conc only (p<0.001), while Pax7+MyoD+ SC content was increased following Conc and Ecc (p<0.001). Follow up analyses demonstrated that CD90+ and PDGFRα+ mononuclear cell proliferation was also increased in response to both Conc and Ecc training (p<0.01). Conclusion: Resistance training results in a decline in pericyte quantity and increase in mesenchymal progenitor cell proliferation, and these events likely influence SC pool expansion and increased activation observed post-training.
Okushima, D., Poole, D. C., Rossiter, H. B., Barstow, T. J., Kondo, N., Ohmae, E., Koga, S., 2015-10-01 08:52:16 AM
Muscle deoxygenation (i.e., deoxy[Hb+Mb]) during exercise assesses the matching of oxygen delivery (Qo2) to oxygen utilization (Vo2). Until now limitations in near-infrared spectroscopy (NIRS) technology did not permit discrimination of deoxy[Hb+Mb] between superficial and deep muscles. In humans, the deep quadriceps is more highly vascularized and oxidative than the superficial quadriceps. Using high-power time resolved NIRS, we tested the hypothesis that deoxygenation of the deep quadriceps would be less than in superficial muscle during incremental cycling exercise in eight males. Pulmonary Vo2 was measured and muscle deoxy[Hb+Mb] was determined in the superficial vastus lateralis (VL), vastus medialis (VM), and rectus femoris (RF-s), and the deeprectus femoris (RF-d). Deoxy[Hb+Mb] in RF-d was significantly less than VL at 70% (67.2±7.0 vs. 75.5±10.7 μM) and 80% (71.4±11.0 vs. 79.0±15.4 μM) of peak work rate (WRpeak), but greater than VL and VM at WRpeak(87.7±32.5 vs. 76.6±17.5 and 75.1±19.9 μM). RF-s was intermediate at WRpeak (82.6±18.7 μM). Total[Hb+Mb] and tissue oxygen saturation were significantly greater in RF-d than RF-s throughout exercise. The slope of deoxy[Hb+Mb] increase (proportional to Qo2/Vo2) in VL and VM slowed markedly above 70% WRpeak, whereas it became greater in RF-d. This divergent deoxygenation pattern may be due to a greater population of slow twitch muscle fibers in the deep RF muscle, and the differential recruitment profiles and vascular and metabolic control properties of specific fiber populations within superficial and deeper muscle regions.
Prak, R. F., Doestzada, M., Thomas, C. K., Tepper, M., Zijdewind, I., 2015-10-01 08:52:16 AM
In able-bodied individuals (AB), voluntary muscle activation declines progressively during sustained contractions. However, little data are available on voluntary muscle activation during sustained contractions in muscles weakened by spinal cord injury (SCI), where greater force declines may limit task performance. SCI-related impairment of muscle activation complicates interpretation of the interpolated twitch technique commonly used to assess muscle activation. We attempted to estimate and correct for the SCI-related-superimposed twitch. Seventeen SCI (AIS C/D) and AB participants produced brief and sustained (2-minute) maximal voluntary contractions (MVC) with the first dorsal interosseous. Force and EMG were recorded together with superimposed (doublet) twitches. The MVC of SCI participants was weaker than AB participants (20.3N, SD 7.1 vs. 37.9N, SD 9.5, p<0.001); MVC-superimposed twitches were larger in SCI participants (SCI-median: 10.1; range: 2.0-63.2%, AB-median: 4.7, range: 0.0-18.4% rest-twitch; p=0.007). After correction for the SCI-related-superimposed twitch no difference was found (median: 6.7, 0.0-17.5% rest-twitch, p=0.402). Thus, during brief contractions, the maximal corticofugal output SCI participants can exert is similar to AB participants. During the sustained contraction, force decline (SCI: 58.0%, SD 15.1; AB: 57.2% SD13.3) was similar (p=0.887) because SCI participants developed less peripheral (p=0.048) but more central fatigue than AB participants. The largest change occurred at the start of the sustained contraction, when the (corrected) superimposed twitches increased more in SCI participants (SCI: 16.3% rest-twitch, SD 20.8; AB: 2.7%, SD 4.7, p=0.01). Greater reduction in muscle activation after SCI may relate to a reduced capacity to overcome fast fatigue-related excitability changes at the spinal level.
Robertson, C. V., Marino, F. E., 2015-10-01 08:52:16 AM
The involvement of the brain in exercise regulation is not a particularly new concept and the fact the motor cortex (MC) is not activated maximally at exhaustion is suggestive that there are pathways upstream of the MC (10), regulating exercise and effectuating termination. Several papers have now addressed the areas of the cortex that are activated during the control of voluntary movement (23) and postulated how areas of the brain may be involved in exercise termination (20, 26, 27). However, the neural pathways for volitional control of movement and their interaction with psychological factors has yet to be established (27).The aim of this viewpoint is not to describe all regions of the brain activated during exercise regulation, but to highlight how the PFC is involved in the process. We propose a model which describes how the PFC acts as a control structure by integrating information produced during exercise, both centrally and peripherally, exerting a top down effect.
MacPherson, R. E. K., Baumeister, P., Peppler, W. T., Wright, D. C., Little, J. P., 2015-10-01 08:52:16 AM
Obesity and type 2 diabetes are significant risk factors in the development of neurodegenerative diseases, such as Alzheimer's disease. A variety of cellular mechanisms, such as altered AKT, AMPK, and increased inflammatory signaling contribute to neurodegeneration. Exercise training can improve markers of neurodegeneration but the underlying mechanisms remain unknown. The purpose of this study was to determine the effects of a single bout of exercise on markers of neurodegeneration and inflammation in brains from mice fed a high fat diet. Male C57BL/6 mice were fed a low (LFD, 10% kcals from lard) or a high fat diet (HFD, 60% kcals from lard) for 7wks. HFD mice underwent an acute bout of exercise (treadmill running: 15m/min, 5% incline, 120min) followed by a recovery period of 2h. The HFD increased body mass and glucose intolerance (both p<0.05). This was accompanied by an ~2 fold increase in the phosphorylation of AKT, ERK, and GSK in the cortex (p<0.05). Following exercise, there was a decrease in beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) (p<0.05) and activity (p<0.001). This was accompanied by a reduction in AMPK phosphorylation, indicative of a decline in cellular stress (p<0.05). AKT and ERK phosphorylation were decreased following exercise in HFD mice to a level similar to that of the LFD mice (p<0.05). This study demonstrates that a single bout of exercise can reduce BACE1 content and activity independent of changes in adiposity. This effect is associated with reductions in AKT, ERK, and AMPK signaling in the cortex.
Kawano, F., Nimura, K., Ishino, S., Nakai, N., Nakata, K., Ohira, Y., 2015-10-01 08:52:16 AM
Numerous studies have reported alterations in skeletal muscle properties and phenotypes in response to various stimuli such as exercise, unloading, and gene mutation. However, a shift in muscle fiber phenotype from fast to slow twitch is not completely induced by stimuli. This limitation is hypothesized to result from the epigenetic differences between muscle types. The main purpose of the present study was to identify the differences in histone modification for the plantaris (fast) and soleus (slow) muscles of adult rats. Genome-wide analysis by a chromatin immunoprecipitation followed by DNA sequencing revealed that tri-methylation at lysine 4 and acetylation of histone 3, which occurs at transcriptionally active gene loci, was less prevalent in the genes specific to the slow-twitch soleus muscle. Conversely, gene loci specific to the fast-twitch plantaris muscle were associated with the aforementioned histone modifications. We also found that the up-regulation of slow genes in the plantaris muscle, which are related to enhanced muscular activity, is not associated with the activating histone modifications. Furthermore, silencing of muscle activity by denervation caused the displacement of acetylated histone and RNA polymerase II (Pol II) in 5' ends of genes in plantaris, but minor effects were seen in soleus. Increased recruitment of Pol II induced by forced acetylation of histone was also suppressed in valproic acid-treated soleus. Our present data indicate that the slow-twitch soleus muscle has a unique set of histone modifications, which may relate to the preservation of the genetic backbone against physiological stimuli.
Castronovo, A. M., Negro, F., Conforto, S., Farina, D., 2015-10-01 08:52:16 AM
α-motor neurons receive synaptic inputs from spinal and supra-spinal centers that comprise components either common to the motor neuron pool or independent. The inpt shared by motor neurons - common input - determines force control. The aim of the study was to investigate the changes in the strength of common synaptic input delivered to motor neurons with changes in force and with fatigue, two conditions that underlie an increase in the net excitatory drive to the motor neurons. High-density surface EMG signals were recorded from the tibialis anterior muscle during contractions at 20%, 50%, and 75% of the maximal voluntary contraction (MVC) force (in three sessions separated by at least two days), all sustained until task failure. EMG signal decomposition identified the activity of a total of 1245 motor units. The coherence values between cumulative motor unit spike trains increased with increasing force especially for low-frequencies. This increase in coherence was not observed when comparing two subsets of motor units having different recruitment thresholds, but detected at the same force level. Moroever, the coherence values for frequencies <5 Hz increased at task failure with respect to the beginning of the contractions for all force levels. In conclusion, the results indicated that the relative strength of common synaptic input to motor neurons with respect to independent input increases when the net excitatory drive to motor neurons increases as a consequence of a change in force and fatigue.
Kwon, O. S., Smuder, A. J., Wiggs, M. P., Hall, S. E., Sollanek, K. K., Morton, A. B., Talbert, E. E., Toklu, H. Z., Tumer, N., Powers, S. K., 2015-10-01 08:52:16 AM
Mechanical ventilation is a life-saving intervention for patients in respiratory failure. Unfortunately, prolonged ventilator support results in diaphragmatic atrophy and contractile dysfunction leading to diaphragm weakness which is predicted to contribute to problems in weaning patients from the ventilator. While it is established that ventilator-induced oxidative stress is required for the development of ventilator-induced diaphragm weakness, the signaling pathway(s) that trigger oxidant production remains unknown. However, recent evidence reveals that increased plasma levels of Angiotensin II results in oxidative stress and atrophy in limb skeletal muscles. Using a well-established animal model of mechanical ventilation, we tested the hypothesis that increased circulating levels of Angiotensin II are required for both ventilator-induced diaphragmatic oxidative stress and diaphragm weakness. Cause and effect was determined by administering an angiotensin-converting enzyme inhibitor (enalapril) to prevent ventilator-induced increases in plasma Angiotensin II levels and the Angiotensin II type 1 receptor antagonist (losartan) was provided to prevent the activation of Angiotensin II type 1 receptors. Enalapril prevented the increase in plasma Angiotensin II levels but did not protect against ventilator-induced diaphragmatic oxidative stress or diaphragm weakness. In contrast, losartan attenuated both ventilator-induced oxidative stress and diaphragm weakness. Indicating that circulating angiotensin II is not essential for development of ventilator-induced diaphragm weakness but that activation of angiotensin II type 1 receptors appears to be a requirement for ventilator-induced diaphragm weakness. Importantly, these experiments provide the first evidence that the Food and Drug Administration approved drug losartan may have clinical benefits to protect against ventilator-induced diaphragm weakness in humans.
Baum, O., Gubeli, J., Frese, S., Torchetti, E., Malik, C., Odriozola, A., Graber, F., Hoppeler, H. H., Tschanz, S. A., 2015-10-01 08:52:16 AM
The ultrastructure of capillaries in skeletal muscle was morphometrically assessed in vastus lateralis muscle (VL) biopsies taken before and after exercise from 22 participants of two training studies. In study-1 (8-weeks of ergometer training), light microscopy revealed capillary-fiber (C/F)-ratio (+27%) and capillary density (+16%) to be higher (P≤0.05) in the post- than the pre-exercise biopsies of all 10 participants. In study-2 (6-months of moderate running), C/F-ratio and capillary density were increased (+23%/+20%; P≤0.05) in VL biopsies of 6 "angiogenesis responders" (AR) after training, while 6 "non-angiogenesis responders" (NR) showed non-significant changes of these structural indicators (-4%/-4%). 40 capillary profiles per participant were evaluated by point and intersection counting on cross-sections after transmission electron microscopy. In study 1, volume density (Vv) and mean arithmetic thickness (T) of endothelial cells (ECs; +19%/+17%) and pericytes (PCs; +20%/+21%) were higher (P≤0.05), while Vv and T of the peri-capillary basement membrane (BM) were -23%/-22%-lower (P≤0.05) in the post-training biopsies. In study 2, exercise-related differences between AR- and NR-groups were found for Vv and T of PCs (AR: +26%/+22%, both P≤0.05; NR: +1%/-3%, both P>0.05) and BM (AR: -14%/-13%, both P≤0.05; NR: -9%/-11%, P=0.07/0.10). Vv and T of ECs were higher (AR: +16%/+18%, NR: +6%/+6%, all P≤0.05) in both groups. The PC-coverage was higher (+13%, P≤0.05) in VL biopsies of AR but non-significantly altered (+3%, P>0.05) in those of NR after training. Our study suggests that intensified PC-mobilization and BM-thinning are related to exercise-induced angiogenesis in human skeletal muscle, while training per se induces EC-thickening.
Yoshihara, T., Ichinoseki-Sekine, N., Kakigi, R., Tsuzuki, T., Sugiura, T., Powers, S. K., Naito, H., 2015-10-01 08:52:16 AM
Controlled mechanical ventilation (CMV) is a life-saving intervention for patients in respiratory failure. Unfortunately, prolonged mechanical ventilation results in diaphragmatic atrophy and contractile dysfunction, both of which are predicted to contribute to problems in weaning patients from the ventilator. Therefore, developing a strategy to protect the diaphragm against ventilator-induced weakness is important. We tested the hypothesis that repeated bouts of heat stress result in diaphragm resistance against MV-induced atrophy and contractile dysfunction. Male Wistar rats were randomly divided into six experimental groups: 1) control, 2) single bout of whole-body heat stress, 3) repeated bouts of whole-body heat stress, 4) 12 hours CMV, 5) single bout of whole-body heat stress 24 hours prior to CMV, and 6) repeated bouts of whole-body heat stress 1, 3, and 5 days prior to 12 hours of CMV. Our results revealed that repeated bouts of heat stress resulted in increased levels of heat shock protein 72 in the diaphragm and protection against both CMV-induced diaphragmatic atrophy and contractile dysfunction at submaximal stimulation frequencies. The specific mechanisms responsible for this protection remain unclear, this heat stress-induced protection against MV-induced diaphragmatic atrophy and weakness may be partially due to reduced diaphragmatic oxidative stress, diminished activation of signal transducer/transcriptional activator-3, lower caspase-3 activation, and decreased autophagy in the diaphragm.
Kolluru, G. K., Prasai, P. K., Kaskas, A. M., Letchuman, V., Pattillo, C. B., 2015-10-01 08:52:16 AM
Molecular oxygen (O2) is an essential component for the survival and development of many organisms. Mammalian and other vertebrate systems are evolved to maintain oxygen homeostasis and respond to changes in O2 concentrations. Variation in O2 levels leads to changes in molecular signaling and thereby physiological functions of many organisms. Nitric oxide (NO) and Hydrogen sulfide (H2S) are two cellular signaling molecules that play key roles in several physiological functions involved in maintaining vascular homeostasis including vasodilation, anti-inflammation and vascular growth. Apart from the aforementioned functions, NO and H2S are believed to play roles in mediating hypoxic responses and as O2 chemosensors in biological systems. In this review, we discuss the roles of NO and H2S during hypoxia.
Brunt, V. E., Fujii, N., Minson, C. T., 2015-10-01 08:52:16 AM
Cutaneous acetylcholine (ACh)-mediated dilation is commonly used to assess microvascular function, but the mechanisms of dilation are poorly understood. Depending on dose and method of administration, nitric oxide (NO) and prostanoids are involved to varying extents and the roles of endothelial-derived hyperpolarizing factors (EDHFs) are unclear. In the present study, five incremental doses of ACh (0.01-100mM) were delivered either as a 1-min bolus (Protocol 1; N=12) or as a ≥20-min continuous infusion (Protocol 2; N=10) via microdialysis fibers infused with 1) Lactated Ringer's, 2) tetraethylammonium (TEA; calcium-activated potassium channel, KCa, and EDHF inhibitor), 3) L-NNA+Ketorolac (NO synthase, NOS, and cyclooxygenase, COX, inhibitors), and 4) TEA+L-NNA+Ketorolac. The hyperemic response was characterized as peak and area under the curve (AUC) cutaneous vascular conductance (CVC) for bolus infusions or plateau CVC for continuous infusions, and reported as %maximal CVC. In Protocol 1, TEA, alone and combined with NOS+COX inhibition, attenuated peak CVC (100mM, Ringer's: 59±6% vs. TEA: 43±5%, p<0.05; L-NNA+Ketorolac: 35±4% vs. TEA+L-NNA+Ketorolac: 25±4%, p<0.05) and AUC (Ringer's: 25,414±3,528 vs. TEA: 21,403±3,416%.sec, p<0.05; L-NNA+Ketorolac: 25,628±3,828%.sec vs. TEA+L-NNA+Ketorolac: 20,772±3,711%.sec; p<0.05), although these effects were only significant at the highest dose of ACh. At lower doses, TEA lengthened the total time of the hyperemic response (10mM, Ringer's: 609±78s vs. TEA: 860±67s; p<0.05). In Protocol 2, TEA alone did not affect plateau CVC, but attenuated plateau in combination with NOS+COX inhibition (100mM: 50.4±6.6% vs. 30.9±6.3%; p<0.05). Therefore, EDHFs contribute to cutaneous ACh-mediated dilation, but their relative contribution is altered by the dose and infusion procedure.
Elliot, J. G., Budgeon, C. A., Harji, S., Jones, R. L., James, A. L., Green, F. H., 2015-10-01 08:52:16 AM
Introduction: When comparing the pathology of airways in individuals with and without asthma, the perimeter of the basement membrane (Pbm) is used as a marker of airway size as it is independent of airway smooth muscle shortening or airway collapse. The extent to which the Pbm is itself altered in asthma has not been quantified. Aim: To compare the Pbm from the same anatomical sites in post-mortem lungs from with (n=55) and without (n=30) asthma (nonfatal or fatal). Methods: Large and small airways were systematically sampled at equidistant "Levels" from the apical segment of the left upper lobes and anterior and basal segments of the left lower lobes of lungs fixed in inflation. The length of the Pbm was estimated from cross-sections of airway at each relative level. Linear mixed models were used to investigate the relationships between Pbm and gender, age, height, smoking status, airway level and asthma group. Results: The final model showed significant interactions between Pbm and airway level in small (<3mm) airways, having asthma (p<0.0001), and gender (p<0.0001). No significant interactions for Pbm between asthma groups were observed for larger airways (equivalent to a diameter of ~3mm and greater) or smoking status. Conclusion: Asthma is not associated with remodeling of the Pbm in large airways. In medium and small airways the decrease in Pbm in asthma (<20%) would not account for the published differences in wall area or area of smooth muscle observed in cases of severe asthma.
Percival, M. E., Martin, B. J., Gillen, J. B., Skelly, L. E., MacInnis, M. J., Green, A. E., Tarnopolsky, M. A., Gibala, M. J., 2015-10-01 08:52:16 AM
We tested the hypothesis that ingestion of sodium bicarbonate (NaHCO3) prior to an acute session of high-intensity interval training (HIIT) would augment signalling cascades and gene expression linked to mitochondrial biogenesis in human skeletal muscle. On two occasions separated by ~1 wk, nine men (22±2 y; 78±13 kg, VO2peak = 48±8 mL kg-1 min-1; mean ± SD) performed 10x60-s cycling efforts at an intensity eliciting ~90% of maximal heart rate (263±40 W), interspersed with 60 s of recovery. In a double-blind, crossover manner, subjects ingested a total of 0.4 g kg b.w.-1 NaHCO3 prior to exercise (BICARB) or an equimolar amount of the placebo, sodium chloride (PLAC). Venous blood bicarbonate and pH were elevated at all time points post-ingestion (p<0.05) in BICARB vs. PLAC. During exercise, muscle glycogen utilization (126±47 vs. 53±38 mmol kg d.w.-1; p < 0.05) and blood lactate accumulation (12.8±2.6 vs. 10.5±2.8 mmol L-1; p < 0.05) were greater in BICARB vs. PLAC. The acute exercise-induced increase in the phosphorylation of acetyl-CoA carboxylase, a downstream marker of AMP-activated protein kinase activity, and p38 mitogen-activated protein kinase were similar between treatments (p>0.05). However, the increase in PGC-1α mRNA expression after 3 h of recovery was higher in BICARB vs. PLAC (~7- vs. 5-fold compared to rest, p<0.05). We conclude that NaHCO3 prior to HIIT alters the mRNA expression of this key regulatory protein associated with mitochondrial biogenesis. The elevated PGC-1α mRNA response provides a putative mechanism to explain the enhanced mitochondrial adaptation seen after chronic NaHCO3-supplemented HIIT in rats.
Dokladny, K., Zuhl, M. N., Moseley, P. L., 2015-10-01 08:52:16 AM
A single layer of enterocytes and tight junctions (intercellular multiprotein complexes) form the intestinal epithelial barrier that controls transport of molecules through transcellular and paracellular pathways. Dysfunctional or "leaky" intestinal tight junction barrier allows augmented permeation of luminal antigens, endotoxins, and bacteria to the blood stream. Various substances and conditions have been shown to affect the maintenance of the intestinal epithelial tight junction barrier. The primary focus of the present review is to analyze the effects of the exertional or non-exertional (passive hyperthermia) heat stress on tight junction barrier function in in-vitro and in-vivo (animals and humans) models. Our secondary focus is to review changes in tight junction proteins in response to exercise or hyperthermic conditions. Finally, we discuss some pharmacological or nutritional interventions providing direct insights into the cellular mechanisms involved in maintaining homeostasis of the intestinal epithelial tight junction barrier during heat stress or exercise.
Cruz, R. S. d. O., De Aguiar, R. A., Turnes, T., Pereira, K. L., Caputo, F., 2015-10-01 08:52:16 AM
Purpose: This study investigated the effects of ischemic preconditioning (IPC) on the ratings of perceived exertion (RPE), surface electromyography (EMG), and pulmonary oxygen uptake (VO2) onset kinetics during cycling until exhaustion at the peak power output attained during an incremental test (PPO). Methods: A group of 12 recreationally trained cyclists volunteered for this study. After determination of PPO, they were randomly subjected on different days to a performance protocol preceded by intermittent bilateral cuff pressure inflation to 220 mm Hg (IPC) or 20 mm Hg (control). To increase data reliability, the performance visits were replicated, also in a random manner. Results: There was an 8.0% improvement in performance after IPC (Control: 303 s, IPC 327 s, factor SDs of x/÷1.13, P = 0.01). This change was followed by a 2.9% increase in peak VO2 (Control: 3.95 L·min-1, IPC: 4.06 L·min-1, factor SDs of x/÷ 1.15, P = 0.04) owing to a higher amplitude of the slow component of the VO2 kinetics (Control: 0.45 L·min-1, IPC: 0.63 L·min-1, factor SDs of x/÷ 2.21, P = 0.05). There was also an attenuation in the rate of increase in RPE (P = 0.01) and a progressive increase in the myoelectrical activity of the vastus lateralis muscle (P = 0.04). Furthermore, the changes in peak VO2 (r = 0.73, P = 0.007) and the amplitude of the slow component (r = 0.79, P = 0.002) largely correlated with performance improvement. Conclusion: These findings provide a link between improved aerobic metabolism and enhanced severe-intensity cycling performance after IPC. Furthermore, the delayed exhaustion after IPC under lower RPE and higher skeletal muscle activation suggest they have a role on the ergogenic effects of IPC on endurance performance.
Dominelli, P. B., Molgat-Seon, Y., Bingham, D., Swartz, P. M., Road, J. D., Foster, G. E., Sheel, A. W., 2015-10-01 08:52:16 AM
We asked if the higher work of breathing (Wb) during exercise in women compared to men is explained by biological sex. We created a statistical model that accounts for both the visco-elastic and the resistive components of the total Wb and independently compares the effects of biological sex. We applied the model to esophageal pressure-derived Wb values obtained during an incremental cycle test to exhaustion. Subjects were healthy men (n=17) and women (n=18) with a range of maximal aerobic capacities (VO2max range: men=40-68, women=39-60 ml•kg-1•min-1). We also calculated the dysanapsis ratio using measures of lung recoil and forced expiratory flow as index of airway caliber. By applying the model we found that the differences in the total Wbduring exercise in women are due to a higher resistive Wb rather than visco-elastic Wb. We also found that the higher resistive Wb is independently explained by biological sex. To account for the known effect of lung volumes on the dysanapsis ratio we compared the sexes with an analysis of covariance procedures and found that when VC accounted for, the adjusted mean dysanapsis ratio is statistically lower in women (0.17 vs. 0.25 au, P<0.05). Our collective findings suggest that innate sex-based differences may exist in human airways, which result in significant male-female differences in the Wb during exercise in health.
Unilateral cervical spinal cord hemisection (i.e., C2Hx) usually interrupts the bulbospinal respiratory pathways and results in respiratory impairment. It has been demonstrated that activation of the serotonin system can promote locomotor recovery after spinal cord injury. The present study was designed to investigate whether serotonergic activation can improve respiratory function during the chronic injury state. Bilateral diaphragm electromyogram (EMG) and tidal volume were measured in anesthetized and spontaneously breathing adult rats at 8 weeks post-C2Hx or C2 laminectomy. A bolus intravenous injection of a serotonin precursor (5-Hydroxytryptophan; 5-HTP, 10 mg/kg), a serotonin reuptake inhibitor (fluoxetine, 10 mg/kg), or a potent agonist for serotonin 2A receptors (TCB-2, 0.05 mg/kg) was used to activate the serotonergic system. Present results demonstrated that 5-HTP and TCB-2 but not fluoxetine significantly increased the inspiratory activity of the diaphragm EMG ipsilateral to the lesion for at least 30 min in C2Hx animals but not in animals that received sham surgery. However, the tidal volume was not increased after administration of 5-HTP or TCB-2, indicating that the enhancement of ipsilateral diaphragm activity is not associated with improvement of the tidal volume. These results suggest that exogenous activation of the serotonergic system can specifically enhance the ipsilateral diaphragmatic motor outputs, but this approach may not be sufficient to improve respiratory functional recovery following chronic cervical spinal injury.
Collier, G. J., Marshall, H., Rao, M., Stewart, N. J., Capener, D., Wild, J. M., 2015-10-01 08:52:16 AM
Recently, dynamic MR imaging of hyperpolarized 3He during inhalation revealed an alternation of the image intensity between left and right lungs with a cardiac origin (Respiratory Physiology & Neurobiology: 185, 468-471,2013). This effect is investigated further using dynamic and phase contrast flow MR imaging with inhaled 3He during slow inhalations (flow rate ~ 100 mL s-1) to elucidate air-flow dynamics in the main lobes in six healthy subjects. The ventilation MR signal and gas inflow in the left lower part of the lungs was found to oscillate clearly at the cardiac frequency in all subjects, whereas the MR signals in the other parts of the lungs had a similar oscillatory behavior but were smaller in magnitude and in anti-phase to the signal in the left lower lung. The airflow in the main bronchi showed periodic oscillations at the frequency of the cardiac cycle. In four of the subjects, backflows were observed for a short period of time of the cardiac cycle, demonstrating a pendelluft effect at the carina bifurcation between the left and right lungs. Additional 1H structural MR images of the lung volume and synchronized ECG recording revealed that maximum inspiratory flow rates in the left lower part of the lungs occurred during systole when the corresponding left lung volume increased whereas the opposite effect was observed during diastole with gas flow being redirected to the other parts of the lung. In conclusion, cardiogenic flow oscillations have a significant effect on regional gas flow and distribution within the lungs.
Ekman, C., Elgzyri, T., Strom, K., Almgren, P., Parikh, H., Dekker Nitert, M., Ronn, T., Manderson Koivula, F., Ling, C., Tornberg, A. B., Wollmer, P., Eriksson, K.-F., Groop, L., Hansson, O., 2015-10-01 08:52:16 AM
Healthy first-degree relatives with heredity of type 2 diabetes (FH+) are known to have metabolic inflexibility when compared to subjects without heredity for diabetes (FH-). In this study, we aimed to test the hypothesis that FH+ individuals have an impaired response to exercise compared to FH-. 16 FH+ and 19 FH- insulin sensitive men similar in age, VO2peak and BMI completed an exercise intervention with heart rate monitoration during exercise for 7 months. Before and after the exercise intervention, the participants underwent a physical examination, tests for glucose tolerance and exercise capacity and muscle biopsies were taken for expression analysis. The participants attended on average 39 training sessions during the intervention and spent 18.8 MJ on exercise. VO2peak/kg increased by 14% and the participants lost 1.2 kg of weight and 3 cm waist circumference. Given that the FH+ group expended 61% more energy during the intervention, we used regression analysis to analyze the response in the FH+ and FH- groups separately. Exercise volume had a significant effect on VO2peak, weight and waist circumference in the FH- group, but not in the FH+ group. After exercise, expression of genes involved in metabolism, oxidative phosphorylation and cellular respiration increased more in the FH-, compared to the FH+ group. This suggests that healthy, insulin sensitive FH+ and FH- participants with similar age, VO2peakand BMI may respond differently to an exercise intervention. The FH+ background might limit muscle adaptation to exercise, which may contribute to the increased susceptibility to type 2 diabetes in FH+ individuals.
Cory, J. M., Schaeffer, M. R., Wilkie, S. S., Ramsook, A. H., Puyat, J. H., Arbour, B., Basran, R., Lam, M., Les, C., MacDonald, B., Jensen, D., Guenette, J. A., 2015-10-01 08:52:16 AM
Understanding sex differences in the qualitative dimensions of exertional dyspnea may provide insight into why women are more affected by this symptom than men. This study explored the evolution of the qualitative dimensions of dyspnea in 70 healthy, young, physically active adults (35M:35F). Participants rated the intensity of their breathing discomfort (Borg 0-10 scale) and selected phrases that best described their breathing from a standardized list ("work/effort", "unsatisfied inspiration", "unsatisfied expiration") throughout each stage of a symptom limited incremental cycle exercise test. Following exercise, participants selected phrases that described their breathing at maximal exercise from a list of 15 standardized phrases. Intensity of breathing discomfort was significantly higher in women for a given ventilation but differences disappeared when ventilation was expressed as a percentage of maximum voluntary ventilation. The dominant qualitative descriptor in both sexes throughout exercise was increased "work/effort" of breathing. At peak exercise, women were significantly more likely to select the following phrases: "my breathing feels shallow", "I cannot get enough air in", "I cannot take a deep breath in", and "my breath does not go in all the way". Women adopted a more rapid and shallow breathing pattern and had significantly higher end-inspiratory lung volumes throughout exercise relative to men. These findings suggest that men and women do not differ in their perceived quality of dyspnea during submaximal exercise, but subjective differences appear at maximal exercise and may be related, at least in part, to underlying sex differences in breathing patterns and operating lung volumes during exercise.
Melanson, E. L., Gavin, K. M., Shea, K. L., Wolfe, P., Wierman, M. E., Schwartz, R. S., Kohrt, W. M., 2015-10-01 08:52:16 AM
Suppressing sex hormones in women for 1 week reduces resting energy expenditure (REE). The effects of more chronic suppression on REE and other components of total energy expenditure (TEE), and whether this is specifically due to loss of estradiol (E2), are not known. We compared the effects of 5 months of sex hormone suppression (gonadotropin releasing hormone agonist therapy, GnRHAG) with placebo (GnRHAG+PL) or (GnRHAG+E2) add-back therapy on REE and the components of TEE. Premenopausal women received GnRHAG(leuprolide acetate 3.75 mg/mo) and were randomized to receive transdermal therapy that was either (E2) (0.075 mg/d; n=24; mean±SD, aged=37±8 yr, BMI=27.3±6.2 kg/m2) or placebo (n=21; aged=34±9 yr, BMI=26.8±6.2 kg/m2). REE was measured using a metabolic cart, and TEE, sleep EE (SEE), exercise EE (ExEE, 2 x 30 min bench stepping), non-Ex EE (NExEE), and the thermic effect of feeding (TEF) were measured using whole-room indirect calorimetry. REE decreased in GnRHAG+PL [mean (95% CI), -54 (-98, -15) kcal/d], but not GnRHAG+E2 [+6 (-33, +45) kcal/d)] (difference in between-group changes, P<0.05). TEE decreased in GnRHAG+PL [-128 (-214, -41) kcal/d] and GnRHAGAG+E2[-96 (-159, -32) kcal/d], with no significant difference in between-group changes (P=0.55). SEE decreased similarly in both GnRHAG+PL [-0.07 (-0.12, -0.03) kcal/min)] and GnRHAG+E2 [-0.07 (-0.12, -0.02) kcal/min)]. ExEE decreased in GnRHAG+PL [-0.46 (-0.79, -0.13) kcal/min)], but not GnRHAG+E2 [-0.30 (-0.65, +0.06) kcal/min]. There were no changes in TEF or NExEE in either group. In summary, chronic pharmacologic suppression of sex hormones reduced REE and this was prevented by E2therapy.
Gasier, H. G., Demchenko, I. T., Allen, B. W., Piantadosi, C. A., 2015-10-01 08:52:16 AM
The endogenous vasodilator and signaling molecule nitric oxide has been implicated in cerebral hyperemia, sympathoexcitation, and seizures induced by hyperbaric oxygen (HBO2) at or above 3 atmospheres absolute (ATA). It is unknown whether these events in the onset of central nervous system oxygen toxicity originate within specific brain structures and whether blood flow is diverted to the brain from peripheral organs with high basal flow, such as the kidney. To explore these questions, total and regional cerebral blood flow (CBF) were measured in brain structures of the central autonomic network in anesthetized rats in HBO2 at 6 ATA. Electroencephalogram (EEG) recordings, cardiovascular hemodynamics, and renal blood flow (RBF) were also monitored. As expected, mean arterial blood pressure and total and regional CBF increased preceding EEG spikes, while RBF was unaltered. Of the brain structures examined, the earliest rise in CBF occurred in the striatum, suggesting increased neuronal activation. Continuous unilateral or bilateral striatal infusion of the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester attenuated CBF responses in that structure, but global EEG discharges persisted and did not differ from controls. Our novel findings indicate that: i) cerebral hyperemia in extreme HBO2 in rats does not occur at the expense of renal perfusion, highlighting the remarkable autoregulatory capability of the kidney, and ii) in spite of a sentinel increase in striatal blood flow, additional brain structure(s) likely govern the pathogenesis of HBO2-induced seizures because EEG discharge latency was unchanged by local blockade of striatal NO production and concomitant hyperemia.
Andrews, C. G., Pagliardini, S., 2015-10-01 08:52:16 AM
Breathing is more vulnerable to apneas and irregular breathing patterns during rapid eye movement (REM) sleep in both humans and rodents. We previously reported that robust and recurrent recruitment of expiratory abdominal (ABD) muscle activity is present in rats during REM epochs despite ongoing REM-induced muscle atonia in skeletal musculature. To develop a further understanding of the characteristics of ABD recruitment during REM epochs and their relationship with breathing patterns and irregularities, we sought to compare REM epochs that displayed ABD muscle recruitment with those that did not, within the same rats. Specifically, we investigated respiratory characteristics that preceded and followed recruitment. We hypothesized that ABD muscle recruitment would be likely to occur following respiratory irregularities and would subsequently contribute to respiratory stability and the maintenance of good ventilation following recruitment. Our data demonstrate that epochs of REM sleep containing ABD recruitments (REMABD+) were characterized by increased respiratory rate variability and increased presence of spontaneous brief central apneas. Within these epochs, respiratory events that displayed ABD muscle activation were preceded by periods of increased respiratory rate variability. Onset of ABD muscle activity increased tidal volume, amplitude of diaphragmatic contractions and minute ventilation compared to the periods preceding ABD muscle activation. These results show that expiratory muscle activity is more likely recruited when respiration is irregular and its recruitment is subsequently associated with an increase in minute ventilation and a more regular respiratory rhythm
Ju, Y.-I., Sone, T., Ohnaru, K., Tanaka, K., Fukunaga, M., 2015-10-01 08:52:16 AM
Swimming is generally considered ineffective for increasing bone mass in humans, at least compared with weight-bearing sports. However, swimming exercise has sometimes been shown to have a strong positive effect on bone mass in small animals. This study investigated the effects of swimming on bone mass, strength, and microarchitecture in ovariectomized (OVX) rats. OVX or sham-operations were performed on 18-week-old female Fisher-344 rats. Rats were randomly divided into 4 groups: sham sedentary (Sham-CON); sham swimming-exercised (Sham-SWI); OVX sedentary (OVX-CON); and OVX swimming-exercised (OVX-SWI). Rats in exercise groups performed swimming in a water bath for 60 min/day, 5 days/week, for 12 weeks. Bone mineral density (BMD) in right femurs was analyzed using dual-energy X-ray absorptiometry. Three-dimensional trabecular architecture at the distal femoral metaphysis was analyzed using microcomputed tomography (micro-CT). Geometrical properties of diaphyseal cortical bone were evaluated in the mid-femoral region using micro-CT. The biomechanical properties of femurs were analyzed using 3-point bending. Femoral BMD was significantly decreased following ovariectomy. This change was suppressed by swimming. Trabecular bone thickness, number, and connectivity were decreased by ovariectomy, whereas structure model index (i.e., ratio of rod-like to plate-like trabeculae) increased. These changes were also suppressed by swimming exercise. Femurs displayed greater cortical width and maximum load in SWI groups than in CON groups. Together, these results demonstrate that swimming exercise drastically alleviated both OVX-induced decreases in bone mass and mechanical strength, and the deterioration of trabecular microarchitecture in rat models of osteoporosis.
Strandberg, E., Edholm, P., Ponsot, E., Wahlin-Larsson, B., Hellmen, E., Nilsson, A., Engfeldt, P., Cederholm, T., Riserus, U., Kadi, F., 2015-10-01 08:52:16 AM
The delivery of efficient non-pharmacological treatment to prevent the loss of muscle mass in elderly is a major challenge and information on the combined effects of training and diet is particularly important. Here we aimed to evaluate the effects of 24 weeks resistance training combined to a healthy dietary approach (n-6/n-3 ratio < 2) in a population of healthy and physically active elderly women (65-70 years). The three-armed randomized controlled trial included a resistance training + healthy diet group (RT-HD), a resistance training group (RT) and controls (CON). All subjects included in the study were physically active and had low levels of serum inflammatory markers. In accordance with the dietary goals, the n-6/n-3 ratio dietary intake significantly decreased only in RT-HD by 42%. An increase in 1RM in leg-extension occurred in RT (+20.4%) and RT-HD (+20.8%) but not in CON. Interestingly, leg lean mass significantly increased only in RT-HD (+1.8%). While there were no changes in serum CRP and IL-6 levels, a significant decrease in serum level of the pro-inflammatory precursor arachidonic acid (-5.3±9.4%) together with an increase in serum n-3 docosahexaenoic acid (+8.3%) occurred only in RT-HD. Altogether, this study demonstrates that the effects of resistance training on muscle mass in healthy elderly can be optimized by the adoption of a healthy diet.
Adenosine is a major signaling nucleoside that orchestrates cellular and tissue adaptation under energy depletion and ischemic/hypoxic conditions by activation of four G-protein coupled receptors (GPCR). The regulation and generation of extracellular adenosine in response to stress is critical in tissue protection. Both mouse and human studies reported that extracellular adenosine signaling plays a beneficial role during acute states. However, prolonged excess extracellular adenosine is detrimental and contributes to the development and progression of various chronic diseases. Recent years, substantial progress has been made to understand the role of adenosine signaling in different conditions and to clarify its significance during the course of disease progression in various organs. These efforts have and will identify potential therapeutic possibilities for protection of tissue injury at acute stage by up-regulation of adenosine signaling or attenuation of chronic disease progression by down-regulation of adenosine signaling. This review is to summarize current progress and the importance of adenosine signaling in different disease stages and its potential therapeutic effects.
Jahani, N., Choi, S., Choi, J., Iyer, K., Hoffman, E. A., Lin, C.-L., 2015-10-01 08:52:16 AM
This study aims to assess regional ventilation, nonlinearity and hysteresis of human lungs during dynamic breathing via image registration of four-dimensional computed tomography (4D-CT) scans. Six healthy adult humans were studied by spiral multi-detector row computed tomography (MDCT) during controlled tidal breathing as well as during total lung capacity (TLC) and functional residual capacity (FRC) breath holds. Static images were utilized to contrast static vs. dynamic (deep vs. tidal) breathing. A rolling-seal piston system was employed to maintain consistent tidal breathing during 4D-CT spiral image acquisition, providing required between-breath consistency for physiologically meaningful reconstructed respiratory motion. Registration-derived variables including local air volume and anisotropic deformation index (ADI, an indicator of preferential deformation in response to local force) were employed to assess regional ventilation and lung deformation. Lobar distributions of air volume change during tidal breathing were correlated with those of deep breathing (R2 0.84). Small discrepancies between tidal and deep breathing were shown to be likely due to different distributions of air volume change in the left and the right lungs. We also demonstrated an asymmetric characteristic of flow rate between inhalation and exhalation. With ADI, we were able to quantify nonlinearity and hysteresis of lung deformation that can only be captured in dynamic images. Nonlinearity quantified by ADI is greater during inhalation, and it is stronger in the lower lobes (P<0.05). Lung hysteresis estimated by the difference of ADIbetween inhalation and exhalation is more significant in the right lungs than that in the left lungs.
Individual variation in the thermoregulatory responses to exercise is notoriously large. Although aerobic fitness (VO2max) and body fatness are traditionally considered important predictors of individual core temperature and sweating responses, recent evidence indicates potentially important and independent roles for biophysical factors. Using stepwise regression we examined the proportion of individual variability in rectal temperature changes (Tre), whole-body sweat loss (WBSL), and steady-state local sweat rate (LSRss) independently described by i) biophysical factors associated with metabolic heat production (Hprod) and evaporative heat balance requirements (Ereq) relative to body size, and ii) factors independently related to VO2max and body fatness. In a total of 69 trials, twenty-eight males of wide-ranging morphological traits and VO2max values cycled at workloads corresponding to a range of absolute Hprod (410-898 W) and relative intensities (32.2-82.0% VO2max) for 60 min in 24.8±0.7°C, 33.4±12.2%RH. Hprod (in W/kg of total body mass) alone described ~50% of the variability in Tre(adjusted R2=0.496; P<0.001), while surface area-to-mass ratio and body fat percentage (BF%) explained an additional 4.3% and 2.3% of variability, respectively. For WBSL, Ereq (in W) alone explained ~71% of variance (adjusted R2=0.713,P<0.001), and the inclusion of BF% explained an additional 1.3%. Similarly, Ereq (in W/m2) correlated significantly with LSRss (adjusted R2=0.603 P<0.001), while %VO2max described an additional ~4% of total variance. In conclusion, biophysical parameters related to Hprod, Ereq, and body size explain 54-71% of the individual variability in Tre, WBSL, and LSRss, and only 1-4% of additional variance is explained by factors related to fitness or fatness.
Chowdhuri, S., Pranathiageswaran, S., Franco-Elizondo, R., Jayakar, A., Hosni, A., Nair, A., Badr, M. S., 2015-10-01 08:52:16 AM
The reason for increased sleep disordered breathing with predominance of central apneas in the elderly is unknown. We speculate that ventilatory control instability may provide a link between aging and the onset of unstable breathing during sleep. We sought to investigate potential underlying mechanisms in healthy elderly adults during sleep. We hypothesized that there is i) a decline in respiratory plasticity or long-term facilitation of ventilation (LTF) and/or ii) increased ventilatory chemosensitivity in older adults during NREM sleep. Fourteen elderly adults underwent fifteen 1-minute episodes of isocapnic hypoxia (EH), nadir O2 saturation: 87.0±0.8%). Measurements were obtained during control, hypoxia, and up to 20 minutes of recovery following the EH protocol, respectively, for minute ventilation (VI), timing and inspiratory upper airway resistances (RUA). Results: i) Compared to baseline, there was a significant increase in VI (158±11%, p<0.05) during EH but this was not accompanied by augmentation of VI during the successive hypoxia trials nor an increase in VI during the recovery period (94.4±3.5%, p=ns), indicating absence of LTF. There was no change in inspiratory RUA during the trials. This is in contrast to our previous findings of respiratory plasticity with reduction in RUA in young adults during sleep. Sham studies did not show a change in any of the measured parameters. ii) We also observed increased chemosensitivity as denoted by increased isocapnic hypoxic ventilatory response and hyperoxic suppression of VIin older vs.young adults during sleep. Thus, increased chemosensitivity unconstrained by respiratory plasticity may explain increased central apneas in the elderly.
Atkinson, C. L., Carter, H. H., Naylor, L. H., Dawson, E. A., Marusic, P., Hering, D., Schlaich, M. P., Thijssen, D. H. J., Green, D. J., 2015-10-01 08:52:16 AM
Introduction. Whilst the impact of changes in blood flow and shear stress on artery function are well documented, the acute effects of increases in arterial pressure are less well described. The aim of this study was to assess the effect of 30-minutes of elevated blood pressure, in the absence of changes in shear stress or sympathetic nervous system (SNS) activation, on conduit arterial diameter. Methods. Ten male subjects undertook 3 sessions of 30-minutes unilateral handgrip (HG) exercise at 5, 10 and 15% of maximal voluntary contractile (MVC) strength. Brachial artery shear and flow were measured simultaneously during exercise in the active and contralateral resting, arms. Bilateral brachial artery diameter was simultaneously assessed prior to- and immediately post-exercise. In a second experiment, 6 subjects repeated the 15% MVC condition whilst continuous vascular measurements were collected along with measures of muscle sympathetic nerve activity (MSNA). Results. Unilateral HG exercise at all intensities induced step-wise elevations in blood pressure (P<0.01). Whilst step-wise increases were evident in shear rate in the exercising arm (P<0.001), no changes were apparent in the non-exercising limb (P=0.42). Brachial diameter increased in the exercising arm (P=0.02), but significantly decreased in the non-exercising arm (P=0.03). At 15% MVC, changes in diameter were significantly different between arms (interaction-effect P=0.01), with no significant changes in MSNA. Conclusion. Acute increases in transmural pressure, independent of shear and SNS activity, reduce arterial calibre in normotensive humans in vivo. These changes in diameter were mitigated by exercise-induced elevations in shear rate in the active limb.
Stec, M. J., Mayhew, D. L., Bamman, M. M., 2015-10-01 08:52:16 AM
The hypertrophic response to resistance training is generally attenuated with aging; yet the mechanisms regulating this phenomenon are largely unknown. Several studies to date have shown blunted translational efficiency following acute resistance exercise in older adults; however, the effects on translational capacity (i.e. ribosome biogenesis) have not yet been examined. Thus, the purpose of this study was to examine changes in markers of ribosome biogenesis following an acute bout of resistance loading (RL; 9 sets x 10 repetitions of knee extensions) in younger (Y; n = 14; 39.2 ± 4.1y) and older (O; n = 12; 75.7 ± 5.7y) adults. Vastus lateralis biopsies were taken pre- and 24h post-RL, and muscle samples were analyzed for total RNA content, 45S pre-rRNA expression, ribosomal protein content, and levels of signaling proteins that regulate ribosome biogenesis. Prior to RL, O had higher total RNA content (+28%; p < 0.05), a trend toward higher 45S pre-rRNA expression (+59%; p = 0.08), and greater protein content of several ribosomal components ( +50-80%; p < 0.05) than Y. However, 24h post-RL, only Y increased 45S pre-rRNA expression (+34%; p< 0.01), possibly driven by higher basal p-Rb (Ser780) (+61%; p = 0.10), and a robust TIF-1a response (+75%; p < 0.05). RL tended to increase protein components of the 40S ribosomal subunit in Y only ( +20-25%; p ≤ 0.12). Overall, the data suggest blunted ribosome biogenesis in response to RL in O, which may be a potential mechanism driving the age-related attenuation of resistance training-induced hypertrophy.
Sweet, J. G., Chan, S.-L., Cipolla, M. J., 2015-10-01 08:52:16 AM
We studied the effect of hypertension and chronic hypoperfusion on brain parenchymal arteriole (PA) structure and function. PAs were studied isolated and pressurized from 18-week old Wistar Kyoto (WKY18; n=8), spontaneously hypertensive stroke prone (SHRSP18; n=8) and 5-week old pre-hypertensive (SHRSP5; n=8) rats. In separate groups, unilateral common carotid artery occlusion (UCCAo) was performed for 4 weeks to cause chronic hypoperfusion in 18-week old WKY (WKY18-CH; n=8) and SHRSP (SHRSP18-CH; n=8). UCCAo caused PAs to have significantly diminished myogenic tone (31±3 vs. 14±6% at 60 mm Hg; p<0.05) and reactivity to pressure from WKY18-CH animals vs. WKY18. The effect of UCCAo was limited to normotensive animals, as there was little effect of chronic hypoperfusion on vascular reactivity or % tone in PAs from SHRSP18 vs. SHRSP18-CH animals (53±4 vs. 41±3%; p>0.05). However, PAs from SHRSP18 and SHRSP5 animals had significantly greater tone compared to WKY18, suggesting an effect of strain and not hypertension per se on PA vasoconstriction. Structurally, PAs from SHRSP18 and SHRSP5 animals had similar sized lumen diameters, but increased wall thickness and distensibility compared to WKY18. Interestingly, chronic hypoperfusion did not affect the structure of PAs from either WKY18-CH or SHRSP18-CH animals. Thus, PAs responded to UCCAo with active vasodilation, but not structural remodeling, an effect that was absent in SHRSP. The increased tone of PAs from SHRSP animals, combined with lack of response to chronic hypoperfusion may contribute to the propensity for ischemic lesions and increased perfusion deficit during hypertension.
Pharmacotherapy in acute mountain sickness (AMS) over for the past half century has largely rested on the use of carbonic anhydrase (CA) inhibitors, such as acetazolamide, and corticosteroids, such as dexamethasone. The benefits of CA inhibitors are thought to arise from their known ventilatory stimulation from inhibition of renal carbonic anhydrase and generation of a mild metabolic acidosis. Those for corticosteroids include their broad based anti-inflammatory and anti-edemagenic effects. What has emerged from more recent work is the strong likelihood that drugs in both classes act on other pathways and signaling beyond their classical actions to prevent and treat AMS. For the CA inhibitors these include reduction in aquaporin-mediated transmembrane water transport, anti-oxidant actions, vasodilation, and anti-inflammatory effects. In the case of corticosteroids these include protection against increases in vascular endothelial and blood-brain barrier permeability, suppression of inflammatory cytokines and reactive oxygen species production, and sympatholysis. The loci of action of both classes of drug include the brain, but may also involve the lung as revealed by benefits that arise with selective administration to the lungs by inhalation. Greater understanding of their pluripotent actions and sites of action in AMS may help guide development of better drugs with more selective action and fewer side effects.
Wilson, M. H., Imray, C. H. E., 2015-10-01 08:52:16 AM
Most hypobaric hypoxia studies have focused on oxygen delivery and therefore cerebral blood inflow. Few have studied venous outflow. However, the volume of blood entering and leaving the skull (approximately 700mls/min) is considerably greater than CSF production (0.35mls/min) or edema formation rates and slight imbalances of in- and out-flow have considerable effects on intracranial pressure (ICP). This dynamic phenomenon is not necessarily appreciated in the currently taught static "Monro-Kellie" doctrine which forms the basis of the "Tight-Fit" hypothesis thought to under lie high altitude headache, acute mountain sickness (AMS) and High Altitude Cerebral Edema (HACE). Investigating both sides of the cerebral circulation was an integral part of the 2007 Xtreme Everest Expedition. The results of the relevant studies performed as part of and subsequent to this expedition are reviewed here. The evidence from recent studies suggests a relative venous outflow insufficiency is an early step in the pathogenesis of high altitude headache. Translation of knowledge gained from high altitude studies is important. Many patients in a critical care environment develop hypoxemia akin to that of high altitude exposure. An inability to drain the hypoxemic induced increase in cerebral blood flow could be an underappreciated regulatory mechanism of intracranial pressure.
Huerta-Sanchez, E., Casey, F. P., 2015-10-01 08:52:16 AM
The Tibetan Plateau, often called the roof of the world, sits at an average altitude exceeding 4500 meters. Due to its extreme altitude, the Plateau is one of the harshest human-inhabited environments in the world. This, however, did not impede human colonization, and the Tibetan people have made the Tibetan Plateau their home for many generations. Many studies have quantified their markedly different physiological response to altitude, and proposed that Tibetans were genetically adapted. Recently, advances in sequencing technologies led to the discovery of a set of candidate genes which harbor mutations that are likely beneficial at high altitudes in Tibetans. Since then, other studies have further characterized this impressive adaptation. Here, in this mini-review, we discuss the progress made since the discovery of the genes involved in Tibetan's adaptation to high altitude with a particular emphasis on describing the series of studies that led us to conclude that archaic human DNA likely contributed to this impressive adaptation.
Greaney, J. L., Alexander, L. M., Kenney, W. L., 2015-10-01 08:52:16 AM
This Synthesis highlights a series of recent studies that has systematically interrogated age-related deficits in cold-induced skin vasoconstriction. In response to cold stress, a reflex increase in sympathetic nervous system activity mediates reductions in skin blood flow. Reflex vasoconstriction during cold exposure is markedly impaired in aged skin, contributing to the relative inability of healthy older adults to maintain core temperature during mild cold stress in the absence of appropriate behavioral thermoregulation. This compromised reflex cutaneous vasoconstriction in healthy aging can occur as a result of functional deficits at multiple points along the efferent sympathetic reflex axis, including blunted sympathetic outflow directed to the skin vasculature, reduced pre-synaptic neurotransmitter synthesis and/or release, and altered end-organ responsiveness at several loci, in addition to potential alterations in afferent thermoreceptor function. Arguments have been made that the relative inability of aged skin to appropriately constrict is due to the aging cutaneous arterioles themselves, while other data point to the neural circuitry controlling those vessels. The argument presented herein provides strong evidence for impaired efferent sympathetic control of the peripheral cutaneous vasculature during whole-body cold exposure as the primary mechanism responsible for attenuated vasoconstriction.
Gifford, J. R., Trinity, J. D., Layec, G., Garten, R. S., Park, S.-Y., Rossman, M. J., Larsen, S., Dela, F., Richardson, R. S., 2015-10-01 08:52:16 AM
This study sought to determine if qualitative alterations in skeletal muscle mitochondrial respiration, associated with decreased mitochondrial efficiency, contribute to exercise intolerance in patients with COPD. Using permeabilized muscle fibers from the vastus lateralis of 13 patients with COPD and 12 healthy controls, complex I (CI) and complex II (CII)-driven State 3 mitochondrial respiration were measured separately (State 3:CI and State 3:CII) and in combination (State 3:CI+CII). State 2 respiration was also measured. Exercise tolerance was assessed by knee extensor exercise (KE) time to fatigue. Per mg of muscle, State 3:CI+CII and State 3:CI were reduced in COPD (P<0.05), while State 3:CII and State 2 were not different between groups. To determine if this altered pattern of respiration represented qualitative changes in mitochondrial function, respiration states were examined as percentages of peak respiration (State 3:CI+CII), which revealed altered contributions from State 3:CI (Con: 83.7 ± 3.4 COPD: 72.1 ± 2.4 %Peak, P<0.05) and State 3:CII (Con: 64.9± 3.2 COPD: 79.5 ± 3.0 %Peak, P<0.05) respiration, but not State 2 respiration in COPD. Importantly, a diminished contribution of CI-driven respiration relative to the metabolically less-efficient CII-driven respiration (CI/CII) was also observed in COPD (Con: 1.28 ± 0.09, COPD: 0.81 ± 0.05, P<0.05), which was related to exercise tolerance of the patients (r=0.64, P<0.05). Overall, this study indicates that COPD is associated with qualitative alterations in skeletal muscle mitochondria that affect the contribution of CI and CII-driven respiration, which potentially contributes to the quadriceps exercise intolerance associated with this disease.
Manley, E., Perosky, J. E., Khoury, B. M., Reddy, A. B., kozloff, K. M., Alford, A. I., 2015-10-01 08:52:16 AM
Thombospondin-2 (TSP2) is a matricellular protein component of the bone extracellular matrix (ECM). Long bones of adult TSP2-deficient mice have increased endosteal bone thickness due to expansion of the osteoblast progenitor cell pool, and these cells display deficits in osteoblastic potential. Here, we investigated the effects of TSP2-deficiency on whole bone geometric and mechanical properties in growing 6-week old male and female wild type (WT) and TSP2-knockout (KO) mice. Micro-computed tomography (µCT) and mechanical testing were conducted on femora and L2 vertebrae to assess morphology and whole bone mechanical properties. In a second series of experiments, femoral diaphsyses were harvested from WT and TSP2-KO mice. Detergent-soluble type I collagen content was determined by Western blot of right femora. Total collagen content was determined by hydroxyproline analysis of left femora. In a third series of experiments, cortical bone was dissected from the anterior and posterior aspects of the femoral mid-diaphysis and imaged by transmission electron microscopy to visualize collagen fibrils. µCT revealed minimal structural effects of TSP2-deficiency. TSP2-deficiency imparted a brittle phenotype on cortical bone. Femoral tissue mineral density was not affected by TSP2 deficiency. Instead, TEM revealed less-intensely stained collagen fibrils with altered morphology in the ECM assembled by osteoblasts on the anterior surface of TSP2-KO femora. Femoral diaphyseal bone displayed comparable amounts of total collagen, but the TSP2-KO bones had higher levels of detergent-extractable type I collagen. Together, our data suggest that TSP2 is required for optimal collagen fibrillogenesis in bone and thereby contributes to normal skeletal tissue quality.
In the last few years, genetic and functional studies have provided important insight on the pathophysiology of excessive erythrocytosis (EE), the main sign of Chronic Mountain Sickness (CMS). The recent finding of the association of the CMS phenotype with a single-nucleotide polymorphism (SNP) in the SENP1 gene, and its differential expression pattern in CMS and non-CMS Andean highlanders, has triggered large interest in the high-altitude field because of the potential role of its gene-product in the control of erythropoiesis. The SENP1 gene encodes for a protease that regulates the function of hypoxia-relevant transcription factors such as HIF and GATA, and thus might have an erythropoietic regulatory role in CMS through the modulation of the expression of Epo or Epo receptors. The different physiological patterns in the Epo-EpoR system found among Andeans, even within CMS highlanders, together with their different degrees of erythropoietic response, might indicate specific underlying genetic backgrounds, which in turn might reflect different levels of adaptation to lifelong high-altitude hypoxia. This mini-review discusses recent genetic findings potentially underlying EE and CMS, and their possible physiological mechanisms in Andean highlanders.
Vutthasathien, P., Wattanapermpool, J., 2015-10-01 08:52:16 AM
Data from the Testosterone in Older Men with Mobility Limitations Trial (TOM) has indicated an association of testosterone administration with increased risk of adverse cardiovascular events. We therefore propose that regular exercise is a cardioprotective alternative that prevents detrimental changes in contractile activation in the condition of male sex hormone deficiency. Ten-wk orchidectomized (ORX) rats were subjected to a 9-wk treadmill running program at moderate intensity starting one week after surgery. Although exercise-induced cardiac hypertrophy was observed in both sham-operated and ORX rats, regular exercise enhanced cardiac myofilament Ca2+ sensitivity and myosin light chain 2 phosphorylation only in sham-operated rats. While the exercised sham rats exhibited no change in maximum developed tension, regular running prevented the suppression of maximum active tension in ORX rat hearts. Regular exercise also prevented the shift of myosin heavy chain (MHC) isoforms toward β-MHC, reduction in sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity, and the increase in SERCA sensitivity in the ORX rat hearts. Neither SERCA content nor its modulating component, phospholamban (PLB), was altered by exercise in both sham-operated and ORX rats. However, decreases in phosphorylated Thr17 form of PLB and phosphorylated Thr287 form of Ca2+/calmodulin-dependent kinase II in ORX rat hearts were abolished after regular exercise. These results, thus, support the use of regular running as a cardioprotective alternative to testosterone replacement in hypogonadal conditions.
Sankari, A., Bascom, A. T., Riehani, A., Badr, M. S., 2015-10-01 08:52:16 AM
Cardiorespiratory plasticity induced by acute intermittent hypoxia (AIH) may contribute to recovery following spinal cord injury (SCI). We hypothesized that patients with cervical SCI would demonstrate higher minute ventilation (VE) following AIH compared to thoracic SCI and able-bodied control subjects. 24 volunteers (8 cervical SCI, 8 thoracic SCI and 8 able-bodied subjects) underwent AIH protocol during wakefulness. Each subject had 15 episodes of isocapnic hypoxia using mixed gases of 100% nitrogen (N2), 8% O2, and 40% CO2 to achieve oxygen saturation ≤90% followed by room air (RA). Measurements were obtained before, during, and 40 minutes after AIH for ventilation and heart rate variability [R-R interval (RRI) and low/high frequency power (LF/HF)]. AIH results were compared to sham studies conducted on RA over the same time. The cervical SCI individuals had higher VE post-AIH compared to able-bodied controls (117.9±23.2% vs. 97.9±11.2%, P<0.05). RRI decreased during hypoxia in the cervical SCI, thoracic SCI and able-bodied groups (from 1009.3±65.0 ms to 750.2±65.0 ms vs. 945.2±65.0 ms to 674.9±65.0 ms vs. 949±75.0 to 682.2±69.5 ms, respectively; P<0.05). LH/HF increased in thoracic SCI and able-bodied groups during recovery (0.54±0.22 vs. 1.34±0.22 and 0.67±0.23 vs. 1.82±0.23, respectively; P<0.05), but remained unchanged in the cervical SCI group. Conclusion: Patients with cervical SCI demonstrate ventilatory LTF following AIH compared to the able-bodied controls. Heart rate responses to hypoxia are present acutely in cervical SCI patients but are absent during post-hypoxic recovery.
Johnson, M. A., Sharpe, G. R., Williams, N. C., Hannah, R., 2015-10-01 08:52:16 AM
This study examined the effects of prior upper body exercise on subsequent high-intensity cycling exercise tolerance and associated changes in neuromuscular function and perceptual responses. Eight males performed 3 fixed work-rate (85% peak power) cycling tests: (1) to the limit of tolerance (CYC); (2) to the limit of tolerance after prior high-intensity arm-cranking exercise (ARM-CYC); (3) without prior exercise and for an equal duration as ARM-CYC (ISOTIME). Peripheral fatigue was assessed via changes in potentiated quadriceps twitch force during supramaximal electrical femoral nerve stimulation. Voluntary activation was assessed using twitch interpolation during maximal voluntary contractions. Cycling time during ARM-CYC and ISOTIME (4.33 ± 1.10 min) was 38% shorter than CYC (7.46 ± 2.79 min) (P < 0.01). Twitch force decreased more after CYC (-38 ± 13%) than ARM-CYC (-26 ± 10%) (P < 0.01) and ISOTIME (-24 ± 10%) (P < 0.05). Voluntary activation was 94 ± 5% at rest and decreased after CYC (89 ± 9%, P < 0.01) and ARM-CYC (91 ± 8%, P < 0.05). Rating of perceived exertion for limb discomfort increased more quickly during ARM-CYC (1.83 ± 0.46 AU•min-1) than CYC (1.10 ± 0.38 AU•min-1) and ISOTIME (1.05 ± 0.43 AU•min-1) (P < 0.01), and this was correlated with the reduced cycling time in ARM-CYC (r = -0.72, P = 0.045. In conclusion, cycling exercise tolerance after prior upper body exercise is potentially mediated by central fatigue and intolerable levels of sensory perception rather than a critical peripheral fatigue limit.
Hopkins, N. D., Dengel, D. R., Stratton, G., Kelly, A. S., Steinberger, J., Zavala, H., Marlatt, K., Perry, D., Naylor, L. H., Green, D. J., 2015-10-01 08:52:16 AM
Background: Flow-mediated dilation (FMD) is a non-invasive technique used to measure conduit artery vascular function. Limited information is available on normative FMD values in healthy children and adolescents. Objective: To assess relationships between age and sex on with FMD across childhood and adolescence. Methods: Nine hundred and seventy-eight asymptomatic children (12+3yrs, range 6 - 18yrs, 530 male) underwent ultrasonic brachial artery assessment prior to, and following five minutes of forearm ischemia. Sex differences in FMD and baseline artery diameter were assessed using mixed linear models. Results: Baseline artery diameter was smaller in females than males (2.96mm (95% CI, 2.92, 3.00) vs 3.24 (3.19, 3.28), P<0.001), and increased with age across the cohort (P<0.001). Diameter increased between 6 and 17 years old in males (2.81mm (2.63, 3.00) to 3.91mm (3.68, 4.14)), but plateaued at age 12 in females. Males had a lower FMD (7.62 (7.33, 7.91) vs 8.31 (7.95, 8.66), P=0.024), specifically at ages 17 and 18. There was a significant effect of age on FMD (P=0.023), with a reduction in FMD apparent post-puberty in males. Conclusions: The brachial artery increases structurally with age in both sexes, however there are sex differences in the timing and rate of growth, in line with typical sex-specific adolescent growth patterns. Males have a lower FMD than females, and FMD appears to decline with age, however these findings are driven by reductions in FMD as males near maturity. The use of age- and sex-specific FMD data may therefore not be pertinent in childhood and adolescence
In 1875 Paul Bert linked high altitude danger to the low partial pressure of oxygen when 2 of 3 French balloonists died euphorically at about 8600 m altitude. World War I fatal crashes of high altitude fighter pilots led to a century of efforts to use oximetry to warn pilots. The carotid body, discovered in 1932 to be the hypoxia detector, led to most current physiologic understanding of the body's respiratory responses to hypoxia and CO2. The author describes some of his UCSF group's work: In 1963, we reported both the brain's ventral medullary near-surface CO2 (and pH) chemosensors and the role of CSF (cerebrospinal fluid) in acclimatization to altitude. In 1966 we reported the effect of altitude on CBF (cerebral blood flow) and later the changes of carotid body sensitivity at altitude and the differences in natives of high altitude. In 1973, pulse oximetry was invented when Japanese biophysicist Takuo Aoyagi read and applied to pulses a largely forgotten 35-year-old discovery by English medical student J R Squire of a method of computing oxygen saturation from red and infrared light passing through both perfused and blanched tissue.
Martin, B. L., Gallagher, T. L., Rastogi, N., Davis, J. P., Beattie, C. E., Amacher, S. L., Janssen, P. M. L., 2015-10-01 08:52:16 AM
The accessible genetics and extensive skeletal musculature of the zebrafish make it a versatile and increasingly used model for studying muscle contraction. We here describe the development of an in vivo assay for measuring the contractile force of intact zebrafish at the larval stage. In addition, as proof of applicability, we have used this assay to quantify contractile strength of zebrafish larvae in a morphant model of deranged rbfox function. Average maximum tetanic (180 Hz) whole-body forces produced by wild-type larvae at 2, 3, 4, and 5 days post fertilization (dpf) amounted to 3.0, 7.2, 9.1, and 10.8 mN, respectively. To compare at potentially different stages of muscle development, we developed an immunohistological assay for empirically determining the cross-sectional area of larval trunk skeletal muscle to quantify muscle-specific force per cross-sectional area. At 4-5 dpf, specific force amounts to about 300 mN/mm2, which is similar to fully developed adult mammalian skeletal muscle. We used these assays to measure contractile strength in zebrafish singly or doubly deficient for two rbfox paralogs, rbfox1l and rbfox2, which encode RNA-binding factors shown previously to modulate muscle function and muscle-specific splicing. We found rbfox2 morphants produce maximal tetanic forces similar to wild-type larvae, while rbfox1l morphants demonstrate significantly impaired function. rbfox1l/rbfox2 morphants are paralyzed and their lack of contractile force production in our assay suggests that paralysis is a muscle-autonomous defect. These quantitative functional results allow measurement of muscle-specific phenotypes independent of neural input.
Mayfield, D. L., Lichtwark, G. A., Cronin, N. J., Avela, J., Cresswell, A. G., 2015-10-01 08:52:16 AM
Activation of skeletal muscle twice in quick succession results in nonlinear force summation (i.e. doublet potentiation). The force contributed by a second activation is typically of augmented amplitude, longer in duration and generated at a greater rate. The purpose of this study was to examine force summation in a muscle attached to a compliant tendon, where considerable internal shortening occurs during a fixed-end contraction. The triceps surae of 21 (Experiment 1) and nine (Experiment 2) young adults were maximally activated with doublet stimulation of different interstimulus intervals (ISIs) (5-100 ms) at several muscle lengths. Ultrasound images acquired from lateral gastrocnemius and soleus muscles allowed quantification of dynamic fascicle behavior. Force summation was muscle length-dependent. Force augmentation was limited to a short muscle length. Lateral gastrocnemius and soleus fascicles underwent large amounts of active shortening and achieved high velocities in response to doublet stimulation, dynamics unfavorable for force production. Summation amplitude and the sensitivity of summation to ISI were dramatically depressed in the triceps surae after comparison to muscles with less fixed-end compliance. We propose that the internal shortening permitted by high series compliance limited force augmentation by offsetting and/or interfering with activation and cross-bridge processes driving augmentation. High series compliance may also reduce the sensitivity of the summated response to ISI, an assertion supported by predictions from a Hill-type muscle model. These muscles may exhibit greater force augmentation during more accustomed stretch-shorten tasks (i.e. hopping), where the compliance of the Achilles tendon actually enables near-isometric fascicle behaviour.
Heinzel, F. R., Hohendanner, F., Jin, G., Sedej, S., Edelmann, F., 2015-10-01 08:52:16 AM
Left ventricular hypertrophy (LVH) is the most common myocardial structural abnormality associated with heart failure with preserved ejection fraction (HFpEF). LVH is driven by neurohumoral activation, increased mechanical load and cytokines associated with arterial hypertension, chronic kidney disease, diabetes and other co-morbidities. Here we discuss the experimental and clinical evidence that links LVH to diastolic dysfunction and qualifies LVH as one diagnostic marker for HFpEF. Mechanisms leading to diastolic dysfunction in LVH are incompletely understood but may include extracellular matrix changes, vascular dysfunction as well as altered cardiomyocyte mechano-elastical properties. Beating cardiomyocytes from HFpEF patients have not yet been studied, but we and others have shown increased Ca2+ turnover and impaired relaxation in cardiomyocytes from hypertrophied hearts. Structural myocardial remodeling can lead to heterogeneity in regional myocardial contractile function, which contributes to diastolic dysfunction in HFpEF. In the clinical setting of patients with compound co-morbidities, diastolic dysfunction may occur independently of LVH. This may be one explanation why current approaches to reduce LVH have not been effective to improve symptoms and prognosis in HFpEF. Exercise training on the other hand, in clinical trials improved exercise tolerance and diastolic function but did not reduce LVH. Thus, current clinical evidence does not support regression of LVH as a surrogate marker for (short-term) improvement of HFpEF.
Weiss, J. W., Tamisier, R., Liu, Y., 2015-10-01 08:52:16 AM
Obstructive sleep apnea (OSA) is characterized by repetitive episodes of upper airway obstruction during sleep. These obstructive episodes are characterized by cyclic intermittent hypoxia (CIH), by sleep fragmentation, and by hemodynamic instability and they result in sustained sympathoexcitation and elevated arterial pressure that persist during waking, after restoration of normoxia. Early studies established that: 1) CIH, rather than sleep disruption, accounts for the increase in arterial pressure; 2) the increase in arterial pressure is a consequence of the sympathoactivation; and, 3) arterial hypertension after CIH exposure requires an intact peripheral chemoreflex. More recently, however, evidence has accumulated that sympathoactivation and hypertension after CIH are also dependent on altered central sympathoregulation. Furthermore, although many molecular pathways are activated in both the carotid chemoreceptor and in the central nervous system by CIH exposure, two specific neuromodulators - endothelin-1 and angiotensin II - appear to play crucial roles in mediating the sympathetic and hemodynamic response to intermittent hypoxia.
Sale, C., Varley, I., Jones, T. W., James, R. M., Tang, J. C. Y., Fraser, W. D., Greeves, J. P., 2015-10-01 08:52:16 AM
PURPOSE: Bone resorption is increased following running, with no change in bone formation. Feeding during exercise might attenuate this increase, preventing associated problems for bone. To investigate the immediate and short-term bone metabolic responses to carbohydrate (CHO) feeding during treadmill running. METHODS: Ten men completed two 7 d trials, once being fed CHO (8% glucose immediately before, every 20 min during and immediately after exercise at a rate of 0.7 gCHO·kg-1BM·h-1) and once placebo (PBO). On day 4 of each trial, participants completed a 120 min treadmill run at 70% VO2max. Blood was taken at baseline (BASE) immediately after exercise (EE), after 60 (R1) and 120 (R2) min of recovery and on 3 follow-up days (FU1-FU3). Markers of bone resorption (β-CTX) and formation (P1NP) were measured, along with OC, PTH, ACa, PO4, GLP-2, IL-6, insulin, cortisol, leptin and OPG. Area under the curve was calculated in terms of the immediate (BASE, EE, R1 and R2) and short-term (BASE, FU1, FU2 and FU3) responses to exercise. RESULTS: β-CTX, P1NP and IL-6 responses to exercise were significantly lower in the immediate post-exercise period with CHO feeding (β-CTX: P=0.028; P1NP: P=0.021; IL-6: P=0.036), although there was no difference in the short-term response (β-CTX: P=0.856; P1NP: P=0.721; IL-6: P=0.327). No other variable was significantly affected by CHO feeding during exercise. CONCLUSION: CHO feeding during exercise attenuated the β-CTX and P1NP responses in the hours but not days following exercise, indicating an acute effect of CHO feeding on bone turnover.
Harrison, D. K., Fasching, M., Fontana-Ayoub, M., Gnaiger, E., 2015-10-01 08:52:16 AM
Mitochondrial control of cellular redox states is a fundamental component of cell signaling in the coordination of core energy metabolism and homeostasis during normoxia and hypoxia. We investigated the relationship between cytochrome redox states and mitochondrial oxygen consumption at steady-state levels of hypoxia in mitochondria isolated from beef and mouse heart (BHImt, MHImt), comparing two species with different cardiac dynamics and local oxygen demands. A low-noise, rapid spectrophotometric system using visible light for the measurement of cytochrome redox states was combined with high-resolution respirometry. Monophasic hyperbolic relations were observed between oxygen consumption, JO2, and oxygen partial pressure, pO2, within the range <1.1 kPa (8.3 mmHg; 13 µM). p50j (pO2 at 0.5•Jmax) was 0.015±0.0004 and 0.021±0.003 kPa (0.11 and 0.16 mmHg) for BHImt and MHImt, respectively. Maximum oxygen consumption, Jmax, was measured at saturating ADP levels (OXPHOS capacity) with Complex I-linked substrate supply. Redox states of cytochromes aa3 and c were biphasic hyperbolic functions of pO2. The relation between cytochrome oxidation state and oxygen consumption revealed a separation of distinct phases from mild to severe and deep hypoxia. When cytochrome c oxidation increased from fully reduced to 45% oxidised at 0.1 Jmax, pO2 was as low as 0.002 kPa (0.02 µM), and trace amounts of oxygen are sufficient to partially oxidize the cytochromes. At higher pO2 under severe hypoxia, respiration increases steeply while redox changes are small. Under mild hypoxia, the steep slope of oxidation of cytochrome c when flux remains more stable represents a cushioning mechanism maintaining respiration high at the onset of hypoxia.
Bloch, K. E., Buenzli, J. C., Latshang, T. D., Ulrich, S., 2015-10-01 08:52:16 AM
Lowlanders commonly report a poor sleep quality during the first few nights after arriving at high altitude. Polysomnographic studies reveal that reductions in slow wave sleep are the most consistent altitude induced changes in sleep structure identified by visual scoring. Quantitative spectral analyses of the sleep electroencephalogram have confirmed an altitude related reduction in the low frequency power (0.8-4.6 Hz). Although some studies suggest an increase in arousals from sleep at high altitude this is not a consistent finding. Whether sleep instability at high altitude is triggered by periodic breathing or vice-versa is still uncertain. Overnight changes in slow wave derived encephalographic measures of neuronal synchronization in healthy subjects were less pronounced at moderately high (2590 m) compared to low altitude (490 m) and this was associated with a decline in sleep related memory consolidation. Correspondingly, exacerbation of breathing and sleep disturbances experienced by lowlanders with obstructive sleep apnea during a stay at 2590 m was associated with poor performance in driving simulator tests. These findings suggest that altitude related alterations in sleep may adversely affect daytime performance. Despite recent advances in our understanding of sleep at altitude further research is required to better establish the role of gender and age in alterations of sleep at different altitudes, to determine the influence of acclimatization and of altitude related illness, and to uncover the characteristics of sleep in highlanders that may serve as a study paradigm of sleep in patients exposed to chronic hypoxia due to cardiorespiratory disease.
Gnyubkin, V., Guignandon, A., Laroche, N., Vanden-Bossche, A., Normand, M., Lafage-Proust, M.-H., Vico, L., 2015-10-01 08:52:16 AM
One of the most important but least studied environmental factors playing a major role in bone physiology is gravity. While the knowledge of deleterious effects of microgravity on the skeleton is expanding, little is known about hypergravity and its osteogenic potential. Centrifugation was used to assess effects of 21-d continuous 2g or 3g acceleration on femur and L2-vertebra of 7 week-old male C57BL/6 mice. Under 3g, body mass growth slowed down, and deleterious skeletal effects were found (p<0.05 compared to control): cortical thinning, osteoclasts surface increase (+41% in femur; +20% in vertebra), and bone formation rate decrease (-34% in femur; -38% in vertebra). A 2g centrifugation did not reduce body mass, and improved trabecular volume (+18% in femur; +13% in vertebra) and microarchitecture (+32% connectivity density in femur; +9% trabecular thickness in vertebra, p<0.05 compared to control). 2g also decreased osteoclast surfaces (-36% in femur; -16% in vertebra) and increased the extent of mineralized surfaces (+31% in femur; +48% in vertebra, p<0.05 compare to control). Quantitative immunohistochemistry revealed an increase of dentin matrix acidic phosphoprotein 1 (DMP1) and decrease of Sclerostin (+60% and -35% respectively, p<0.001 compared to control) in the femur cortex of 2g mice. In the distal femur metaphysis the number and volume of blood vessels increased by 22% and 44% respectively (p<0.05 compare to control). In conclusion, the effects of continuous hypergravity were bone compartment-specific and depended on the gravity level, with a threshold between beneficial 2g and deleterious 3g effects.
Bihari, S., Wiersema, U. F., Schembri, D., Pasquale, C. G. D., Dixon, D.-L., Prakash, S., Lawrence, M. D., Bowden, J. J., Bersten, A. D., 2015-10-01 08:52:16 AM
Rapid intravenous infusion of 0.9% saline alters respiratory mechanics in healthy subjects. However, the relative cardiovascular and respiratory effects of bolus intravenous crystalloid versus colloid are unknown. Six healthy male volunteers were given 30 ml/kg intravenous 0.9% saline, 4% albumin and 5% glucose at a rate of 100 ml/minute on three separate days in a double-blind randomized crossover study. Impulse oscillometry, spirometry, lung volumes, diffusing capacity and blood samples were measured before and after fluid administration. Lung ultrasound B-line score (indicating interstitial pulmonary edema) and Doppler echocardiography indices of cardiac preload were measured before, midway, immediately after and one hour after fluid administration. Infusion of 0.9% saline increased small airway resistance at 5 Hz (P = 0.04) and lung ultrasound B-line score (P = 0.01), without changes in Doppler echocardiography measures of preload. In contrast, 4% albumin increased diffusing capacity, decreased lung volumes, and increased Doppler echocardiopraphy mitral E velocity (P = 0.001) and E to lateral/septal e' ratio, estimated blood volume and NT-proBNP (P = 0.01), but not lung ultrasound B-line score; consistent with increased pulmonary blood volume without interstitial pulmonary edema. There were no significant changes with 5% glucose. Plasma angiopoietin-2 concentration increased only after 0.9% saline (P = 0.001), suggesting an inflammatory mechanism associated with edema formation. In healthy subjects 0.9% saline and 4% albumin have differential pulmonary effects not attributable to passive fluid filtration. This may reflect either different effects of these fluids on active signaling in the pulmonary circulation, or a protective effect of albumin.
De Lisio, M., Farup, J., Sukiennik, R. A., Clevenger, N., Nallabelli, J., Nelson, B., Ryan, K., Rahbek, S. K., de Paoli, F., Vissing, K., Boppart, M. D., 2015-10-01 08:52:16 AM
Skeletal muscle pericytes increase in quantity following eccentric exercise (ECC) and contribute to myofiber repair and adaptation in mice. The purpose of the present investigation was to examine pericyte quantity in response to muscle-damaging ECC and protein supplementation in human skeletal muscle. Male subjects were divided into protein supplement (WHY; n=12) or isocaloric placebo (CHO; n=12) groups, and completed ECC using an isokinetic dynamometer. Supplements were consumed 3 times/day throughout the experimental time course. Biopsies were collected prior to (PRE) and 3, 24, 48, and 168 hours following ECC. Reflective of the damaging protocol, integrin subunits, including α7, β1A and β1D increased (3.8-fold, 3.6-fold and 3.9-fold, p<0.01) 24 hours post-ECC with no difference between supplements. Pericyte quantity did not change post-ECC. WHY resulted in a small, but significant decrease in ALP+ pericytes when expressed as a percentage of myonuclei (CHO: 6.8 ± 0.3% vs. WHY: 5.8 ± 0.3%, p<0.05) or per myofiber (CHO: 0.119 ± 0.01 vs. WHY: 0.098 ± 0.01, p<0.05). The quantity of myonuclei expressing SRF, and the number of pericytes expressing SRF did not differ as a function of time post-ECC or supplement. These data demonstrate that acute muscle-damaging ECC increases α7β1 integrin content in human muscle, yet pericyte quantity is largely unaltered. Future studies should focus on the capacity for ECC to influence pericyte function, specifically paracrine factor release as a mechanism towards pericyte contribution to repair and adaptation post-exercise.
Horsman, H. M., Peebles, K. C., Tzeng, Y.-C., 2015-10-01 08:52:16 AM
Evidence derived from spontaneous measures of cardiovagal baroreflex sensitivity (BRS) suggests that slow breathing at 6 breaths min-1 augments BRS. However, increases in BRS associated with slow breathing may simply reflect the frequency-dependent nature of the baroreflex rather than the modulation of baroreflex function by changes in breathing rate per se. To test this hypothesis we employed a crossover study design (n=14) wherein breathing rate and systolic arterial blood pressure (SAP) oscillation induced via the application of oscillating lower body negative pressure (OLBNP), were independently varied at fixed frequencies. Breathing rate was controlled at 6 or 10 breaths min-1 with the aid of a metronome, and SAP oscillations were driven at 0.06 Hz and 0.1 Hz using OLBNP. The magnitudes of SAP and R-R interval (cardiac period) oscillations were quantified using power spectral analysis, and the transfer function gain between SAP and R-R interval was used to estimate BRS. Linear mixed-effects models were used to examine the main effects and interactions between breathing rate and OLBNP frequency. There was no statistical interaction between breathing and OLBNP frequency (p=0.59), indicating that the effect of breathing rate on BRS did not differ according to OLBNP frequency (and vice versa). Additionally, there was no main effect for breathing rate (p=0.28). However, we observed a significant main effect for OLBNP frequency (p=0.01) consistent with the frequency-dependent nature of baroreflex. These findings suggest that increases in spectral indices of BRS reflect the frequency-dependence of the baroreflex, and are not due to slow breathing per se.
Gibson, O. R., Turner, G., Tuttle, J. A., Taylor, L., Watt, P. W., Maxwell, N. S., 2015-10-01 08:52:16 AM
Heat acclimation attenuates physiological strain in hot conditions via phenotypic and cellular adaptation. The aim of this study was to determine whether HA reduced physiological strain, and Hsp72 and Hsp90α mRNA responses in acute normobaric hypoxia. Sixteen male participants completed ten 90 min sessions of isothermic heat acclimation (HA; 40°C/40%RH) or exercise training (CON; 20°C/40% RH). HA or CON were preceded (HYP1) and proceeded (HYP2) by a 30min normobaric hypoxic exposure (FiO2=0.12; 10min rest, 10min cycling at 40%V.O2peak, 10min cycling at 65%V.O2peak). HA induced greater rectal temperatures (Trec), sweat rate (SR) and heart rates (HR) than CON during the training sessions. HA, but not CON, reduced resting Trec, resting HR and increased SR and plasma volume. Haemoglobin mass did not change following HA nor CON. Hsp72 and Hsp90α mRNA increased in response to each HA session, but did not change with CON. HR during HYP2 was lower and O2 saturation higher at 65%V.O2peak following HA, but not CON. V.O2/HR was greater at rest and 65% V.O2peak in HYP2 following HA, but was unchanged after CON. At rest, the respiratory exchange ratio reduced during HYP2 following HA, but not CON. The increase in Hsp72 mRNA during HYP1, did not occur in HYP2 following HA. In CON, Hsp72 mRNA expression was unchanged during HYP1 and HYP2. In HA and CON, increases in Hsp90α mRNA during HYP1 were maintained in HYP2. HA reduces physiological strain, and the transcription of Hsp72, but not Hsp90α mRNA in acute normobaric hypoxia.
Lewis, M. I., Fournier, M., Wang, H., Storer, T. W., Casaburi, R., Kopple, J. D., 2015-10-01 08:52:16 AM
We previously reported reduced limb muscle fiber succinate dehydrogenase (SDH) activity and capillarity density and increased cross-sectional areas (CSAs) of all fiber types in maintenance hemodialysis (MHD) patients compared with matched controls that may contribute to their effort intolerance and muscle weakness. This study evaluated whether endurance training (ET), strength training (ST) or their combination (EST) alters these metabolic and morphometric aberrations, as a mechanism for functional improvement. Five groups were evaluated: 1) Controls; 2) MHD/no Training; 3) MHD/ET; 4) MHD/ST; and 5) MHD/EST. Training duration was 21.5 ± 0.7 weeks. Vastus lateralis muscle biopsies were obtained after HD at baseline and at study end. Muscle fibers were classified immunohistochemically and fiber CSAs computed. Individual fiber SDH activity was determined by a microdensitometric assay. Capillaries were identified using antibodies against endothelial cells. Type I and IIA fiber CSAs decreased significantly (10%) with EST. In the ET group, SDH activity increased 16.3% in type IIA and 19.6% in type IIX fibers. Capillary density increased significantly by 28% in the EST group and 14.3% with ET. The number of capillaries surrounding individual fiber type increased significantly in EST and ET groups. Capillary to fiber ratio increased significantly by 11% and 9.6% in EST and ET groups, respectively. We conclude that increments in capillarity and possibly SDH activity in part underlie improvements in endurance of MHD patients post training. We speculate that improved specific force and/or neural adaptations to exercise underlie improvements in limb muscle strength of MHD patients.
Gassmann, M., Muckenthaler, M. U., 2015-10-01 08:52:16 AM
Adequate acclimatization time to enable adjustment to hypoxic conditions is one of the most important aspects for mountaineers ascending to high altitude. Accordingly, most reviews emphasize mechanisms that cope with reduced oxygen supply. However during sojourns to high altitude adjustment to elevated iron demand is equally critical. Thus, in this review we focus on the interaction between oxygen and iron homeostasis. We review the role of iron (i) in the oxygen sensing process and erythropoietin (Epo) synthesis, (ii) in gene expression control mediated by the hypoxia-inducible factor-2 (HIF-2), and (iii) as an oxygen-carrier in hemoglobin, myoglobin and cytochromes. The blood hormone Epo that is abundantly expressed by the kidney under hypoxic conditions stimulates erythropoiesis in the bone marrow, a process requiring high iron levels. To ensure that sufficient iron is provided Epo-controlled erythroferrone that is expressed in erythroid precursor cells acts in the liver to reduce expression of the iron hormone hepcidin. Consequently, suppression of hepcidin allows for elevated iron release from storage organs and enhanced absorption of dietary iron by enterocytes. As recently observed in sojourners at high altitude however, iron uptake may be hampered by reduced appetite and gastrointestinal bleeding. Reduced iron availability, as observed in a hypoxic mountaineer, enhances hypoxia-induced pulmonary hypertension and may contribute to other hypoxia-related diseases. Overall, adequate systemic iron availability is an important prerequisite to adjust to high-altitude hypoxia and may have additional implications for disease-related hypoxic conditions.
Recent evidence suggests that results from multiple-breath washout (MBW) using nitrogen (N2) as washout gas are different to those obtained by using sulfur hexafluoride (SF6). Explanations were mainly related to different MBW equipment and gas properties. We aim to mention a new aspect, namely using the same cut-off in both techniques to determine lung clearance index (usually 2.5% of initial tracer concentration) irrespective of additional contribution of tissue-nitrogen in N2-MBW. In a simple model calculation we subtracted 1% tissue-N2from the N2-MBW in real washout traces from two children, one with cystic fibrosis (CF) and one healthy. This "SF6-washout simulation" decreased LCI differently in the children. In the healthy subject 1/40th (2.5%) was achieved two breaths earlier compared to the original signal and changed LCI from 6.7 to 5.9 (12%), while in CF 1/40th was achieved 19 breaths earlier leading to a LCI decrease from 13.7 to 10.0 (27%). It would have been required to wash out SF6 until 1/66th (1.5%) to be comparable to N2 washout at 1/40th (2.5%), or to stop N2-MBW already at 3.5% of the starting concentration to make both techniques comparable. We show that a basic physiological-mathematical difference between both techniques additionally accounts for different sensitivities and poor agreement between SF6- and N2-MBW. The best way of adjusting for the contribution of tissue-N2 needs to be examined in future studies. Thus, despite increasing use in different disease groups, the books on MBW technology are obviously not closed yet.
Berger, M. M., Macholz, F., Mairbaurl, H., Bartsch, P., 2015-10-01 08:52:16 AM
Preconditioning refers to exposure to brief episodes of potentially adverse stimuli, which protects from injury during subsequent exposures. This was first described in the heart, where episodes of ischemia/reperfusion render the myocardium resistant to subsequent ischemic injury, which is likely caused by reactive oxygen species (ROS) and pro-inflammatory processes. Protection of the heart was also found when preconditioning was performed in an organ different from the target, which is called remote ischemic preconditioning (RIPC). The mechanisms causing protection seem to include stimulation of nitric oxide synthase, increase in anti-oxidant enzymes, and down-regulation of pro-inflammatory cytokines. These pathways are also thought to play a role in high altitude diseases: High altitude pulmonary edema (HAPE) is associated with decreased bioavailability of nitric oxide and increased generation of ROS, whereas mechanisms causing acute mountain sickness (AMS) and high altitude cerebral edema (HACE) seem to involve cytotoxic effects by ROS and inflammation. Based on these apparent similarities between ischemic damage and AMS, HACE, and HAPE, it is reasonable to assume that RIPC might be protective and improve altitude tolerance. In studies addressing high altitude/hypoxia tolerance, RIPC has been shown to decrease pulmonary arterial systolic pressure in normobaric hypoxia (13% O2) and at high altitude (4342m). Our own results indicate that RIPC transiently decreases the severity of AMS at 12% O2. Thus, preliminary studies show some benefit, but clearly further experiments to establish the efficacy and potential mechanism of RIPC are needed.
Following shock, persistent oxygen extraction deficit despite the apparent adequate recovery of systemic hemodynamic and oxygen-derived variables has been a source of uncertainty and controversy. Dysfunction of oxygen transport pathways during intensive care underlies the sequelae that lead to organ failure, and the limitations of techniques used to measure tissue oxygenation in vivo have contributed to the lack of progress in this area. Novel techniques have provided detailed quantitative insight into the determinants of microcirculatory and mitochondrial oxygenation. These techniques which are based on the oxygen-dependent quenching of phosphorescence or delayed luminescence are briefly reviewed. The application of these techniques to animal models of shock and resuscitation revealed the heterogeneous nature of oxygen distributions and the alterations in oxygen distribution in the microcirculation and in mitochondria. These studies identified functional shunting in the microcirculation as an underlying cause of oxygen extraction deficit observed in states of shock and resuscitation. The translation of these concepts to the bedside has been enabled by our development and clinical introduction of hand-held microscopy. This tool facilitates the direct observation of the microcirculation and its alterations at the bedside under the conditions of shock and resuscitation. Studies identified loss of coherence between the macrocirculation and the microcirculation, in which resuscitation successfully restore systemic circulation but did not alleviate microcirculatory perfusion alterations. Various mechanisms responsible for these alterations underlie the loss of hemodynamic coherence during unsuccessful resuscitation procedures. Therapeutic resolving persistent heterogeneous microcirculatory alterations is expected to improve outcomes in critically ill patients.
Frise, M. C., Robbins, P. A., 2015-10-01 08:52:16 AM
The human pulmonary vasculature vasoconstricts in response to a reduction in alveolar oxygen tension - a phenomenon termed hypoxic pulmonary vasoconstriction (HPV). This review describes the time course of this behaviour, which occurs in distinct phases, and then explores the importance for HPV of the hypoxia-inducible factor (HIF) pathway. Next, the HIF-hydroxylase enzymes that act as molecular oxygen-sensors within the HIF-pathway are discussed. These enzymes are particularly sensitive to intracellular iron availability, which confers iron-sensing properties on the HIF-pathway. Human studies of iron chelation and supplementation are then reviewed. These demonstrate that the iron sensitivity of the HIF-pathway evident from in vitro experiments is relevant to human pulmonary vascular physiology. Next, the importance of iron status in high-altitude illness and chronic cardiopulmonary disease is explored, and the therapeutic potential of intravenous iron discussed. The review concludes by highlighting some further complexities that arise from interactions between the HIF-pathway and other intracellular iron-sensing mechanisms.
Heinonen, I., Sorop, O. E., de Beer, V. J., Duncker, D. J., Merkus, D., 2015-10-01 08:52:16 AM
Coronary microvascular function and cardiac function are closely related in that proper cardiac function requires adequate oxygen delivery through the coronary microvasculature. Due to the close proximity of cardiomyocytes and coronary microvascular endothelium, cardiomyocytes not only communicate their metabolic needs to the coronary microvasculature, but endothelium-derived factors also directly modulate cardiac function. This review summarizes evidence that the myocardial oxygen balance is disturbed in the failing heart due to increased extravascular compressive forces and coronary microvascular dysfunction. The perturbations in myocardial oxygen balance are exaggerated during exercise and are due to alterations in neurohumoral influences, endothelial function and oxidative stress. Although there is some evidence from animal studies that myocardial oxygen balance can be partly restored by exercise training, it is largely unknown to what extent the beneficial effects of exercise training include improvements in endothelial function and/or oxidative stress in the coronary microvasculature and how these improvements are impacted by risk factors such as diabetes, obesity and hypercholesterolemia.
In humans, the net effect of acute systemic hypoxia in quiescent skeletal muscle is vasodilation despite reflex increases in muscle sympathetic vasoconstrictor nerve activity. This vasodilation increases tissue perfusion and oxygen delivery to maintain tissue oxygen consumption. Although several mechanisms may be involved, we recently tested the roles of two endothelial-derived substances during conditions of sympathoadrenal blockade to isolate local vascular control mechanisms: nitric oxide (NO) and prostaglandins (PGs). Our findings indicate that (1) NO normally plays a role in regulating vascular tone during hypoxia independent of the PG pathway; (2) PGs do not normally contribute to vascular tone during hypoxia, however do impact vascular tone when NO is inhibited; (3) NO and PGs are not independently obligatory to observe hypoxic vasodilation when assessed as a response from rest to steady-state hypoxia; and (4) combined NO and PG inhibition abolishes hypoxic vasodilation in human skeletal muscle. When the stimulus is exacerbated via combined submaximal rhythmic exercise and systemic hypoxia to cause further red blood cell (RBC) deoxygenation, blood flow is augmented compared with normoxic exercise via local dilator mechanisms to maintain oxygen delivery to the active tissue. Data obtained in a follow-up study indicate that combined NO and PG inhibition during hypoxic exercise blunts the augmented vasodilation and hyperemia compared with control (normoxic) conditions ~50%, however the response is not abolished implicating other local substances are involved. Factors associated with greater RBC deoxygenation such as ATP release and/or nitrite reduction to NO likely play a role in regulating this response.
Gonzalez-Rothi, E. J., Lee, K.-Z., Dale, E. A., Reier, P. J., Mitchell, G. S., Fuller, D. D., 2015-10-01 08:52:16 AM
In recent years, it has become clear that brief, repeated presentations of hypoxia (i.e., acute intermittent hypoxia, AIH) can boost the efficacy of more traditional therapeutic strategies in certain cases of neurologic dysfunction. This hypothesis derives from a series of studies in animal models and human subjects performed over the past 35 years. In 1980, Milhorn and colleagues showed that electrical stimulation of carotid chemoafferent neurons produced a persistent, serotonin-dependent increase in phrenic motor output that outlasts the stimulus for more than 90 minutes (i.e., a "respiratory memory"). AIH elicits similar phrenic "long term facilitation" (LTF) by a mechanism that requires cervical spinal serotonin receptor activation and de novo protein synthesis. From 2003-present, a series of studies demonstrated that AIH can induce neuroplasticity in the injured spinal cord, causing functional recovery of breathing capacity after cervical spinal injury. Subsequently, it was demonstrated that repeated AIH (rAIH) can induce recovery of limb function, and the functional benefits of rAIH are greatest when paired with task-specific training. Since uncontrolled and/or prolonged intermittent hypoxia can elicit pathophysiology, a challenge of intermittent hypoxia research is to ensure that therapeutic protocols are well below the threshold for pathogenesis. This is possible since many low dose rAIH protocols have induced functional benefits without evidence of pathology. We propose that carefully controlled rAIH is a safe and non-invasive modality that can be paired with other neurorehabilitative strategies including traditional activity-based physical therapy or cell-based therapies such as intraspinal transplantation of neural progenitors.
Mifflin, S. W., Cunningham, J. T., Toney, G. M., 2015-10-01 08:52:16 AM
Sleep apnea (SA) leads to metabolic abnormalities and cardiovascular dysfunction. Rodent models of nocturnal intermittent hypoxia (IH) are used to mimic arterial hypoxemias that occur during SA. This mini-review focuses on our work examining CNS mechanisms whereby nocturnal IH results in increased sympathetic nerve discharge (SND) and hypertension (HTN) that persist throughout the 24 hr diurnal period. Within the first 1-2 days of IH, arterial pressure (AP) increases even during non-IH periods of the day. Exposure to IH for 7 days biases nucleus tractus solitarius (NTS) neurons receiving arterial chemoreceptor inputs toward increased discharge, providing a substrate for persistent activation of sympathetic outflow. IH HTN is blunted by manipulations that reduce angiotensin (AngII) signaling within the forebrain lamina terminalis suggesting that central AngII supports persistent IH HTN. Inhibition of the hypothalamic paraventricular nucleus (PVN) reduces ongoing SND and acutely lowers AP in IH conditioned animals. These findings support a role for the PVN, which integrates information ascending from NTS and descending from the lamina terminalis, in sustaining IH HTN. In sum, our findings indicate that IH rapidly and persistently activates a central circuit that includes the NTS, forebrain lamina terminalis and the PVN. Our working model holds that NTS neuromodulation increases transmission of arterial chemoreceptor inputs, increasing SND via connections with PVN and RVLM. Increased circulating AngII sensed by the lamina terminalis generates yet another excitatory drive to PVN. Together with adaptations intrinsic to the PVN, these responses to IH support rapid onset neurogenic HTN.
Zuo, L., Chuang, C.-C., Hemmelgarn, B. T., Best, T. M., 2015-10-01 08:52:16 AM
The understanding of complex molecular mechanisms underlying heart failure (HF) is constantly under revision. Recent research has paid much attention to understanding the growing number of patients that exhibit HF symptoms, yet have an ejection fraction similar to a normal phenotype. Termed heart failure with preserved ejection fraction (HFpEF), this novel hypothesis traces its roots to a proinflammatory state initiated in part by the existence of comorbidities that create a favorable environment for the production of reactive oxygen species (ROS). Triggering a cascade that involves reduced nitric oxide (NO) availability, elevated ROS levels in the coronary endothelium eventually contribute to hypertrophy and increased resting tension in cardiomyocytes. Improved understanding of the molecular pathways associated with HFpEF have led to studies that concentrate on reducing ROS production in the heart, boosting NO availability, and increasing exercise capacity for HFpEF patients. This review will explore the latest research into the role of ROS and NO in the progression of HFpEF, as well as discuss the encouraging results of numerous therapeutic studies.
Vohwinkel, C. U., Hoegl, S., Eltzschig, H. K., 2015-10-01 08:52:16 AM
Acute lung injury (ALI) is an inflammatory lung disease that manifests itself in patients as acute respiratory distress syndrome and thereby contributes significantly to the morbidity and mortality of patients experiencing critical illness. Even though it may seem counterintuitive, as the lungs are typically well oxygenated organs, hypoxia signaling pathways have recently been implicated in the resolution of ALI. For example, functional studies suggest that transcriptional responses under the control of the hypoxia-inducible factor (HIF) are critical in optimizing alveolar epithelial carbohydrate metabolism, and thereby dampen lung inflammation during ALI. In the present review we discuss functional roles of oxygenation, hypoxia and HIFs during ALI, mechanisms of how HIFs are stabilized during lung inflammation and how HIFs can mediate lung protection during ALI.
Remote preconditioning (rPC) is the phenomenon whereby brief organ ischemia evokes an endogenous response such that a different (remote) organ is protected against subsequent, normally injurious ischemia. Experiments show rPC to be effective at evoking cardioprotection against ischemic heart injury, and more recently neuroprotection against brain ischemia. Such is the enthusiasm for rPC, that human studies have been initiated. Clinical trials suggest rPC to be safe (phase II trial) and effective in reducing stroke incidence in a population with high stroke risk. However, despite the therapeutic potential of rPC, there is a large gap in knowledge regarding the effector mechanisms of rPC and how it might be orchestrated to improve outcome following stroke. Here we provide a critical review of mechanisms which are directly attributable to rPC-induced neuroprotection in pre-clinical trials of rPC.
Semenza, G. L., Prabhakar, N. R., 2015-10-01 08:52:16 AM
Obstructive sleep apnea (OSA) is one of the most common causes of hypertension in western societies. OSA causes chronic intermittent hypoxia (CIH) in specialized O2-sensing glomus cells of the carotid body. CIH generates increased reactive oxygen species (ROS) that trigger a feed-forward mechanism in which increased intracellular calcium levels ([Ca2+]i) trigger increased HIF-1α synthesis and increased HIF-2α degradation. As a result, the normal homeostatic balance between HIF-1α-dependent pro-oxidant and HIF-2α-dependent anti-oxidant enzymes is disrupted, leading to further increases in ROS. Carotid body sensory nerves project to the nucleus tractus solitarius, from which the information is relayed via interneurons to the rostral ventrolateral medulla in the brainstem, which sends sympathetic neurons to the adrenal medulla to stimulate the release of epinephrine and norepinephrine, catecholamines that increase blood pressure. At each synapse, neurotransmitters trigger increased [Ca2+]i, HIF-1α:HIF-2α and Nox2:Sod2 activity that generates increased ROS levels. These responses are not observed in other regions of the brainstem that do not receive input from the carotid body or signal to the sympathetic nervous system. Thus, sympathetic nervous system homeostasis is dependent on a balance between HIF-1α and HIF-2α, disruption of which results in hypertension in OSA patients.
Stenmark, K. R., Tuder, R. M., El Kasmi, K. C., 2015-10-01 08:52:16 AM
Pulmonary hypertension (PH) is a complex, multifactorial, syndrome that remains poorly understood despite decades of research. PH is characterized by profound pulmonary artery (PA) remodeling, that include significant fibro-proliferative and inflammatory changes of the PA adventitia. In line with the emerging concept that PH shares key features with cancer, recent work centers on the idea that PH results from a multi-step process driven by reprogramming of gene expression patterns that govern changes in cell metabolism, inflammation, and proliferation. Data demonstrate that in addition to PA endothelial cells and smooth muscle cells, adventitial fibroblasts from animals with experimental hypoxic PH and from humans with PH (hereafter termed PH-Fibs) exhibit pro-inflammatory activation, increased proliferation, and apoptosis resistance, all in the context of metabolic reprograming to aerobic glycolysis. PH-Fibs can also recruit, retain, and activate naïve macrophages (M) toward a pro-inflammatory/pro-remodeling phenotype through secretion of chemokines, cytokines, and glycolytic metabolites among, which IL6 and lactate play key roles. Further, these fibroblast-activated M (hereafter termed FAM) exhibit aerobic glycolysis together with high expression of Arg1, Vegfa, and Il1b, all of which require HIF1α and STAT3 signaling. Strikingly, in situ, the adventitial FAM phenotype in the remodeled PA closely resembles the FAM induced by fibroblasts in vitro, suggesting that fibroblast-macrophage cross-talk involving metabolic and inflammatory signals is a critical pathogenetic component of vascular remodeling. This review discusses metabolic and inflammatory changes in fibroblasts and macrophages in PH with the goal of raising ideas about new interventions to abrogate remodeling in hypoxic forms of PH.
Campbell, K. S., Sorrell, V. L., 2015-10-01 08:52:16 AM
Heart Failure with preserved Ejection Fraction (HFpEF) is the default diagnosis for patients who have symptoms of heart failure, an ejection fraction greater than 0.5, and evidence of diastolic dysfunction. The clinical condition, which was largely unrecognized 30 years ago, is now a major clinical problem and currently accounts for 50% of all patients with heart failure. Clinical studies show that patients with HFpEF exhibit increased passive stiffness of the ventricles and a slower rate of pressure decline during diastole. This review discusses some of the cell and molecular level mechanisms that contribute to these effects and focuses on data obtained using human samples. Collagen cross-linking, modulation of protein kinase G-related pathways, Ca2+-handling, and strain-dependent detachment of cross-bridges are highlighted as potential factors which could be modulated to improve ventricular function in patients with HFpEF
Liu, X., Gebremedhin, D., Harder, D. R., Koehler, R. C., 2015-10-01 08:52:16 AM
Adenosine A2A receptors and KATP channels contribute to part of the cerebral vasodilatory response to systemic hypoxia, but other mediators are likely involved. Epoxyeicosatrienoic acids (EETs) are cerebral vasodilators and are released from astrocytes exposed to hypoxia. Moreover, stimulation of metabotropic glutamate receptors (mGluR) produces vasodilation by an EET-dependent mechanism. Here, we tested the hypothesis that EET signaling and mGluR activation contribute to hypoxic vasodilation. Laser-Doppler flow (LDF) was measured over cerebral cortex of anesthetized rats subjected to stepwise reductions in arterial oxygen saturation to 50-70%. Hypoxic reactivity was calculated as the slope of the change in LDF versus the reciprocal of arterial oxygen content. Hypoxic reactivity significantly decreased from 9.2±1.9 (±95% confidence interval) in controls with vehicle treatment to 2.6±1.4 with the EET antagonist 14,15-EEZE, to 3.0±1.5 with the EET synthesis inhibitor MS-PPOH, to 1.9±2.3 with the combined mGluR subtype 1 and 5 antagonists MPEP and LY367385, to 5.6±1.2 with the KATP channel inhibitor glibenclamide, and to 5.8±2.3 with the A2A receptor antagonist SCH58261. However, reactivity was not significantly altered by the A2B receptor antagonist MRS1754 (6.7±1.8; P=0.28 Dunnett's test) or by the 20-HETE synthesis inhibitor HET0016 (7.5±2.3; P=0.6). These data indicate that in addition to the known contributions of A2A receptors and KATP channels to the increase in cerebral blood flow during hypoxia, EETs and mGluRs make a major contribution, possibly by mGluR stimulation and hypoxia-induced release of EETs. In contrast, A2B receptors do not make a major contribution, and 20-HETE does not significantly limit hypoxic vasodilation.
Siebenmann, C., Cathomen, A., Hug, M., Keiser, S., Lundby, A.-K. M., Hilty, M. P., Goetze, J. P., Rasmussen, P., Lundby, C., 2015-10-01 08:52:16 AM
High altitude (HA) exposure facilitates a rapid contraction of plasma volume (PV) and a slower occurring expansion of hemoglobin mass (Hbmass). The kinetics of the Hbmass expansion has never been examined by multiple repeated measurements and this was our primary study aim. The second aim was to investigate the mechanisms mediating the PV contraction. Nine healthy, normally-trained sea-level (SL) residents (8 males, 1 female) sojourned for 28 days at 3,454 m. Hbmass was measured and PV estimated by carbon monoxide re-breathing at SL, on every fourth day at HA, and one and two weeks upon return to SL. Four weeks at HA increased Hbmass by 5.26 % (range 2.5 - 11.1 %; p<0.001). The individual Hbmass increases commenced with up to 12 days delay and reached a maximal rate of 4.04 ± 1.02 g.d-1 after 14.9 ± 5.2 days. The probability for Hbmass to plateau increased steeply after 20-24 days. Upon return to SL Hbmass decayed by -2.46 ± 2.3 g.d-1, reaching values similar to baseline after two weeks. PV, aldosterone concentration and renin activity were reduced at HA (p<0.001) while the total circulating protein mass remained unaffected. In summary the Hbmass response to HA exposure followed a sigmoidal pattern with a delayed onset and a plateau after ~3 weeks. The decay rate of Hbmass upon descent to SL did not indicate major changes in the rate of erythrolysis. Moreover, our data supports that PV contraction at HA is regulated by the renin-angiotensin-aldosterone axis and not by changes in oncotic pressure.
Stembridge, M., Ainslie, P. N., Hughes, M. G., Stohr, E. J., Cotter, J. D., Tymko, M. M., Day, T. A., Bakker, A., Shave, R. E., 2015-10-01 08:52:16 AM
Impaired myocardial systolic contraction and diastolic relaxation have been suggested as possible mechanisms contributing to the decreased stroke volume (SV) observed at high altitude (HA). To determine whether intrinsic myocardial performance is a limiting factor in the generation of SV at HA, we assessed left ventricular (LV) systolic and diastolic mechanics and volumes in 10 healthy participants (aged 32 ± 7; mean ± SD) at rest and during exercise at sea level (SL; 344 m) and following 10 days at 5050 m. In contrast to SL, LV end-diastolic volume was ~19% lower at rest (p=0.004) and did not increase during exercise despite a greater untwisting velocity. Furthermore, resting SV was lower at HA (~17%; 60±10 vs. 70±8 ml) despite higher LV twist (43%), apical rotation (115%) and circumferential strain (17%). With exercise at HA, the increase in SV was limited (12 ml vs. 22 ml at SL), and LV apical rotation failed to augment. For the first time, we have demonstrated that EDV does not increase upon exercise at high altitude despite enhanced in vivo diastolic relaxation. The increase in LV mechanics at rest may represent a mechanism by which SV is defended in the presence of a reduced EDV. However, likely due to the higher LV mechanics at rest, no further increase was observed up to 50% peak power. Consequently, whilst hypoxia does not suppress systolic function per se, the capacity to increase SV through greater deformation during submaximal exercise at HA is restricted.
Fowler, M. R., Smith, G. L., 2015-10-01 08:52:16 AM
The myriad of intracellular signalling pathways involving intracellular Ca2+ means Ca2+ plays a role in everything from cellular metabolism to cell death. In heart muscle Ca2+ is primarily known for its role in cellular contraction. Regulation of cardiac muscle contractility is achieved through modulation of the spatio-temporal nature of intracellular Ca2+ signals, operating in areas of restricted diffusion or microdomains, close to Ca2+ release sites. This Viewpoint article briefly integrates experimental evidence in support of this concept.
The etiology of muscle fatigue remains incompletely solved especially in vivo (3). The causes of muscle fatigue vary according to the type, duration and intensity of exercise, and to the physical fitness and health status of the subjects. Nevertheless, an elevated sarcolemmal lactate (and proton) transport capacity constitutes an advantage during muscle activity. During moderate-intensity exercise, efficient lactate exchanges contribute to the cell-cell lactate shuttle i.e., the delivery of lactate for its utilization as fuel by neighboring or distant active and oxidative muscles fibers or as substrate by other tissues (e.g. for neoglucogenesis by the liver) (1). During high-intensity exercise, the lactate exchange ability was positively correlated with the capacity to prolong exercise (4). Whether this correlation between the lactate exchange ability and performance was (directly or indirectly) causal or coincidental, the question is still under debate. Nevertheless, it remains that an elevated lactate exchange ability seems to constitute a protective mechanism against muscle fatigue. Since the transport of lactate across the sarcolemma is mediated mainly by the lactate-H+ cotransport via the monocarboxylate transporters MCT1 and MCT4, an elevated lactate transport capacity delays both muscle lactate accumulation and intracellular pH decrease and seems to favor muscle activity. In accordance, previous experiments have shown that metabolic alkalosis enhances the net lactate release rate from the active muscles and work capacity (2, 5) contrary to acidosis that reduces lactate efflux from muscle and exercise tolerance (5). All this makes an elevated sarcolemmal lactate (and proton) transport capacity an advantage during muscle activity.