Journal of Applied Physiology recent issues

Estrogen and HRT promote a proanabolic skeletal muscle environment in older women

Tiidus, P. M. — Wed, 04 Nov 2009 10:56:55 PST

Calpain and caspase-3 are required for sepsis-induced diaphragmatic weakness

Powers, S. K. — Wed, 04 Nov 2009 10:56:55 PST

Cerebral blood flow during exercise: mechanisms of regulation

Ogoh, S., Ainslie, P. N. — Wed, 04 Nov 2009 10:56:55 PST

The response of cerebral vasculature to exercise is different from other peripheral vasculature; it has a small vascular bed and is strongly regulated by cerebral autoregulation and the partial pressure of arterial carbon dioxide (Pa_CO₂). In contrast to other organs, the traditional thinking is that total cerebral blood flow (CBF) remains relatively constant and is largely unaffected by a variety of conditions, including those imposed during exercise. Recent research, however, indicates that cerebral neuronal activity and metabolism drive an increase in CBF during exercise. Increases in exercise intensity up to ~60% of maximal oxygen uptake produce elevations in CBF, after which CBF decreases toward baseline values because of lower Pa_CO₂ via hyperventilation-induced cerebral vasoconstriction. This finding indicates that, during heavy exercise, CBF decreases despite the cerebral metabolic demand. In contrast, this reduced CBF during heavy exercise lowers cerebral oxygenation and therefore may act as an independent influence on central fatigue. In this review, we highlight methodological considerations relevant for the assessment of CBF and then summarize the integrative mechanisms underlying the regulation of CBF at rest and during exercise. In addition, we examine how CBF regulation during exercise is altered by exercise training, hypoxia, and aging and suggest avenues for future research.

Influence of hormone replacement therapy on eccentric exercise induced myogenic gene expression in postmenopausal women

Wed, 04 Nov 2009 10:56:55 PST

Hormone replacement therapy (HRT) is used in postmenopausal women to relieve symptoms of menopause and prevent osteoporosis. We sought to evaluate changes in mRNA expression of key myogenic factors in postmenopausal women taking and not taking HRT following a high-intensity eccentric resistance exercise. Fourteen postmenopausal women were studied and included 6 control women not using HRT (59 ± 4 years, 63 ± 17 kg) and 8 women using traditional HRT (59 ± 4 yr, 89 ± 24 kg). Both groups performed 10 sets of 10 maximal eccentric repetitions of single-leg extension on a Cybex dynamometer at 60°/s. Muscle biopsies of the vastus lateralis were obtained from the exercised leg at baseline and 4 h after the exercise bout. Gene expression was determined using RT-PCR for follistatin, forkhead box 3A (FOXO3A), muscle atrophy F-box (MAFbx), muscle ring finger-1 (MuRF-1), myogenic differentiation factor (MyoD), myogenin, myostatin, myogenic factor 5 (Myf5), and muscle regulatory factor 4 (MRF4). At rest, the HRT group expressed higher levels of MyoD, myogenin, Myf5, MRF4, and follistatin (P < 0.05). In response to eccentric exercise, follistatin, MyoD, myogenin, Myf5, and MRF4 were significantly increased (P ≤ 0.05) and FOXO3A, MAFbx, MuRF-1, and myostatin were significantly decreased in the control and HRT groups (P ≤ 0.05). Significantly greater changes in mRNA expression of follistatin, FOXO3A, MAFbx, MuRF-1, MyoD, myogenin, myostatin, Myf5, and MRF4 (p≤0.05) occurred in the HRT group than in the control group after exercise. These data suggest that postmenopausal women using HRT express higher myogenic regulatory factor gene expression, which may reflect an attempt to preserve muscle mass. Furthermore, postmenopausal women using HRT experienced a greater myogenic response to maximal eccentric exercise.

Caspase and calpain activation both contribute to sepsis-induced diaphragmatic weakness

Supinski, G. S., Wang, W., Callahan, L. A. — Wed, 04 Nov 2009 10:56:55 PST

The cecal ligation perforation (CLP) model of sepsis is known to induce severe diaphragm dysfunction, but the cellular mechanisms by which this occurs remain unknown. We hypothesized that CLP induces diaphragm caspase-3 and calpain activation, and that these two enzymes act at the level of the contractile proteins to reduce muscle force generation. Rats (n = 4/group) were subjected to 1) sham surgery plus saline (intraperitoneal); 2) CLP; 3) CLP plus administration of calpain inhibitor peptide III (12 mg/kg ip); or 4) CLP plus administration of a caspase inhibitor, zVAD-fmk (3 mg/kg). At 24 h, diaphragms were removed, and the following were determined: 1) calpain and caspase-3 activities by fluorogenic assay; 2) caspase-3 and calpain I protein levels; 3) the intact diaphragm force-frequency relationship; and 4) the force generated by contractile proteins of single, permeabilized diaphragm fibers in response to exogenous calcium. CLP significantly increased diaphragm calpain activity (P < 0.02), caspase-3 activity (P < 0.02), active calpain I protein levels (P < 0.02), and active caspase-3 protein (P < 0.02). CLP also reduced the force generated by intact diaphragm muscle (P < 0.001) and the force generated by single-fiber contractile proteins (P < 0.001). Administration of either calpain inhibitor III or zVAD-fmk markedly improved force generation of both intact diaphragm muscle (P < 0.01) and single-fiber contractile proteins (P < 0.001). CLP induces significant reductions in diaphragm contractile protein force-generating capacity. This force reduction is mediated by the combined effects of activated caspase and calpain. Inhibition of these pathways may prevent diaphragm weakness in infected patients.

Human diaphragm efficiency estimated as power output relative to activation increases with hypercapnic hyperpnea

Finucane, K. E., Singh, B. — Wed, 04 Nov 2009 10:56:55 PST

Hyperpnea with exercise or hypercapnia causes phasic contraction of abdominal muscles, potentially lengthening the diaphragm at end expiration and unloading it during inspiration. Muscle efficiency in vitro varies with load, fiber length, and precontraction stretch. To examine whether these properties of muscle contractility determine diaphragm efficiency (Eff_di) in vivo, we measured Eff_di in six healthy adults breathing air and during progressive hypercapnia at three levels of end-tidal Pco₂ with mean values of 48 (SD 2), 55 (SD 2), and 61 (SD 1) Torr. Eff_di was estimated as the ratio of diaphragm power (di) [the product of mean inspiratory transdiaphragmatic pressure, diaphragm volume change (Vdi) measured fluoroscopically, and 1/inspiratory duration (Ti^–1)] to activation [root mean square values of inspiratory diaphragm electromyogram (RMS_di) measured from esophageal electrodes]. At maximum hypercapnea relative to breathing air, 1) gastric pressure and diaphragm length at end expiration (Pg_ee and Ldi_ee, respectively) increased 1.4 (SD 0.2) and 1.13 (SD 0.08) times, (P < 0.01 for both); 2) inspiratory change () in Pg decreased from 4.5 (SD 2.2) to –7.7 (SD 3.8) cmH₂O (P < 0.001); 3) Vdi·Ti^–1, di, RMS_di, and Eff_di increased 2.7 (SD 0.6), 4.9 (SD 1.8), 2.6 (SD 0.9), and 1.8 (SD 0.3) times, respectively (P < 0.01 for all); and 4) net and inspiratory di were not different (P = 0.4). Eff_di was predicted from Ldi_ee (P < 0.001), Pg_ee (P < 0.001), Pg·Ti^–1 (P = 0.03), and Pg (P = 0.04) (r² = 0.52) (multivariate regression analysis). We conclude that, with hypercapnic hyperpnea, 1) ~47% of the maximum increase of di was attributable to increased Eff_di; 2) Eff_di increased due to preinspiratory lengthening and inspiratory unloading of the diaphragm, consistent with muscle behavior in vitro; 3) passive recoil of the diaphragm did not contribute to inspiratory di or Eff_di; and 4) phasic abdominal muscle activity with hyperpnea reduces diaphragm energy consumption.

Microgravity alters respiratory abdominal and rib cage motion during sleep

Sa, R. C., Prisk, G. K., Paiva, M. — Wed, 04 Nov 2009 10:56:55 PST

The abdominal and rib cage contributions to tidal breathing differ between rapid-eye-movement (REM) and non-NREM sleep. We hypothesized that abdominal relative contribution during NREM and REM sleep would be altered in different directions when comparing sleep on Earth with sleep in sustained microgravity (µG), due to conformational changes and differences in coupling between the rib cage and the abdominal compartment induced by weightlessness. We studied respiration during sleep in five astronauts before, during, and after two Space Shuttle missions. A total of 77 full-night (8 h) polysomnographic studies were performed; abdominal and rib cage respiratory movements were recorded using respiratory inductive plethysmography. Breath-by-breath analysis of respiration was performed for each class: awake, light sleep, deep sleep, and REM sleep. Abdominal contribution to tidal breathing increased in µG, with the first measure in space being significantly higher than preflight values, followed by a return toward preflight values. This was observed for all classes. Preflight, rib cage, and abdominal movements were found to be in phase for all but REM sleep, for which an abdominal lead was observed. The abdominal leading role during REM sleep increased while deep sleep showed the opposite behavior, the rib cage taking a leading role in-flight. In µG, the percentage of inspiratory time in the overall breath, the duty cycle (T_I/T_Tot), decreased for all classes considered when compared with preflight, while normalized inspiratory flow, taking the awake values as reference, increased in-flight for light sleep, deep sleep, and REM. Changes in abdominal-rib cage displacements probably result from a less efficient operating point for the diaphragm and a less efficient coupling between the abdomen and the apposed portion of the rib cage in µG. However, the preservation of total ventilation suggests that short-term adaptive mechanisms of ventilatory control compensate for these mechanical changes.

Effect of contrasting physical exercise interventions on rapid force capacity of chronically painful muscles

Wed, 04 Nov 2009 10:56:55 PST

Rapid force capacity of chronically painful muscles is inhibited markedly more than maximal force capacity and is therefore relevant to assess in rehabilitation settings. Our objective was to investigate the effect of two contrasting types of physical exercise on rapid force capacity, as well as neural and muscular adaptations in women with chronic neck muscle pain. A group of employed women (n = 42) with a clinical diagnosis of trapezius myalgia participated in a 10-wk randomized controlled trial; specific strength training of the neck/shoulder muscles, general fitness training performed as leg-bicycling; or a reference intervention without physical activity. Maximal voluntary shoulder abductions were performed at static angles of 35° and 115° with simultaneous recording of electromyography (EMG) in the trapezius and deltoid. Maximal muscle strength and activation (peak torque and peak EMG) as well as rapid muscle strength and activation [rate of torque development (RTD) and rate of EMG rise] were subsequently determined. Trapezius muscle fiber characteristics were determined with ATPase histochemistry. Significant changes were observed only in the specific strength training group. Whereas peak torque increased 18–29% (P < 0.01), RTD increased 61–115% (P < 0.001). Peak EMG and rate of EMG rise increased correspondingly (P < 0.05–0.001), and trapezius type II muscle fibers hypertrophied 20% (P < 0.001). In conclusion, rapid force capacity of chronically painful muscles is highly responsive to rehabilitation with specific strength training. The underlying mechanisms were related to both pain reduction and general neuromuscular adaptations to strength training. Potentially, the present method can be a useful clinical screening tool of muscle function in rehabilitation settings.

Effect of nandrolone decanoate administration on recovery from bupivacaine-induced muscle injury

White, J. P., Baltgalvis, K. A., Sato, S., Wilson, L. B., Carson, J. A. — Wed, 04 Nov 2009 10:56:55 PST

Although testosterone administration elicits well-documented anabolic effects on skeletal muscle mass, the enhancement of muscle regeneration after injury has not been widely examined. The purpose of this study was to determine whether anabolic steroid administration improves skeletal muscle regeneration from bupivacaine-induced injury. Male C57BL/6 mice were castrated 2 wk before muscle injury induced by an intramuscular bupivacaine injection into the tibialis anterior (TA) muscle. Control mice received an intramuscular PBS injection. Anabolic steroid [nandrolone decanoate (ND), 6 mg/kg] or sesame seed oil was administered at the time of initial injury and continued every 7 days for the study's duration. Mice were randomly assigned to one of four treatment groups for 5, 14, or 42 days of recovery, as follows: 1) control (uninjured); 2) ND only (uninjured + ND); 3) bupivacaine only (injured); or 4) bupivacaine + ND (injured + ND). TA morphology, protein, and gene expression were analyzed at 14 and 42 days after injury; protein expression was analyzed at 5 days after injury. After 14 days of recovery, the injury and injury + ND treatments induced small-diameter myofiber incidence and also decreased mean myofiber area. The increase in small-myofiber incidence was 65% greater in injury + ND muscle compared with injury alone. At 14 days, injury + ND induced a fivefold increase in muscle IGF-I mRNA expression, which was greater than injury alone. Muscle Akt activity and glycogen synthetase kinase-3β activity were also induced by injury + ND at 14 days of recovery, but not by injury alone. ND had a main effect for increasing muscle MyoD and cyclin D1 mRNA expression at 14 days. After 42 days of recovery, injury + ND increased large-diameter myofiber incidence compared with injury only. Nandrolone decanoate (ND) administration can enhance castrated mouse muscle regeneration during the recovery from bupivacaine-induced injury.

Microgravity decreases and hypergravity increases exhaled nitric oxide

Wed, 04 Nov 2009 10:56:55 PST

Inhalation of toxic dust during planetary space missions may cause airway inflammation, which can be monitored with exhaled nitric oxide (NO). Gravity will differ from earth, and we hypothesized that gravity changes would influence exhaled NO by altering lung diffusing capacity and alveolar uptake of NO. Five subjects were studied during microgravity aboard the International Space Station, and 10 subjects were studied during hypergravity in a human centrifuge. Exhaled NO concentrations were measured during flows of 50 (all gravity conditions), 100, 200, and 500 ml/s (hypergravity). During microgravity, exhaled NO fell from a ground control value of 12.3 ± 4.7 parts/billion (mean ± SD) to 6.6 ± 4.4 parts/billion (P = 0.016). In the centrifuge experiments and at the same flow, exhaled NO values were 16.0 ± 4.3, 19.5 ± 5.1, and 18.6 ± 4.7 parts/billion at one, two, and three times normal gravity, where exhaled NO in hypergravity was significantly elevated compared with normal gravity (P ≤ 0.011 for all flows). Estimated alveolar NO was 2.3 ± 1.1 parts/billion in normal gravity and increased significantly to 3.9 ± 1.4 and 3.8 ± 0.8 parts/billion at two and three times normal gravity (P < 0.002). The findings of decreased exhaled NO in microgravity and increased exhaled and estimated alveolar NO values in hypergravity suggest that gravity-induced changes in alveolar-to-lung capillary gas transfer modify exhaled NO.

Roles of nitric oxide synthase isoforms in cutaneous vasodilation induced by local warming of the skin and whole body heat stress in humans

Kellogg, D. L., Zhao, J. L., Wu, Y. — Wed, 04 Nov 2009 10:56:55 PST

Nitric oxide (NO) participates in the cutaneous vasodilation caused by increased local skin temperature (Tloc) and whole body heat stress in humans. In forearm skin, endothelial NO synthase (eNOS) participates in vasodilation due to elevated Tloc and neuronal NO synthase (nNOS) participates in vasodilation due to heat stress. To explore the relative roles and interactions of these isoforms, we examined the effects of a relatively specific eNOS inhibitor, N-amino-l-arginine (LNAA), and a specific nNOS inhibitor, N-propyl-l-arginine (NPLA), both separately and in combination, on skin blood flow (SkBF) responses to increased Tloc and heat stress in two protocols. In each protocol, SkBF was monitored by laser-Doppler flowmetry (LDF) and mean arterial pressure (MAP) by Finapres. Cutaneous vascular conductance (CVC) was calculated (CVC = LDF/MAP). Intradermal microdialysis was used to treat one site with 5 mM LNAA, another with 5 mM NPLA, a third with combined 5 mM LNAA and 5 mM NPLA (Mix), and a fourth site with Ringer only. In protocol 1, Tloc was controlled with combined LDF/local heating units. Tloc was increased from 34°C to 41.5°C to cause local vasodilation. In protocol 2, after a period of normothermia, whole body heat stress was induced (water-perfused suits). At the end of each protocol, all sites were perfused with 58 mM nitroprusside to effect maximal vasodilation for data normalization. In protocol 1, at Tloc = 34°C, CVC did not differ between sites (P > 0.05). LNAA and Mix attenuated CVC increases at Tloc = 41.5°C to similar extents (P < 0.05, LNAA or Mix vs. untreated or NPLA). In protocol 2, in normothermia, CVC did not differ between sites (P > 0.05). During heat stress, NPLA and Mix attenuated CVC increases to similar extents, but no significant attenuation occurred with LNAA (P < 0.05, NPLA or Mix vs. untreated or LNAA). In forearm skin, eNOS mediates the vasodilator response to increased Tloc and nNOS mediates the vasodilator response to heat stress. The two isoforms do not appear to interact during either response.

Pulmonary responses to subacute ozone exposure in obese vs. lean mice

Wed, 04 Nov 2009 10:56:56 PST

The purpose of this study was to determine whether obesity affects pulmonary responses following a 3-day ozone exposure. Obese db/db and lean wild-type mice were exposed to ozone (0.3 ppm) for 72 h. In wild-type mice, ozone exposure caused pulmonary injury and inflammation, and these events were associated with reduced pulmonary compliance. In db/db mice, ozone-induced neutrophil recruitment to the lung was reduced and no reduction in compliance was observed. Similar results were obtained in obese Cpe^fat mice, indicating that loss of leptin signaling in db/db mice does not account for these obesity-related changes. To examine the role of interleukin (IL)-6 in this obesity-related difference in ozone responsiveness, wild-type and IL-6-deficient mice were raised on 10% or 60% fat diets. Compared with 10% fat-fed mice, wild-type 60% fat-fed mice were obese and had reduced neutrophil recruitment following ozone. IL-6 deficiency reduced ozone-induced neutrophil recruitment in 10% fat-fed mice. In contrast, in obese mice, no effect of IL-6 deficiency on neutrophil recruitment was observed. Obesity-related differences in the effect of ozone on compliance were observed in both wild-type and IL-6-deficient mice. Obesity-related differences in serum IL-6 were observed and may account for obesity-related differences in the effect of IL-6 deficiency on neutrophil recruitment. In summary, the neutrophilic inflammation induced by prolonged low level ozone exposure was attenuated in obese mice and appeared to result from an absence of IL-6-dependent neutrophil recruitment in the obese mice.

Synergistic and antagonistic interactions in the rat forelimb: acute effects of coactivation

Maas, H., Huijing, P. A. — Wed, 04 Nov 2009 10:56:56 PST

The goals of the present study were 1) to assess effects of antagonist coactivation on mechanical interactions between synergistic muscles, and 2) to quantify the extent of epimuscular myofascial force transmission between synergistic and antagonistic muscles in the rat forelimb. Connective tissues enveloping the muscle bellies in the antebrachium were left intact. Forces exerted at the distal tendons of flexor carpi ulnaris (FCU), palmaris longus (PL), and extensor carpi ulnaris (ECU) muscles were measured at various FCU lengths for two different stimulation protocols: 1) simultaneous stimulation of ulnar/median nerve complex (exciting all wrist flexors, including synergistic FCU and PL) and radial nerve (exciting all wrist extensors, including antagonistic ECU); and 2) stimulation of the ulnar/median nerve exclusively. PL and ECU were kept at a constant length. In addition, muscle forces were measured during stimulation of one of the indicated nerves, with later addition of stimulation of the second nerve during the maintained tetanic contraction. Coactivation of antagonistic muscles increased FCU isometric forces (on average, by 10% of optimal force) and PL forces (on average, by 13% of maximal force), but mechanical interaction between FCU and PL was unchanged. Changing the length and relative position of FCU significantly affected PL (by 20%) as well as ECU forces (by 8%). In addition, distal tetanic force of FCU kept at a constant high length was determined by the order of nerve stimulation onset. These results indicate effects of myofascial pathways between synergistic and antagonistic muscles in the rat forelimb. Coactivation may enhance the stiffness of connective tissues between muscles, but the present data suggest that activation of all wrist flexors already preloaded the myofascial pathways to the greatest extent. The stimulation order effects were explained by dynamic features of muscle and connective tissues (i.e., length-history dependence and viscoelasticity).

Maturation of respiratory control and the propensity for breathing instability in a sheep model

Wed, 04 Nov 2009 10:56:56 PST

Limited evidence suggests that the ventilatory interaction between O₂ and CO₂ is additive after birth and becomes multiplicative with postnatal development. Such a switch may be linked to the propensity for periodic breathing (PB) in infancy. To test this idea, we characterized the maturation of the respiratory controller and its effect on breathing stability in ~10-day-old lambs and 6-mo-old sheep. We measured 1) carotid body sensitivity via dynamic ventilatory responses to step changes in O₂ and CO₂, 2) steady-state ventilatory sensitivity to CO₂ under hypoxic and hyperoxic conditions, 3) the dependence of the apneic threshold on arterial Po₂, and 4) the effect of hypoxic or hypercapnic gas inhalation during induced PB. Stability of the system was assessed using surrogate measures of loop gain. Peripheral sensitivity to O₂ was higher in newborn than in older animals (P < 0.05), but peripheral CO₂ sensitivity was unchanged. Central CO₂ sensitivity was reduced with age, but the slopes of the ventilatory responses to CO₂ were the same in hypoxia and hyperoxia. Reduced arterial Po₂ caused a leftward shift in the apneic threshold at both ages. Inspiration of hypoxic gas during PB immediately halted PB, whereas hypercapnia stopped PB only after one or two further PB cycles. We conclude that the controller in the sheep remains additive over the first 6 mo of life. Our results also show that the loop gain of the respiratory control system is reduced with age, possibly as a result of a reduction of peripheral O₂ sensitivity.

Protective mechanical ventilation does not exacerbate lung function impairment or lung inflammation following influenza A infection

Zosky, G. R., Cannizzaro, V., Hantos, Z., Sly, P. D. — Wed, 04 Nov 2009 10:56:56 PST

The degree to which mechanical ventilation induces ventilator-associated lung injury is dependent on the initial acute lung injury (ALI). Viral-induced ALI is poorly studied, and this study aimed to determine whether ALI induced by a clinically relevant infection is exacerbated by protective mechanical ventilation. Adult female BALB/c mice were inoculated with 10^4.5 plaque-forming units of influenza A/Mem/1/71 in 50 µl of medium or medium alone. This study used a protective ventilation strategy, whereby mice were anesthetized, tracheostomized, and mechanically ventilated for 2 h. Lung mechanics were measured periodically throughout the ventilation period using a modification of the forced oscillation technique to obtain measures of airway resistance and coefficients of tissue damping and tissue elastance. Thoracic gas volume was measured and used to obtain specific airway resistance, tissue damping, and tissue elastance. At the end of the ventilation period, a bronchoalveolar lavage sample was collected to measure inflammatory cells, macrophage inflammatory protein-2, IL-6, TNF-, and protein leak. Influenza infection caused significant increases in inflammatory cells, protein leak, and deterioration in lung mechanics that were not exacerbated by mechanical ventilation, in contrast to previous studies using bacterial and mouse-specific viral infection. This study highlighted the importance of type and severity of lung injury in determining outcome following mechanical ventilation.

Insulin resistance without elevated mammalian target of rapamycin complex 1 activity in muscles of mice fed a high-fat diet

Reynolds, T. H., Cinquino, N., Anthony, M., Phelps, C. B., Zachary Berk, E. — Wed, 04 Nov 2009 10:56:56 PST

The mammalian target of rapamycin complex 1 (mTORC1) appears to mediate the development of insulin resistance in cultured cells. We studied in vivo insulin action and mTORC1 signaling in skeletal muscles of mice fed a normal chow [control (CON)] diet or a high-fat diet (HFD) for 16 wk. We assessed in vivo insulin action by measuring glucose tolerance (GT), insulin tolerance (IT), and insulin-assisted GT (IAGT). Although GT was not altered, the HFD significantly reduced IT and IAGT. Acute treatment with rapamycin, a highly specific inhibitor of mTORC1, did not improve GT, IT, or IAGT in mice fed the CON diet or the HFD. Phosphorylation of S6 kinase (S6K) on Thr³⁸⁹, a surrogate measure of mTORC1 kinase activity, was assessed in skeletal muscles of mice 15 min after an intraperitoneal injection of insulin or saline. In the basal state and after insulin stimulation, phosphorylation of S6K on Thr³⁸⁹ was similar in muscles of mice fed the HFD and mice fed the CON diet, indicating that mTORC1 activity is not elevated. Furthermore, phosphorylation of insulin receptor substrate 1 on Ser⁶³⁶, a site phosphorylated by mTORC1, was similar in muscles of mice fed the HFD and mice fed the CON diet. Taken together, these findings indicate that in vivo insulin resistance can occur without an increase in mTORC1 activity in skeletal muscle and that inhibition of mTORC1 with rapamycin does not improve insulin action.

Sex differences in response to cognitive stress during a fatiguing contraction

Yoon, T., Keller, M. L., De-Lap, B. S., Harkins, A., Lepers, R., Hunter, S. K. — Wed, 04 Nov 2009 10:56:56 PST

This study compared the time to task failure for a submaximal fatiguing contraction in the presence and absence of a cognitive stressor in men and women. In study 1, 10 men and 10 women (22 ± 3 yr of age) performed an isometric fatiguing contraction at 20% maximal voluntary contraction force until task failure with the elbow flexor muscles during two separate sessions. Subjects performed a mental-math task during one of the fatiguing contractions that aimed to increase anxiety and stress (stressor session). Salivary cortisol and reported levels of arousal (visual analog scale for anxiety, and State-Trait Anxiety Inventory scores) were elevated during the stressor session compared with a control session for both sexes (P < 0.05). Time to task failure, however, was briefer during the stressor session compared with control (P = 0.005) but more so for the women (27.3 ± 20.1%) than the men (8.6 ± 23.1%) (P = 0.03). The briefer time to task failure was associated with target force (r² = 0.21) and accompanied by a higher mean arterial pressure, heart rate, and rate-pressure product during the fatiguing contraction in the stressor session compared with control in women. In study 2 (11 men and 8 women, 20 ± 3 yr of age), time to task failure was similar for a fatiguing contraction with simple mental-math that did not increase stress (mental-attentiveness session) and control for both men and women. The greater change in fatigability of women than men with performance of a cognitive stressor involved initial strength and increases in indexes of sympathetic neural activity and cardiac work compared with control conditions.

Discerning aortic waves during intra-aortic balloon pumping and their relation to benefits of counterpulsation in humans

Kolyva, C., Pantalos, G. M., Giridharan, G. A., Pepper, J. R., Khir, A. W. — Wed, 04 Nov 2009 10:56:56 PST

An explanation of the mechanisms leading to the beneficial hemodynamic effects of the intra-aortic balloon pump (IABP) is lacking. We hypothesized that inflation and deflation of the balloon would generate a compression (BCW) and an expansion (BEW) wave, respectively, which, when analyzed with wave intensity analysis, could be used to explain the hemodynamic benefits of IABP support. Simultaneous ascending aortic pressure (P_ao) and flow rate (Q_ao) were recorded in 25 patients during control conditions and with IABP support of 1:1 and 1:2. Diastolic aortic pressure augmentation (P_aug) and end-diastolic aortic pressure (ED P_ao) reduction were calculated from P_ao. Energies of the BCW and BEW were obtained by integrating the wave intensity contour over time. P_aug was 19.1 mmHg (SD 13.6) during 1:2 support. During 1:1 support significantly higher P_aug of 21.1 mmHg (SD 13.4) was achieved (P < 0.001). ED P_ao decreased from 50.9 mmHg (SD 15.1) to 43.9 mmHg (SD 15.7) (P < 0.0001) during 1:1 assistance and the decrease was not statistically different with 1:2. During 1:1 support the energy of BCW was correlated positively to P_aug (r = 0.83, P < 0.0001) and energy of the BEW correlated negatively to ED P_ao (r = 0.78, P < 0.005); these relationships were not statistically different during 1:2. In conclusion, the energies of the BCW and BEW are directly related to P_aug and ED P_ao, which are the conventional hemodynamic parameters indicating IABP benefits. These findings imply a cause and effect mechanism between the energies of BCW and BEW, and IABP hemodynamic effects.

Estimating the diameter of airways susceptible for collapse using crackle sound

Majumdar, A., Hantos, Z., Tolnai, J., Parameswaran, H., Tepper, R., Suki, B. — Wed, 04 Nov 2009 10:56:56 PST

Airways that collapse during deflation generate a crackle sound when they reopen during subsequent reinflation. Since each crackle is associated with the reopening of a collapsed airway, the likelihood of an airway to be a crackle source is identical to its vulnerability to collapse. To investigate this vulnerability of airways to collapse, crackles were recorded during the first inflation of six excised rabbit lungs from the collapsed state, and subsequent reinflations from 5, 2, 1, and 0 cmH₂O end-expiratory pressure levels. We derived a relationship between the amplitude of a crackle sound at the trachea and the generation number (n) of the source airway where the crackle was generated. Using an asymmetrical tree model of the rabbit airways with elastic walls, airway vulnerability to collapse was also determined in terms of airway diameter D. During the reinflation from end-expiratory pressure = 0 cmH₂O, the most vulnerable airways were estimated to be centered at n = 12 with a peak. Vulnerability in terms of D ranged between 0.1 and 1.3 mm, with a peak at 0.3 mm. During the inflation from the collapsed state, however, vulnerability was much less localized to a particular n or D, with maximum values of n = 8 and D = 0.75 mm. Numerical simulations using a tree model that incorporates airway opening and closing support these conclusions. Thus our results indicate that there are airways of a given range of diameters that can become unstable during deflation and vulnerable to collapse and subsequent injury.

Surround inhibition depends on the force exerted and is abnormal in focal hand dystonia

Beck, S., Schubert, M., Richardson, S. P., Hallett, M. — Wed, 04 Nov 2009 10:56:56 PST

There is evidence that surround inhibition (SI), a neural mechanism to enhance contrast between signals, may play a role in primary motor cortex during movement initiation, while it is deficient in patients with focal hand dystonia (FHD). To further characterize SI with respect to different force levels, single- and paired-pulse transcranial magnetic stimulation was applied at rest and during index finger movement to evoke potentials in the nonsynergistic, abductor policis muscle. In Experiment 1, in 19 healthy volunteers, SI was tested using single-pulse transcranial magnetic stimulation. Motor-evoked potentials at rest were compared with those during contraction using four different force levels [5, 10, 20, and 40% of maximum force (F_max)]. In Experiments 2 and 3, SI and short intracortical inhibition (SICI) were tested, respectively, in 16 patients with FHD and 20 age-matched controls for the 10% and 20% F_max levels. SI was most pronounced for 10% F_max and abolished for the 40% F_max level in controls, whereas FHD patients had no SI at all. In contrast, a loss of SICI was observed in FHD patients, which was more pronounced for 10% F_max than for 20% F_max. Our results suggest that SI is involved in the generation of fine finger movements with low-force levels. The greater loss of SICI for the 10% F_max level in patients with FHD than for the 20% F_max level indicates that this inhibitory mechanism is more abnormal at lower levels of force.

Evidence against a 40{degrees}C core temperature threshold for fatigue in humans

Wed, 04 Nov 2009 10:56:56 PST

Evidence suggests that core temperatures of ~40°C can induce fatigue, although this may be confounded by coincident elevations in skin temperatures and maximal cardiovascular strain. In an observational field study to examine core temperature threshold for fatigue, we investigated whether running performance is impaired when rectal temperature (T_re) is >40°C and skin temperature remains modest. Seventeen competitive runners (7/10 women/men: 8 km best 1,759 ± 78/1,531 ± 60 s) completed 8-km track time trials in cool (WBGT ~13°C; n = 6), warm (WBGT ~27°C; n = 4), or both (n = 7) conditions. T_re, chest skin temperature, and heart rate were logged continuously; elapsed time was recorded every 200 m. Running velocity for T_re >40°C was compared with that for T_re <40°C for each runner. Changes in running velocity over the last 600 m were compared between runners with T_re >40°C and <40°C. Twelve runners achieved T_re >40.0°C with ≥600 m remaining (range 600–3,400 m). Average running velocity for T_re <40°C (282 ± 27 m/min) was not different from that for T_re >40°C (279 ± 28 m/min; P = 0.82). There were no differences in running velocity during the final 600 m between runners with final T_re >40°C or <40°C (P = 0.16). Chest skin temperature ranged from 30 to 34°C, and heart rate was >95% of age-predicted maximum. Our observation that runners were able to sustain running velocity despite T_re >40°C is evidence against 40°C representing a "critical" core temperature limit to performance.

Underwater study of arterial blood pressure in breath-hold divers

Sieber, A., L'Abbate, A., Passera, M., Garbella, E., Benassi, A., Bedini, R. — Wed, 04 Nov 2009 10:56:56 PST

Knowledge regarding arterial blood pressure (ABP) values during breath-hold diving is scanty. It derives from a few reports of measurements performed at the water's surface, showing slight or no increase in ABP, and from a single study of two simulated deep breath-hold dives in a hyperbaric chamber. Simulated dives showed an increase in ABP to values considered life threatening by standard clinical criteria. For the first time, using a novel noninvasive subaquatic sphygmomanometer, we successfully measured ABP in 10 healthy elite breath-hold divers at a depth of 10 m of freshwater (mfw). ABP was measured in dry conditions, at the surface (head-out immersion), and twice at a depth of 10 mfw. Underwater measurements of ABP were obtained in all subjects. Each measurement lasted 50–60 s and was accomplished without any complications or diver discomfort. In the 10 subjects as a whole, mean ABP values were 124/93 mmHg at the surface and 123/94 mmHg at a depth of 10 mfw. No significant statistical differences were found when blood pressure measurements at the water surface were compared with breath-hold diving conditions at a depth of 10 mfw. No systolic blood pressure values >140 mmHg or diastolic blood pressure values >115 mmHg were recorded. In conclusion, direct measurements of ABP during apnea diving showed no or only mild increases in ABP. However, our results cannot be extended over environmental conditions different from those of the present study.

Vitamin C and E supplementation prevents mitochondrial damage of ileum myocytes caused by intense and exhaustive exercise training

Wed, 04 Nov 2009 10:56:56 PST

Intense and exhaustive exercise (IEE) is associated with oxidative stress in skeletal muscle, and we recently reported that intestine is sensitive to IEE. In the present study, we investigated the possible relationship between the effects of IEE on morphology and oxidative markers in the ileum and isolated mitochondria. C57BL/6 mice were ascribed either to a control group comprising two subgroups, one sedentary and another exercised for 10 days (E10), or to a corresponding supplemented control group again comprising two subgroups, one sedentary and another exercised for 10 days (E10-V). The IEE program consisted of a single daily treadmill running session at 85% of V_max, until animal exhaustion. Vitamins C (10 mg/kg) and E (10 mg/kg) were concurrently intraperitoneally administered 2 h before the exercise sessions. IEE was shown to cause 1) impairment of ileum internal membrane mitochondria verified by ultramicrography analysis; 2) increase in ileum carbonyl content (117%) and reduction in antioxidant capacity (36%); 3) increase in mitochondria carbonyl content (38%), increase in the percentage of ruptured mitochondria (25.3%), increase in superoxide dismutase activity (186%), and reduction in citrate synthase activity (40.4%) compared with control animals. Observations in the vitamin-supplemented exercised animals (E10-V) were 1) healthy appearance of myocyte mitochondria; 2) decrease in ileum carbonyl content (66%) and increase in antioxidant capacity (53%); 3) decrease in mitochondria carbonyl content (43%), decrease in the percentage of ruptured mitochondria (30%), slight increase in superoxide dismutase activity (7%), and significant increase in citrate synthase activity (121%) compared with E10 animals. Therefore, the present results strongly corroborate the hypothesis that IEE leads to marked disturbances in intestinal mitochondria, mainly in redox status, and affects whole intestinal redox status.

Marginal DCS events: their relation to decompression and use in DCS models

Howle, L. E., Weber, P. W., Vann, R. D., Campbell, M. C. — Wed, 04 Nov 2009 10:56:56 PST

We consider the nature and utility of marginal decompression sickness (DCS) events in fitting probabilistic decompression models to experimental dive trial data. Previous works have assigned various fractional weights to marginal DCS events, so that they contributed to probabilistic model parameter optimization, but less so than did full DCS events. Inclusion of fractional weight for marginal DCS events resulted in more conservative model predictions. We explore whether marginal DCS events are correlated with exposure to decompression or are randomly occurring events. Three null models are developed and compared with a known decompression model that is tuned on dive trial data containing only marginal DCS and non-DCS events. We further investigate the technique by which marginal DCS events were previously included in parameter optimization, explore the effects of fractional weighting of marginal DCS events on model optimization, and explore the rigor of combining data containing full and marginal DCS events for probabilistic DCS model optimization. We find that although marginal DCS events are related to exposure to decompression, empirical dive data containing marginal and full DCS events cannot be combined under a single DCS model. Furthermore, we find analytically that the optimal weight for a marginal DCS event is 0. Thus marginal DCS should be counted as no-DCS events when probabilistic DCS models are optimized with binomial likelihood functions. Specifically, our study finds that inclusion of marginal DCS events in model optimization to make the dive profiles more conservative is counterproductive and worsens the model's fit to the full DCS data.

Effects of the molecular mass of tense-state polymerized bovine hemoglobin on blood pressure and vasoconstriction

Wed, 04 Nov 2009 10:56:56 PST

Despite recent advances in the design of hemoglobin (Hb)-based oxygen carriers (HBOCs), vasoconstriction, presumably caused by nitric oxide (NO) scavenging, vessel wall hyperoxygenation, and/or extravasation, has been identified as the principal road block hampering commercial development of HBOCs. This study was designed to analyze systemic and microvascular responses to the molecular mass and plasma concentration of tense (T)-state polymerized bovine Hb (PolybHb) solutions. Experiments were performed using the hamster window chamber model subjected to successive hypervolemic infusions of T-state PolybHb solutions. PolybHb plasma concentrations were evaluated, namely, 0.5, 1.0 and 1.5 g/dl, respectively. Infusion of PolybHb solutions with molecular mass >500 kDa elicited hypertension and vasoconstriction proportional to the plasma concentration and inversely proportional to the PolybHb cross-link density. However, two high-molecular mass PolybHb solutions, PolybHb(40:1)_high PolybHb(50:1)_high, did not elicit vasoconstriction at all concentrations studied, whereas PolybHb(50:1)_high only elicited moderate hypertension at the highest concentration studied. In contrast, infusion of PolybHb solutions with molecular mass <500 kDa elicited significant hypertension and vasoconstriction compared with PolybHb solutions with molecular mass >500 kDa that was proportional to the plasma concentration and inversely proportional to the PolybHb cross-link density. We present promising results for highly cross-linked T-state PolybHb solutions with molecular mass >500 kDa [PolybHb(40:1)_high PolybHb(50:1)_high], which supports the concept that HBOC size/molecular mass influences its proximity to the vascular endothelium and molecular diffusivity. The hemodynamics of HBOC within the plasma layer surrounding the abluminal side endothelium regulates NO production and consumption, vessel oxygen flux, and extravasation. Although mechanistically attractive, neither of these hypotheses can be directly tested in vivo and will require further investigation.

Pulmonary perfusion heterogeneity is increased by sustained, heavy exercise in humans

Wed, 04 Nov 2009 10:56:56 PST

Exercise presents a considerable stress to the pulmonary system and ventilation-perfusion (Va/Q) heterogeneity increases with exercise, affecting the efficiency of gas exchange. In particular, prolonged heavy exercise and maximal exercise are known to increase Va/Q heterogeneity and these changes persist into recovery. We hypothesized that the spatial heterogeneity of pulmonary perfusion would be similarly elevated after prolonged exercise. To test this, athletic subjects (n = 6, Vo_2max = 61 ml· kg^–1·min^–1) with exercising Va/Q heterogeneity previously characterized by the multiple inert gas elimination technique (MIGET), performed 45 min of cycle exercise at ~70% Vo_2max. MRI arterial spin labeling measures of pulmonary perfusion were acquired pre- and postexercise (at 20, 40, 60 min post) to quantify the spatial distribution in isogravitational (coronal) and gravitationally dependent (sagittal) planes. Regional proton density measurements allowed perfusion to be normalized for density and quantified in milliliters per minute per gram. Mean lung density did not change significantly in either plane after exercise (P = 0.19). Density-normalized perfusion increased in the sagittal plane postexercise (P = <0.01) but heterogeneity did not (all P ≥ 0.18), likely because of perfusion redistribution and vascular recruitment. Density-normalized perfusion was unchanged in the coronal plane postexercise (P = 0.66), however, perfusion heterogeneity was significantly increased as measured by the relative dispersion [RD, pre 0.62(0.07), post 0.82(0.21), P < 0.0001] and geometric standard deviation [GSD, pre 1.74(0.14), post 2.30(0.56), P < 0.005]. These changes in heterogeneity were related to the exercise-induced changes of the log standard deviation of the ventilation distribution, an MIGET index of Va/Q heterogeneity (RD R² = 0.68, P < 0.05, GSD, R² = 0.55, P = 0.09). These data are consistent with but not proof of interstitial pulmonary edema as the mechanism underlying exercise-induced increases in both spatial perfusion heterogeneity and Va/Q heterogeneity.

Noninvasive quantification of heterogeneous lung growth following extensive lung resection by high-resolution computed tomography

Wed, 04 Nov 2009 10:56:56 PST

To quantify the in vivo magnitude and distribution of regional compensatory lung growth following extensive lung resection, we performed high-resolution computed tomography at 15- and 30-cmH₂O transpulmonary pressures and measured air and tissue (including microvascular blood) volumes within and among lobes in six adult male foxhounds, before and after balanced 65% lung resection (~32% removed from each side). Each lobe was identified from lobar fissures. Intralobar gradients in air and tissue volumes were expressed along standardized x,y,z-coordinate axes. Fractional tissue volume (FTV) was calculated as the volume ratio of tissue/(tissue + air). Following resection compared with before, lobar air and tissue volumes increased 1.8- to 3.5-fold, and whole lung air and tissue volumes were 67 and 90% of normal, respectively. Lobar-specific compliance doubled post-resection, and whole lung-specific compliance normalized. These results are consistent with vigorous compensatory growth in all remaining lobes. Compared with pre-resection, post-resection interlobar heterogeneity of FTV, assessed from the coefficient of variation, decreased at submaximal inflation, but was unchanged at maximal inflation. The coefficient of variation of intralobar FTV gradients changed variably due to the patchy development of thickened pleura and alveolar septa, with elevated alveolar septal density and connective tissue content in posterior-caudal and peripheral regions of the remaining lobes; these areas likely experienced disproportional mechanical stress. We conclude that HRCT can noninvasively and quantitatively assess the magnitude and spatial distribution of compensatory lung growth. Following extensive resection, heterogeneous regional mechanical lung strain may exceed the level that could be sustained solely by existing connective tissue elements.

Prenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome

Wed, 04 Nov 2009 10:56:56 PST

During pregnancy, exposure to nicotine and other compounds in cigarette smoke increases the risk of the sudden infant death syndrome (SIDS) two- to fivefold. Serotonergic (5-HT) abnormalities are found, in infants who die of SIDS, in regions of the medulla oblongata known to modulate cardiorespiratory function. Using a baboon model, we tested the hypothesis that prenatal exposure to nicotine alters 5-HT receptor and/or transporter binding in the fetal medullary 5-HT system in association with cardiorespiratory dysfunction. At 87 (mean) days gestation (dg), mothers were continuously infused with saline (n = 5) or nicotine (n = 5) at 0.5 mg/h. Fetuses were surgically instrumented at 129 dg for cardiorespiratory monitoring. Cesarean section delivery and retrieval of fetal medulla were performed at 161 (mean) dg for autoradiographic analyses of nicotinic and 5-HT receptor and transporter binding. In nicotine-exposed fetuses, high-frequency heart rate variability was increased 55%, possibly reflecting increases in the parasympathetic control of heart rate. This effect was more pronounced with greater levels of fetal breathing and age. These changes in heart rate variability were associated with increased 5-HT_1A receptor binding in the raphé obscurus (P = 0.04) and increased nicotinic receptor binding in the raphé obscurus and vagal complex (P < 0.05) in the nicotine-exposed animals compared with controls (n = 6). The shift in autonomic balance in the fetal primate toward parasympathetic predominance with chronic exposure to nicotine may be related, in part, to abnormal 5-HT-nicotine alterations in the raphé obscurus. Thus increased risk for SIDS due to maternal smoking may be partly related to the effects of nicotine on 5-HT and/or nicotinic receptors.

{micro}-Opioid receptor agonist injections into the presumed pre-Botzinger complex and the surrounding region of awake goats do not alter eupneic breathing

Wed, 04 Nov 2009 10:56:56 PST

Opioids are clinically important in the alleviation of pain. An undesirable side effect of opioids is depression of breathing. Data from isolated preparations suggest this effect is due to attenuation of discharge activity of neurons in the pre-Bötzinger complex (preBötzC), a medullary area with respiratory rhythmogenic properties. The purpose of this study was to examine how [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), a µ-opioid receptor agonist, affected breathing after injection into the presumed preBötzC of the adult awake goat. We hypothesized that DAMGO would cause breathing to decrease and become irregular when injected into the presumed preBötzC and the surrounding region of the conscious animal. We further hypothesized that ventilatory sensitivity to CO₂ and hypoxia would be blunted after the injection of DAMGO. Microtubules were bilaterally implanted into the presumed preBötzC of 10 adult female goats. After recovery from the surgery, DAMGO (0.5–10 µl, 1 nM–10 µM) was injected into the presumed preBötzC during the awake state. DAMGO had no effect on pulmonary ventilation [inspiratory minute ventilation (Vi)], respiratory rhythm and pattern, the activation pattern of inspiratory and expiratory muscles, or arterial blood gases during eupneic breathing conditions (P > 0.10). However, DAMGO attenuated (P < 0.05) the evoked increase in breathing frequency when inspired CO₂ was increased, and DAMGO attenuated the Vi response to reduction of inspired O₂ to 10.8% (P < 0.05). We conclude that our data do not provide support for the concept that in awake mammals opioid depression of breathing is due to a directed action of opioids on preBötzC neurons.

Local NSAID infusion inhibits satellite cell proliferation in human skeletal muscle after eccentric exercise

Wed, 04 Nov 2009 10:56:56 PST

Despite the widespread consumption of nonsteroidal anti-inflammatory drugs (NSAIDs), the influence of these drugs on muscle satellite cells is not fully understood. The aim of the present study was to investigate the effect of a local NSAID infusion on satellite cells after unaccustomed eccentric exercise in vivo in human skeletal muscle. Eight young healthy males performed 200 maximal eccentric contractions with each leg. An NSAID was infused via a microdialysis catheter into the vastus lateralis muscle of one leg (NSAID leg) before, during, and for 4.5 h after exercise, with the other leg working as a control (unblocked leg). Muscle biopsies were collected before and 8 days after exercise. Changes in satellite cells and inflammatory cell numbers were investigated by immunohistochemistry. Satellite cells were identified using antibodies against neural cell adhesion molecule and Pax7. The number of Pax7⁺ cells per myofiber was increased by 96% on day 8 after exercise in the unblocked leg (0.14 ± 0.04, mean ± SE) compared with the prevalue (0.07 ± 0.02, P < 0.05), whereas the number of Pax7⁺ cells was unchanged in the leg muscles exposed to the NSAID (0.07 ± 0.01). The number of inflammatory cells (CD68⁺ or CD16⁺ cells) was not significantly increased in either of the legs 8 days after exercise and was unaffected by the NSAID. The main finding in the present study was that the NSAID infusion for 7.5 h during the exercise day suppressed the exercise-induced increase in the number of satellite cells 8 days after exercise. These results suggest that NSAIDs negatively affect satellite cell activity after unaccustomed eccentric exercise.

Heat stress increases myonuclear number and fiber size via satellite cell activation in rat regenerating soleus fibers

Wed, 04 Nov 2009 10:56:57 PST

To investigate the effects of heat stress (hyperthermia) on muscle degeneration-regeneration, the soleus muscles of adult male Wistar rats were injected bilaterally with a single injection of bupivacaine. The rats were assigned to a sedentary control (Con), heat stress (Heat), bupivacaine-injected (BPVC), or bupivacaine-injected plus heat stress (BPVC+Heat) group. Heat stress was induced in the Heat and BPVC+Heat groups by immersion of the lower half of the body into water maintained at 42 ± 1°C for 30 min 48 h after the injection of bupivacaine and every other day during the following 1 or 2 wk. The soleus muscles in all groups were excised 24 h after the final bout of heat stress. Mean muscle weight, fiber cross-sectional area, myonuclear number, and heat shock protein 72 (Hsp72) and calcineurin protein levels were lower in the BPVC than in the Con or Heat groups at both time points. In contrast, several of these parameters in the BPVC+Heat group were not different or higher than in the Con or Heat groups at the 1- and/or 2-wk time points. The number of total and activated satellite cells, estimated by analyses of Pax7-negative, M-cadherin-negative, and MyoD-positive nuclei, was greater in BPVC+Heat than in all other groups. Combined, the results indicate that heat stress-related activation of satellite cells and upregulation of Hsp72 and calcineurin expression played important roles in the regeneration of the soleus fibers after bupivacaine injection.

Evidence for dysanapsis using computed tomographic imaging of the airways in older ex-smokers

Wed, 04 Nov 2009 10:56:57 PST

We sought to determine the relationship between lung size and airway size in men and women of varying stature. We also asked if men and women matched for lung size would still have differences in airway size and if so where along the pulmonary airway tree would these differences exist. We used computed tomography to measure airway luminal areas of the large and central airways. We determined airway luminal areas in men (n = 25) and women (n = 25) who were matched for age, body mass index, smoking history, and pulmonary function and in a separate set of men (n = 10) and women (n = 11) who were matched for lung size. Men had greater values for the larger airways and many of the central airways. When male and female subjects were pooled there were significant associations between lung size and airway size. Within the male and female groups the magnitudes of these associations were decreased or nonsignificant. In males and females matched for lung size women had significantly smaller airway luminal areas. The larger conducting airways in females are significantly smaller than those of males even after controlling for lung size.

Fat circadian biology

Gimble, J. M., Floyd, Z. E. — Wed, 04 Nov 2009 10:56:57 PST

While adipose tissue has long been recognized for its major role in metabolism, it is now appreciated as an endocrine organ. A growing body of literature has emerged that identifies circadian mechanisms as a critical regulator of adipose tissue differentiation, metabolism, and adipokine secretory function in both health and disease. This concise review focuses on recent data from murine and human models that highlights the interplay between the core circadian regulatory proteins and adipose tissue in the context of energy, fat, and glucose metabolism. It will be important to integrate circadian mechanisms and networks into future descriptions of adipose tissue physiology.

Clock genes and metabolic disease

Marcheva, B., Ramsey, K. M., Affinati, A., Bass, J. — Wed, 04 Nov 2009 10:56:57 PST

The circadian system is a key integrator of behavior and metabolism that synchronizes physiological processes with the rotation of the Earth on its axis. In mammals, the clock is present not only within the central pacemaker neurons of the hypothalamus, but also within extra-suprachiasmatic nucleus (SCN) regions of brain and nearly all peripheral tissues. Recent evidence suggests that the complex feedback networks that encompass both the circadian and metabolic systems are intimately intertwined and that disruption of either system leads to reciprocal disturbances in the other. We anticipate that improved understanding of the interconnections between the circadian and metabolic networks will open new windows on the treatment of sleep and metabolic disorders, including diabetes mellitus and obesity.

Working around the clock: circadian rhythms and skeletal muscle

Zhang, X., Dube, T. J., Esser, K. A. — Wed, 04 Nov 2009 10:56:57 PST

The study of the circadian molecular clock in skeletal muscle is in the very early stages. Initial research has demonstrated the presence of the molecular clock in skeletal muscle and that skeletal muscle of a clock-compromised mouse, Clock mutant, exhibits significant disruption in normal expression of many genes required for adult muscle structure and metabolism. In light of the growing association between the molecular clock, metabolism, and metabolic disease, it will also be important to understand the contribution of circadian factors to normal metabolism, metabolic responses to muscle training, and contribution of the molecular clock in muscle-to-muscle disease (e.g., insulin resistance). Consistent with the potential for the skeletal muscle molecular clock modulating skeletal muscle physiology, there are findings in the literature that there is significant time-of-day effects for strength and metabolism. Additionally, there is some recent evidence that temporal specificity is important for optimizing training for muscular performance. While these studies do not prove that the molecular clock in skeletal muscle is important, they are suggestive of a circadian contribution to skeletal muscle function. The application of well-established models of skeletal muscle research in function and metabolism with available genetic models of molecular clock disruption will allow for more mechanistic understanding of potential relationships.

Translational signaling responses preceding resistance training-mediated myofiber hypertrophy in young and old humans

Mayhew, D. L., Kim, J.-s., Cross, J. M., Ferrando, A. A., Bamman, M. M. — Wed, 04 Nov 2009 10:56:57 PST

While skeletal muscle protein accretion during resistance training (RT)-mediated myofiber hypertrophy is thought to result from upregulated translation initiation signaling, this concept is based on responses to a single bout of unaccustomed resistance exercise (RE) with no measure of hypertrophy across RT. Further, aging appears to affect acute responses to RE, but whether age differences in responsiveness persist during RT leading to impaired RT adaptation is unclear. We therefore tested whether muscle protein fractional synthesis rate (FSR) and Akt/mammalian target of rapamycin (mTOR) signaling in response to unaccustomed RE differed in old vs. young adults, and whether age differences in acute responsiveness were associated with differences in muscle hypertrophy after 16 wk of RT. Fifteen old and 21 young adult subjects completed the 16-wk study. The phosphorylation states of Akt, S6K1, ribosomal protein S6 (RPS6), eukaryotic initiation factor 4E (eIF4E) binding protein (4EBP1), eIF4E, and eIF4G were all elevated (23–199%) 24 h after a bout of unaccustomed RE. A concomitant 62% increase in FSR was found in a subset (6 old, 8 young). Age x time interaction was found only for RPS6 phosphorylation (+335% in old subjects only), while there was an interaction trend (P = 0.084) for FSR (+96% in young subjects only). After 16 wk of RT, gains in muscle mass, type II myofiber size, and voluntary strength were similar in young and old subjects. In conclusion, at the level of translational signaling, we found no evidence of impaired responsiveness among older adults, and for the first time, we show that changes in translational signaling after unaccustomed RE were associated with substantial muscle protein accretion (hypertrophy) during continued RT.

Point: The kinetics of oxygen uptake during muscular exercise do manifest time-delayed phases

Whipp, B. J. — Wed, 04 Nov 2009 10:56:57 PST

Counterpoint: The kinetics of oxygen uptake during muscular exercise do not manifest time-delayed phases

Stirling, J. R., Zakynthinaki, M. — Wed, 04 Nov 2009 10:56:57 PST

Rebuttal from Whipp

Wed, 04 Nov 2009 10:56:57 PST

Rebuttal from Stirling and Zakynthinaki

Wed, 04 Nov 2009 10:56:57 PST

Comments on Point:Counterpoint: The kinetics of oxygen uptake during muscular exercise do/do not manifest time-delayed phases

Wed, 04 Nov 2009 10:56:57 PST

Last Word on Point:Counterpoint: The kinetics of oxygen uptake during muscular exercise do/do not manifest time-delayed phases

Stirling, J. R., Zakynthinaki, M. — Wed, 04 Nov 2009 10:56:57 PST

Beware of the pickle: health effects of nitrate intake

Derave, W., Taes, Y. — Wed, 04 Nov 2009 10:56:57 PST

Reply to Derave and Taes

Benjamin, N., Bailey, S. J., Vanhatalo, A., Winyard, P., Jones, A. M. — Wed, 04 Nov 2009 10:56:57 PST

Impact factor and its role in academic promotion: A statement adopted by the International Respiratory Journal Editors Roundtable

Dempsey, J. A. — Thu, 15 Oct 2009 07:50:19 PDT

Edward F. Adolph Distinguished Lecture: Muscle as an endocrine organ: IL-6 and other myokines

Pedersen, B. K. — Thu, 15 Oct 2009 07:50:20 PDT

Skeletal muscle is an endocrine organ that produces and releases myokines in response to contraction. Some myokines are likely to work in a hormone-like fashion, exerting specific endocrine effects on other organs such as the liver, the brain, and the fat. Other myokines will work locally via paracrine mechanisms, exerting, e.g., angiogenetic effects, whereas yet other myokines work via autocrine mechanisms and influence signaling pathways involved in fat oxidation and glucose uptake. The finding that muscles produce and release myokines creates a paradigm shift and opens new scientific, technological, and scholarly horizons. This finding represents a breakthrough within integrative physiology and contributes to our understanding of why regular exercise protects against a wide range of chronic diseases. Thus the myokine field provides a conceptual basis for the molecular mechanisms underlying, e.g., muscle-fat, muscle-liver, muscle-pancreas, and muscle-brain cross talk.

What to do about apnea of prematurity?

Martin, R. J., Wilson, C. G. — Thu, 15 Oct 2009 07:50:20 PDT

Stabilizing immature breathing patterns of preterm infants using stochastic mechanosensory stimulation

Bloch-Salisbury, E., Indic, P., Bednarek, F., Paydarfar, D. — Thu, 15 Oct 2009 07:50:20 PDT

Breathing patterns in preterm infants consist of highly variable interbreath intervals (IBIs) that might originate from nonlinear properties of the respiratory oscillator and its input-output responses to peripheral and central signals. Here, we explore a property of nonlinear control, the potential for large improvement in the stability of breathing using low-level exogenous stochastic stimulation. Stimulation was administered to 10 preterm infants (postconceptional age: mean 33.3 wk, SD 1.7) using a mattress with embedded actuators that delivered small stochastic displacements (0.021 mm root mean square, 0.090 mm maximum, 30–60 Hz); this stimulus was subthreshold for causing arousal from sleep to wakefulness or other detectable changes in the behavioral state evaluated with polysomnography. We used a test-retest protocol with multiple 10-min intervals of stimulation, each paired with 10-min intervals of no stimulation. Stimulation induced an ~50% reduction (P = 0.003) in the variance of IBIs and an ~50% reduction (P = 0.002) in the incidence of IBIs > 5 s. The improved stability of eupneic breathing was associated with an ~65% reduction (P = 0.04) in the duration of O₂ desaturation. Our findings suggest that nonlinear properties of the immature respiratory control system can be harnessed using afferent stimuli to stabilize eupneic breathing, thereby potentially reducing the incidence of apnea and hypoxia.

Sulforaphane treatment protects skeletal muscle against damage induced by exhaustive exercise in rats

Thu, 15 Oct 2009 07:50:20 PDT

Sulforaphane (SF), one of the most important isothiocyanates in the human diet, present in cruciferous vegetables, is known to have chemopreventive activities in different tissues. No data are available on its effects in the prevention of skeletal muscle damage. In this study, we investigated the potential protective effects of SF treatment on muscle damage and oxidative stress induced by an acute bout of exhaustive exercise in rats. Male Wistar rats were treated with SF (25 mg/kg body wt ip) for 3 days before undergoing an acute exhaustive exercise protocol in a treadmill (+7% slope and 24 m/min). Acute exercise resulted in a significant increase in plasma lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) activities. It also resulted in a significant increase in thiobarbituric acid-reactive substances, in a significant decrease in tissue total antioxidant capacity, and in a significant decrease in NAD(P)H:quinone oxidoreductase 1 (NQO1) expression and activity in vastus lateralis muscle. SF treatment significantly increased muscle NQO1, glutathione-S-transferase, and glutathione reductase expression and activity, with no effect on glutathione peroxidase and thioredoxin reductase. The observed SF-induced upregulation of phase II enzymes was accompanied by a significant increase in nuclear erythroid 2 p45-related factor 2 expression and correlated with a significant increase in total antioxidant capacity and a decrease in plasma LDH and CPK activities. Our data demonstrate that SF acts as an indirect antioxidant in skeletal muscle and could play a critical role in the modulation of the muscle redox environment, leading to the prevention of exhaustive exercise-induced muscle damage.

Intracoronary intermedin 1-47 augments cardiac perfusion and function in anesthetized pigs: role of calcitonin receptors and {beta}-adrenoreceptor-mediated nitric oxide release

Thu, 15 Oct 2009 07:50:20 PDT

Systemic intermedin (IMD)1–47 administration has been reported to result in vasodilation and marked hypotension through calcitonin-related receptor complexes. However, its effects on the coronary circulation and the heart have not been examined in vivo. The present study was therefore planned to determine the primary in vivo effect of IMD1–47 on coronary blood flow and cardiac function and the involvement of the autonomic nervous system and nitric oxide (NO). In 35 anesthetized pigs, IMD1–47, infused into the left anterior descending coronary artery at doses of 87.2 pmol/min, at constant heart rate and arterial blood pressure, augmented coronary blood flow and cardiac function. These responses were graded in a further five pigs by increasing the infused dose of IMD1–47 between 0.81 and 204.1 pmol/min. In the 35 pigs, the blockade of cholinergic receptors (intravenous atropine, 5 pigs), -adrenoceptors (intravenous phentolamine, 5 pigs), and β₁-adrenoceptors (intravenous atenolol, 5 pigs) did not abolish the cardiac response to IMD1–47, the effects of which were prevented by blockade of β₂-adrenoceptors (intravenous butoxamine, 5 pigs), NO synthase (intracoronary N-nitro-l-arginine methyl ester, 5 pigs), and calcitonin-related receptors (intracoronary CGRP8–37/AM22–52, 10 pigs). In porcine coronary endothelial cells, IMD1–47 induced the phosphorylation of endothelial NO synthase and NO production through cAMP signaling leading to ERK, Akt, and p38 activation, which was prevented by the inhibition of β₂-adrenoceptors, calcitonin-related receptor complexes, and K⁺ channels. In conclusion, IMD1–47 primarily augmented coronary blood flow and cardiac function through the involvement of calcitonin-related receptor complexes and β₂-adrenoreceptor-mediated NO release. The intracellular signaling involved cAMP-dependent activation of kinases and the opening of K⁺ channels.

Short-term pressure induced suppression of the short-latency response: a new methodology for investigating stretch reflexes

Thu, 15 Oct 2009 07:50:20 PDT

During experiments involving ischemic nerve block, we noticed that the short-latency response (SLR) of evoked stretches in m. soleus decreased immediately following inflation of a pneumatic cuff surrounding the lower leg. The present study aimed to investigate this short-term effect of pressure application in more detail. Fifty-eight healthy subjects were divided into seven protocols. Unilateral stretches were applied to the calf muscles to elicit a SLR, and bilateral stretches to evoke a subsequent medium-latency response (MLR). Furthermore, H-reflexes and sensory nerve action potentials (SNAPs) were recorded. Additionally, stretches were applied with different velocities and amplitudes. Finally, the SLR was investigated during hopping and in two protocols that modified the ability of the muscle-tendon complex distal to the cuff to stretch. All measurements were performed with deflated and inflated cuff. Results of the protocols were as follows: 1) inflation of the cuff reduced the SLR but not the MLR; 2) the H-reflex, the M-wave, and, 3) SNAPs of n. tibialis remained unchanged with deflated and inflated cuff; 4) the SLR was dependent on the stretch velocity with deflated and also inflated cuff; 5 and 6) the reduction of the SLR by the cuff was dependent on the elastic properties of the muscle-tendon complex distal to the cuff; and 7) the cuff reduced the SLR during hopping. The present results suggest that the cuff did not affect the reflex arc per se. It is proposed that inflation restricted stretch of the muscles underlying the cuff so that most of the length change occurred in the muscle-tendon complex distal to the cuff. As a consequence, the muscle spindles lying within the muscle may be less excited, resulting in a reduced SLR. Due to its applicability in functional tasks, the introduced method can be a useful tool to study afferent feedback in motor control.

Cyclooxygenase and thromboxane/prostaglandin receptor contribute to aortic endothelium-dependent dysfunction in aging female spontaneously hypertensive rats

Graham, D. A., Rush, J. W. E. — Thu, 15 Oct 2009 07:50:21 PDT

Cyclooxygenase (COX)-derived vasoconstrictory prostanoids contribute to impaired endothelium-dependent vasorelaxation in aging male (m) spontaneously hypertensive rats (SHR); however, vasomotor responses in aging female (f) SHR and sex differences in aging SHR are unknown. Examining mechanisms governing dysfunction in aging fSHR will contribute to understanding sex-dependent vascular complications in advanced hypertension. Aortic endothelium-dependent relaxation dose responses (ACh) of 16- and 30-wk-old mSHR and fSHR and normotensive Wistar-Kyoto rats were examined in the absence (no drug control) and presence of COX inhibition [indomethacin (Indo)] and thromboxane/prostaglandin receptor inhibition (SQ-29548). No drug control-treated 16-wk mSHR exhibited considerable blunting of the peak relaxation response to ACh (e.g., 77 ± 4% relaxation to 10^–5 mol/l) vs. Wistar-Kyoto controls (89 ± 6%), and greater dysfunction occurred in 30-wk mSHR (63 ± 2%). Interestingly, ACh relaxations of fSHR were unimpaired at 16 wk (101 ± 2% to 10^–5 mol/l), but blunted in 30 wk (76 ± 4%). Indo and SQ-29548 restored robust ACh vasorelaxation in all groups (e.g., 113 ± 3 and 112 ± 3%, respectively, in Indo- and SQ-29548-treated 30-wk fSHR). Aortic COX-1 protein expression was elevated by 75% in 30-wk vs. 16-wk fSHR, whereas group-averaged ACh-stimulated aortic PGI₂ release (assessed as 6- keto-PGF₁) was 30% greater in 30-wk vs. 16-wk fSHR (9,926 ± 890 vs. 7,621 ± 690 pg·ml^–1·mg dry wt^–1), although this did not reach significance (P = 0.0758). Dramatic deterioration of endothelium-dependent vasomotor function in fSHR across this age range involves COX and thromboxane/prostaglandin receptor, supporting a mechanism of impairment similar to that which occurs in aging mSHR.

A simple method for assessing the energy cost of running during incremental tests

di Prampero, P. E., Salvadego, D., Fusi, S., Grassi, B. — Thu, 15 Oct 2009 07:50:21 PDT

The energy cost of running (Cr) is classically determined from steady-state oxygen consumption (Vo₂) at constant speed, divided by running speed. In the present study, Cr was determined during incremental treadmill tests in the course of the assessment of Vo_2max and related parameters as follows. Assume that the running speed is increased by a constant amount (v) at regular short intervals (T) and that, during each intensity transient below the gas exchange threshold, Vo₂ increases exponentially, without time delay, toward the steady state. If Vo₂ is averaged over homologous times within each speed step, neglecting the initial 10 s, the Vo₂ difference between corresponding time values becomes constant and equal to the difference between the appropriate steady states. Thus Cr was obtained from the ratio of the difference between the Vo₂ averages for any two homologous times, within subsequent periods, to the corresponding speed difference. Since in aerobic conditions, Cr on the treadmill is independent of the speed, and since v and T were constant, the relationship between Vo₂ and speed is described by straight lines, where the slope yields Cr above resting. This was indeed experimentally observed, the slopes of the linear regressions (R² range: 0.78 to 0.97 n = 9 to 16) within the three time windows being essentially equal. In six subjects, the grand-average of Cr amounted to 0.177 ± 0.011 ml O₂/(kg·m) [3.70 ± 0.23 J/(kg·m)]. This value is essentially equal to that obtained for the same subjects by applying the "classical" procedure [0.177 ± 0.015 ml O₂/(kg·m); 3.70 ± 0.31 J/(kg·m)], so confirming the validity of the incremental approach for assessing the energy cost of treadmill running.

Aging affects the cardiovascular responses to cold stress in humans

Hess, K. L., Wilson, T. E., Sauder, C. L., Gao, Z., Ray, C. A., Monahan, K. D. — Thu, 15 Oct 2009 07:50:21 PDT

Cardiovascular-related mortality peaks during cold winter months, particularly in older adults. Acute physiological responses, such as increases in blood pressure, in response to cold exposure may contribute to these associations. To determine whether the blood pressure-raising effect (pressor response) of non-internal body temperature-reducing cold stress is greater with age, we measured physiological responses to 20 min of superficial skin cooling, via water-perfused suit, in 12 younger [25 ± 1 (SE) yr old] and 12 older (65 ± 2 yr old) adults. We found that superficial skin cooling elicited an increase in blood pressure from resting levels (pressor response; P < 0.05) in younger and older adults. However, the magnitude of this pressor response (systolic and mean blood pressure) was more than twofold higher in older adults (P < 0.05 vs. younger adults). The magnitude of the pressor response was similar at peripheral (brachial) and central (estimated in the aorta) measurement sites. Regression analysis revealed that aortic pulse wave velocity, a measure of central arterial stiffness obtained before cooling, was the best predictor of the increased pressor response to superficial skin cooling in older adults, explaining ~63% of its variability. These results indicate that there is a greater pressor response to non-internal body temperature-reducing cold stress with age in humans that may be mediated by increased levels of central arterial stiffness.

Lung function in developing lambs: is it affected by preterm birth?

De Matteo, R., Snibson, K., Thompson, B., Koumoundouros, E., Harding, R. — Thu, 15 Oct 2009 07:50:21 PDT

Children born before term often have reduced lung function, but the effects of preterm birth alone are difficult to determine owing to iatrogenic factors such as mechanical ventilation. Our objective was to determine the effects of preterm birth alone on airway resistance, airway reactivity, and ventilatory heterogeneity as an index of intrapulmonary gas mixing. Preterm birth was induced in sheep 12 days before term; controls were born at term (~147 days). Lung function was assessed at 8 wk postterm. To assess medium-large airway function we measured airway resistance and reactivity to carbachol. Multiple breath N₂ washout (MBW) was used to assess ventilatory heterogeneity in conducting (S_cond) and acinar (S_acin) airways. Baseline airway resistance and responsiveness to carbachol were similar in preterm and term lambs. Airway responsiveness to carbachol was greater in females than males (P < 0.05), and baseline airway resistance tended to be higher in females than males (P = 0.06). There were no significant differences in ventilatory heterogeneity between preterm and term lambs; for all animals combined, mean S_acin was 0.29 ± 0.05 liter^–1 and S_cond was 0.26 ± 0.03 liter^–1. Males had significantly higher S_cond than females, indicating poorer gas mixing in small conducting airways; there was no sex difference in S_acin. We conclude that preterm birth per se in lambs does not affect baseline airway resistance, airway responsiveness, or ventilatory heterogeneity as measured by MBW. The observed sex-related differences in airway responsiveness and ventilatory heterogeneity in the conducting airways could help explain sex differences in lung function observed in humans.

Galvanic vestibular stimulation counteracts hypergravity-induced plastic alteration of vestibulo-cardiovascular reflex in rats

Abe, C., Tanaka, K., Awazu, C., Morita, H. — Thu, 15 Oct 2009 07:50:21 PDT

Recent data from our laboratory demonstrated that, when rats are raised in a hypergravity environment, the sensitivity of the vestibulo-cardiovascular reflex decreases. In a hypergravity environment, static input to the vestibular system is increased; however, because of decreased daily activity, phasic input to the vestibular system may decrease. This decrease may induce use-dependent plasticity of the vestibulo-cardiovascular reflex. Accordingly, we hypothesized that galvanic vestibular stimulation (GVS) may compensate the decrease in phasic input to the vestibular system, thereby preserving the vestibulo-cardiovascular reflex. To examine this hypothesis, we measured horizontal and vertical movements of rats under 1-G or 3-G environments as an index of the phasic input to the vestibular system. We then raised rats in a 3-G environment with or without GVS for 6 days and measured the pressor response to linear acceleration to examine the sensitivity of the vestibulo-cardiovascular reflex. The horizontal and vertical movement of 3-G rats was significantly less than that of 1-G rats. The pressor response to forward acceleration was also significantly lower in 3-G rats (23 ± 1 mmHg in 1-G rats vs. 12 ± 1 mmHg in 3-G rats). The pressor response was preserved in 3-G rats with GVS (20 ± 1 mmHg). GVS stimulated Fos expression in the medial vestibular nucleus. These results suggest that GVS stimulated vestibular primary neurons and prevent hypergravity-induced decrease in sensitivity of the vestibulo-cardiovascular reflex.

Dietary quercetin supplementation is not ergogenic in untrained men

Thu, 15 Oct 2009 07:50:21 PDT

Quercetin supplementation increases muscle oxidative capacity and endurance in mice, but its ergogenic effect in humans has not been established. Our study investigates the effects of short-duration chronic quercetin supplementation on muscle oxidative capacity; metabolic, perceptual, and neuromuscular determinants of performance in prolonged exercise; and cycling performance in untrained men. Using a double-blind, pretest-posttest control group design, 30 recreationally active, but not endurance-trained, young men were randomly assigned to quercetin and placebo groups. A noninvasive measure of muscle oxidative capacity (phosphocreatine recovery rate using magnetic resonance spectroscopy), peak oxygen uptake (Vo_2peak), metabolic and perceptual responses to submaximal exercise, work performed on a 10-min maximal-effort cycling test following the submaximal cycling, and voluntary and electrically evoked strength loss following cycling were measured before and after 7–16 days of supplementation with 1 g/day of quercetin in a sports hydration beverage or a placebo beverage. Pretreatment-to-posttreatment changes in phosphocreatine recovery time constant, Vo_2peak, substrate utilization, and perception of effort during submaximal exercise, total work done during the 10-min maximal effort cycling trial, and voluntary and electrically evoked strength loss were not significantly different (P > 0.05) in the quercetin and placebo groups. Short duration, chronic dietary quercetin supplementation in untrained men does not improve muscle oxidative capacity; metabolic, neuromuscular and perceptual determinants of performance in prolonged exercise; or cycling performance. The null findings indicate that metabolic and physical performance consequences of quercetin supplementation observed in mice should not be generalized to humans.

Moderate intensity of regular exercise improves cardiac SR Ca2+ uptake activity in ovariectomized rats

Bupha-Intr, T., Laosiripisan, J., Wattanapermpool, J. — Thu, 15 Oct 2009 07:50:21 PDT

The impact of regular exercise in protecting cardiac deteriorating results of female sex hormone deprivation was evaluated by measuring changes in intracellular Ca²⁺ removal activity of sarcoplasmic reticulum (SR) in ovariectomized rats following 9-wk treadmill running exercise at moderate intensity. Despite induction of cardiac hypertrophy in exercised groups of both sham-operated and ovariectomized rats, exercise training had no effect on SR Ca²⁺ uptake and SR Ca²⁺-ATPase (SERCA) in hormone intact rat heart. However, exercise training normalized the suppressed maximum SR Ca²⁺ uptake and SERCA activity in ovariectomized rat heart. While exercise training normalized the leftward shift in pCa (–log[Ca²⁺])-SR Ca²⁺ uptake relation in ovariectomized rats, no effect was detected in exercised sham-operated rats. Similar phenomena were also observed on SERCA and on phospholamban (PLB) phosphorylation levels; exercise training in ovariectomized rats enhanced SERCA expression to reach the level as that in sham-operated rats, in which there were no differences in SERCA and phospho-PLB levels between sedentary and exercised groups. In addition, the reduction in phospho-Thr¹⁷ PLB in myocardium of ovariectomized rats was abolished by exercise training. These results showed that regular exercise maintains the molecular activation of cardiac SR Ca²⁺ uptake under normal physiological conditions and is able to induce a protective impact on cardiac SR Ca²⁺ uptake in ovarian sex hormone-deprived status.

Influence of central command and muscle afferent activation on anterior cerebral artery blood velocity responses to calf exercise in humans

Vianna, L. C., Araujo, C. G. S., Fisher, J. P. — Thu, 15 Oct 2009 07:50:21 PDT

The purpose of the present study was to determine the relative importance of peripheral feedback from mechanically (mechanoreflex) and metabolically (metaboreflex) sensitive muscle afferents and central signals arising from higher centers (central command) to the exercise-induced increases in regional cerebral perfusion. To accomplish this, anterior cerebral artery (ACA) mean blood velocity (V_mean) responses were assessed during sustained and rhythmic passive calf muscle stretch (mechanoreflex), volitional calf exercise (mechanoreflex, metaboreflex, and central command), and electrically stimulated calf exercise (mechanoreflex and metaboreflex but no central command) at 35% of maximum voluntary contraction (n = 16). In addition, a period of postexercise muscle ischemia (PEMI) was used to isolate the metaboreflex. Blood pressure, cardiac output, and the end-tidal partial pressure of carbon dioxide (Pet_CO₂) were also measured. ACA V_mean was unchanged from rest during either sustained or rhythmic calf muscle stretch (P > 0.05). However, ACA V_mean was increased from rest during both isometric (+15 ± 1%) and rhythmic (+15 ± 2%, voluntary exercise P < 0.05) but remained unchanged during stimulated exercise (P > 0.05). Isometric and rhythmic exercise-induced increases in blood pressure and cardiac output were similar during voluntary and stimulated exercise (P > 0.05 between conditions). Blood pressure remained elevated during PEMI after all exercise conditions (P < 0.05 vs. rest), whereas cardiac output and ACA V_mean were not different from rest (P > 0.05). Pet_CO₂ was unchanged from rest throughout. These data suggest that selective activation of skeletal muscle afferents (i.e., stretch, PEMI, or stimulated exercise) does not increase ACA V_mean and that increases in ACA V_mean during volitional contractions of an exercising calf muscle are dependent on the presence of central command.

Ketorolac alters blood flow during normothermia but not during hyperthermia in middle-aged human skin

Holowatz, L. A., Jennings, J. D., Lang, J. A., Kenney, W. L. — Thu, 15 Oct 2009 07:50:21 PDT

In young healthy humans full expression of reflex cutaneous vasodilation is dependent on cyclooxygenase (COX)- and nitric oxide synthase (NOS)-dependent mechanisms. Chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation potentially through both platelet and vascular COX-dependent mechanisms. We hypothesized the contribution of COX-dependent vasodilators to reflex cutaneous vasodilation during localized acute COX inhibition would be attenuated in healthy middle-aged humans due to a shift toward COX-dependent vasoconstrictors. Four microdialysis fibers were placed in forearm skin of 13 middle-aged (53 ± 2 yr) normotensive healthy humans, serving as control (Ringer), COX-inhibited (10 mM ketorolac), NOS-inhibited (10 mM N^G-nitro-l-arginine methyl ester), and combined NOS- and COX-inhibited sites. Red blood cell flux was measured over each site by laser-Doppler flowmetry as reflex vasodilation was induced by increasing oral temperature (T_or) 1.0°C using a water-perfused suit. Cutaneous vascular conductance was calculated (CVC = flux/mean arterial pressure) and normalized to maximal CVC (CVC_max; 28 mM sodium nitroprusside). CVC_max was not affected by localized microdialysis drug treatment (P > 0.05). Localized COX inhibition increased baseline (18 ± 3%CVC_max; P < 0.001) compared with control (9 ± 1%CVC_max), NOS-inhibited (7 ± 1%CVC_max), and combined sites (10 ± 1%CVC_max). %CVC_max in the COX-inhibited site remained greater than the control site with T_or ≤ 0.3°C; however, there was no difference between these sites with T_or ≥ 0.4°C. NOS inhibition and combined COX and NOS inhibition attenuated reflex vasodilation compared with control (P < 0.001), but there was no difference between these sites. Localized COX inhibition with ketorolac significantly augments baseline CVC but does not alter the subsequent skin blood flow response to hyperthermia, suggesting a limited role for COX-derived vasodilator prostanoids in reflex cutaneous vasodilation and a shift toward COX-derived vasoconstrictors in middle-aged human skin.

Adenosine receptor antagonist and augmented vasodilation during hypoxic exercise

Thu, 15 Oct 2009 07:50:22 PDT

We tested the hypothesis that adenosine contributes to augmented skeletal muscle vasodilation during hypoxic exercise. In separate protocols, subjects performed incremental rhythmic forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O₂ saturation). In protocol 1 (n = 8), subjects received an intra-arterial administration of saline (control) and aminophylline (adenosine receptor antagonist). In protocol 2 (n = 10), subjects received intra-arterial phentolamine (-adrenoceptor antagonist) and combined phentolamine and aminophylline administration. Forearm vascular conductance (FVC; in ml·min^–1·100 mmHg^–1) was calculated from forearm blood flow (in ml/min) and blood pressure (in mmHg). In protocol 1, the change in FVC (FVC; change from normoxic baseline) during hypoxic exercise with saline was 172 ± 29 and 314 ± 34 ml·min^–1·100 mmHg^–1 (10% and 20%, respectively). Aminophylline administration did not affect FVC during hypoxic exercise at 10% (190 ± 29 ml·min^–1·100 mmHg^–1, P = 0.4) or 20% (287 ± 48 ml·min^–1·100 mmHg^–1, P = 0.3). In protocol 2, FVC due to hypoxic exercise with phentolamine infusion was 313 ± 30 and 453 ± 41 ml·min^–1·100 mmHg^–1 (10% and 20% respectively). FVC was similar at 10% (352 ± 39 ml·min^–1·100 mmHg^–1, P = 0.8) and 20% (528 ± 45 ml·min^–1·100 mmHg^–1, P = 0.2) hypoxic exercise with combined phentolamine and aminophylline. In contrast, FVC to exogenous adenosine was reduced by aminophylline administration in both protocols (P < 0.05 for both). These observations suggest that adenosine receptor activation is not obligatory for the augmented hyperemia during hypoxic exercise in humans.

Myoglobin concentration in skeletal muscle fibers of chronic heart failure patients

Thu, 15 Oct 2009 07:50:22 PDT

The purpose of this study was to determine the myoglobin concentration in skeletal muscle fibers of chronic heart failure (CHF) patients and to calculate the effect of myoglobin on oxygen buffering and facilitated diffusion. Myoglobin concentration, succinate dehydrogenase (SDH) activity, and cross-sectional area of individual muscle fibers from the vastus lateralis of five control and nine CHF patients were determined using calibrated histochemistry. CHF patients compared with control subjects were similar with respect to myoglobin concentration: type I fibers 0.69 ± 0.11 mM (mean ± SD), type II fibers 0.52 ± 0.07 mM in CHF vs. type I fibers 0.70 ± 0.09 mM, type II fibers 0.49 ± 0.07 mM in control, whereas SDH activity was significantly lower in CHF in both fiber types (P < 0.01). The myoglobin concentration in type I fibers was higher than in type II fibers (P < 0.01). Consequently, the oxygen buffering capacity, calculated from myoglobin concentration/SDH activity was increased in CHF: type I fibers 11.4 ± 2.1 s, type II fibers 13.6 ± 3.9 s in CHF vs. type I fibers 7.8 ± 0.9 s, type II fibers 7.5 ± 1.0 s in control, all P < 0.01). The calculated extracellular oxygen tension required to prevent core anoxia (Po₂_crit) in muscle fibers was similar when controls were compared with patients in type I fibers 10.3 ± 0.9 Torr in CHF and 11.5 ± 3.3 Torr in control, but was lower in type II fibers of patients 6.1 ± 2.8 Torr in CHF and 14.7 ± 6.2 Torr in control, P < 0.01. The lower Po₂_crit of type II fibers may facilitate oxygen extraction from capillaries. Reduced exercise tolerance in CHF is not due to myoglobin deficiency.

Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans

Thu, 15 Oct 2009 07:50:22 PDT

Pharmacological sodium nitrate supplementation has been reported to reduce the O₂ cost of submaximal exercise in humans. In this study, we hypothesized that dietary supplementation with inorganic nitrate in the form of beetroot juice (BR) would reduce the O₂ cost of submaximal exercise and enhance the tolerance to high-intensity exercise. In a double-blind, placebo (PL)-controlled, crossover study, eight men (aged 19–38 yr) consumed 500 ml/day of either BR (containing 11.2 ± 0.6 mM of nitrate) or blackcurrant cordial (as a PL, with negligible nitrate content) for 6 consecutive days and completed a series of "step" moderate-intensity and severe-intensity exercise tests on the last 3 days. On days 4–6, plasma nitrite concentration was significantly greater following dietary nitrate supplementation compared with PL (BR: 273 ± 44 vs. PL: 140 ± 50 nM; P < 0.05), and systolic blood pressure was significantly reduced (BR: 124 ± 2 vs. PL: 132 ± 5 mmHg; P < 0.01). During moderate exercise, nitrate supplementation reduced muscle fractional O₂ extraction (as estimated using near-infrared spectroscopy). The gain of the increase in pulmonary O₂ uptake following the onset of moderate exercise was reduced by 19% in the BR condition (BR: 8.6 ± 0.7 vs. PL: 10.8 ± 1.6 ml·min^–1·W^–1; P < 0.05). During severe exercise, the O₂ uptake slow component was reduced (BR: 0.57 ± 0.20 vs. PL: 0.74 ± 0.24 l/min; P < 0.05), and the time-to-exhaustion was extended (BR: 675 ± 203 vs. PL: 583 ± 145 s; P < 0.05). The reduced O₂ cost of exercise following increased dietary nitrate intake has important implications for our understanding of the factors that regulate mitochondrial respiration and muscle contractile energetics in humans.

Combined effects of fatigue and eccentric damage on muscle power

Choi, S. J., Widrick, J. J. — Thu, 15 Oct 2009 07:50:22 PDT

Many physical activities can induce both transient and long-lasting muscle dysfunction. The separate and interactive effects of short-term fatigue and long-lasting contraction-induced damage were evaluated in an in vitro mouse soleus preparation (35°C) using the work loop technique. Repetitive fatiguing work loops reduced positive work (work produced by the muscle), increased negative work (work required to reextend the muscle), and reduced cyclical power (net work/time) immediately after treatment. These changes were readily reversible. The fatigue treatment had no long-term effects on optimal muscle length (L_o) and isometric force (P_o). High strain lengthening work loops, where the muscle contracted eccentrically, resulted in both immediate and long-lasting positive work, power, and P_o deficits as well as a shift in L_o to longer lengths. When the treatments were combined, i.e., fatigued muscles subjected to eccentric activity, the immediate power deficit exceeded the sum of the power deficits noted for the other two treatments. Much of this effect was due to an exaggerated rise in negative work. However, in the long term, power and P_o deficits and the shift in L_o were reduced compared with the damage-only treatment. These results show that 1) the immediate effects of combined fatigue and damage on cyclical power are synergistic, in large part because of a reduced ability of the muscle to relax; and 2) fatigued muscles are less susceptible to long-term contraction-induced dysfunction. Fatigue may protect against long-term damage by reducing the probability that sarcomeres are lengthened beyond myofilament overlap.

Acute hypoxia impairs dynamic cerebral autoregulation: results from two independent techniques

Subudhi, A. W., Panerai, R. B., Roach, R. C. — Thu, 15 Oct 2009 07:50:22 PDT

We investigated the effect of acute hypoxia (AH) on dynamic cerebral autoregulation (CA) using two independent assessment techniques to clarify previous, conflicting reports. Twelve healthy volunteers (6 men, 6 women) performed six classic leg cuff tests, three breathing normoxic (Fi_O₂ = 0.21) and three breathing hypoxic (Fi_O₂ = 0.12) gas, using a single blinded, Latin squares design with 5-min washout between trials. Continuous measurements of middle cerebral artery blood flow velocity (CBFv; DWL MultiDop X2) and radial artery blood pressure (ABP; Colin 7000) were recorded in the supine position during a single experimental session. Autoregulation index (ARI) scores were calculated using the model of Tiecks et al. (Tiecks FP, Lam AM, Aaslid R, Newell DW. Stroke 26: 1014–1019, 1995) from ABP and CBFv changes following rapid cuff deflation (cuff ARI) and from ABP to CBFv transfer function, impulse, and step responses (TFA ARI) obtained during a 4-min period prior to cuff inflation. A new measure of %CBFv recovery 4 s after peak impulse was also derived from TFA. AH reduced cuff ARI (5.65 ± 0.70 to 5.01 ± 0.96, P = 0.04), TFA ARI (4.37 ± 0.76 to 3.73 ± 0.71, P = 0.04), and %Recovery (62.2 ± 10.9% to 50.8 ± 9.9%, P = 0.03). Slight differences between TFA and cuff ARI values may be attributed to heightened sympathetic activity during cuff tests as well as differential sensitivity to low- and high-frequency components of CA. Together, results provide consistent evidence that CA is impaired with AH. In addition, these findings demonstrate the potential utility of TFA ARI and %Recovery scores for future CA investigations.

Effects of aging on human skeletal muscle after immobilization and retraining

Thu, 15 Oct 2009 07:50:22 PDT

Inactivity is a recognized compounding factor in sarcopenia and muscle weakness in old age. However, while the negative effects of unloading on skeletal muscle in young individuals are well elucidated, only little is known about the consequence of immobilization and the regenerative capacity in elderly individuals. Thus the aim of this study was to examine the effect of aging on changes in muscle contractile properties, specific force, and muscle mass characteristics in 9 old (61–74 yr) and 11 young men (21–27 yr) after 2 wk of immobilization and 4 wk of retraining. Both young and old experienced decreases in maximal muscle strength, resting twitch peak torque and twitch rate of force development, quadriceps muscle volume, pennation angle, and specific force after 2 wk of immobilization (P < 0.05). The decline in quadriceps volume and pennation angle was smaller in old compared with young (P < 0.05). In contrast, only old men experienced a decrease in quadriceps activation. After retraining, both young and old regained their initial muscle strength, but old had smaller gains in quadriceps volume compared with young, and pennation angle increased in young only (P < 0.05). The present study is the first to demonstrate that aging alters the neuromuscular response to short-term disuse and recovery in humans. Notably, immobilization had a greater impact on neuronal motor function in old individuals, while young individuals were more affected at the muscle level. In addition, old individuals showed an attenuated response to retraining after immobilization compared with young individuals.

Isometric contractions reduce plantar flexor moment, Achilles tendon stiffness, and neuromuscular activity but remove the subsequent effects of stretch

Kay, A. D., Blazevich, A. J. — Thu, 15 Oct 2009 07:50:22 PDT

The effects of isometric contractions and passive stretching on muscle-tendon mechanics and muscle activity were studied in 16 healthy human volunteers. First, peak concentric and passive ankle joint moment data were recorded on an isokinetic dynamometer with electromyographic monitoring of the triceps surae; real-time motion analysis of the lower leg and ultrasound imaging of the Achilles-medial gastrocnemius muscle-tendon junction were simultaneously conducted. Second, the subjects performed six 8-s maximal voluntary isometric contractions (MVICs) before repeating the passive and active trials. Although there was no decrease in isometric joint moment after MVICs, peak concentric moment was significantly reduced (11.5%, P < 0.01). This was accompanied by, and correlated with (r = 0.90, P < 0.01), significant reductions in peak triceps surae electromyographic amplitude (21.0%, P < 0.01). Achilles tendon stiffness (10.9%, P < 0.01) and passive joint moment (4.9%, P < 0.01) were also significantly reduced. Third, the subjects performed three 60-s static plantar flexor stretches before being retested 2 and 30 min after stretch. The stretch protocol caused no significant change in any measure. At 30 min after stretching, significant recovery in concentric moment and muscle activity was detected at dorsiflexed joint angles, while Achilles tendon stiffness and passive joint moment remained significantly reduced. These data show that the performance of MVICs interrupts the normal stretch-induced losses in active and passive plantar flexor joint moment and neuromuscular activity, largely because concentric strength and tendon properties were already affected. Importantly, the decrease in Achilles tendon stiffness remained 30 min later, which may be an important etiological factor for muscle-tendon strain injury risk.

Neuromuscular transmission failure and muscle fatigue in ankle muscles of the adult rat after spinal cord injury

Ollivier-Lanvin, K., Lemay, M. A., Tessler, A., Burns, A. S. — Thu, 15 Oct 2009 07:50:22 PDT

Current evidence suggests that significant morphological changes occur in nerve-muscle connections caudal to spinal cord injury (SCI). To determine whether neuromuscular junction (NMJ) function is compromised after SCI, we investigated the contribution of NMJ failure to hindlimb muscle fatigue in control and spinalized adult rats. Repetitive supramaximal nerve stimulation was applied to two muscle-nerve preparations: medial gastrocnemius (MG)-tibial and tibialis anterior (TA)-peroneal. NMJ transmission failure was evident in control and SCI animals after repetitive stimulation. At 2 wk post-SCI, NMJ transmission failure was greater in SCI animals compared with controls, but the difference was not significant (P = 0.205 for the MG and P = 0.053 for the TA). At 6 wk post-SCI, there was a significant but small difference in NMJ transmission failure for the TA between control and spinal animals. These results demonstrate that, although there may be a mild decrement in NMJ function, NMJ transmission remains largely intact for supramaximal nerve stimulation.

Computational modeling of flow and gas exchange in models of the human maxillary sinus

Hood, C. M., Schroter, R. C., Doorly, D. J., Blenke, E. J. S. M., Tolley, N. S. — Thu, 15 Oct 2009 07:50:22 PDT

The present study uses numerical modeling to increase the understanding of sinus gas exchange, which is thought to be a factor in sinus disease. Order-of-magnitude estimates and computational fluid dynamics simulations were used to investigate convective and diffusive transport between the nose and the sinus in a range of simplified geometries. The interaction between mucociliary transport and gas exchange was modeled and found to be negligible. Diffusion was the dominant transport mechanism for small ostia and large concentration differences between the sinus and the nose, whereas convection was important for larger ostia or smaller concentration differences. The presence of one or more accessory ostia can increase the sinus ventilation rate by several orders of magnitude, because it allows a net flow through the sinus. Estimates of nitric oxide (NO) transport through the ostium based on measured sinus and nasal NO concentrations suggest that the sinuses cannot supply all the NO in nasally exhaled air.

Rapid muscle atrophy response to unloading: pretranslational processes involving MHC and actin

Giger, J. M., Bodell, P. W., Zeng, M., Baldwin, K. M., Haddad, F. — Thu, 15 Oct 2009 07:50:23 PDT

Skeletal muscles, especially weight-bearing muscles, are very sensitive to changes in loading state. The aim of this paper was to characterize the dynamic changes in the unloaded soleus muscle in vivo following a short bout of hindlimb suspension (HS), testing the hypothesis that transcriptional events respond early to the atrophic stimulus. In fact, we observed that after only 1 day of HS, primary transcript levels of skeletal -actin and type I myosin heavy chain (MHC) genes were significantly reduced by more than 50% compared with ground control levels. The degree of the decline for the mRNA expression of actin and type I MHC lagged behind that of the pre-mRNA levels after 1 day of HS, but by 2 and 7 days of HS, large decreases were observed. Although the faster MHC isoforms, IIx and IIb, began to be expressed in soleus after 1 day of HS, a relatively significant shift in mRNA expression from the slow MHC isoform type I toward these fast MHC isoforms did not emerge until 7 days of HS. One day of HS was sufficient to show significant decreases in mRNA levels of putative signaling factors serum response factor (SRF), suppressor of cytokine signaling-3 (SOCS3), and striated muscle activator of Rho signaling (STARS), although transcription factors yin-yang-1 (YY1) and transcriptional enhancing factor-1 (TEF-1) were not significantly affected by HS. The protein levels of actin and type I MHC were significantly decreased after 2 days of HS, and SRF protein was significantly decreased after 7 days HS. Our results show that after only 1 day of unloading, pre-mRNA and mRNA expression of muscle proteins and muscle-specific signaling factors are significantly reduced, suggesting that the downregulation of the synthesis side of the protein balance equation that occurs in atrophying muscle is initiated rapidly.

Systemic hypoxia enhances exercise-mediated bactericidal and subsequent apoptotic responses in human neutrophils

Wang, J.-S., Chiu, Y.-T. — Thu, 15 Oct 2009 07:50:23 PDT

Phagocytosis and oxidative burst are critical host defense mechanisms in which neutrophils clear invading pathogens. Clearing phagocytic neutrophils by triggering apoptosis is an essential process for controlling inflammation. This study elucidates how various exercise bouts with/without hypoxia affected neutrophil bactericidal activity and subsequent apoptosis in humans. Fifteen sedentary males performed six distinct experimental tests in an air-conditioned normobaric hypoxia chamber: two normoxic exercises [strenuous exercise (SE; up to maximal O₂ consumption) and moderate exercise (ME; 50% maximal O₂ consumption for 30 min) while exposed to 21% O₂], two hypoxic exercises (ME for 30 min while exposed to 12% and 15% O₂), and two hypoxic exposures (resting for 30 min while exposed to 12% and 15% O₂). The results showed that 1) plasma complement-C3a desArg/C4a desArg/C5a concentrations were increased, 2) expressions of L-selectin/lymphocyte functin-associated antigen-1/Mac-1/C5aR on neutrophils were enhanced, 3) phagocytosis of neutrophils to Esherichia coli and release of neutrophil oxidant products by E. coli were elevated, and 4) E. coli-induced phosphotidylserine exposure or caspase-3 activation of neutrophils were promoted immediately and 2 h after both 12% O₂ exposure at rest and with ME as well as normoxic SE. Although neither normoxic ME nor breathing 15% O₂ at rest influenced these complement- and neutrophil-related immune responses, ME at both 12% and 15% O₂ resulted in enhanced complement activation in the blood, expressions of opsonic/complement receptors on neutrophils, or the bactericidal activity and apoptosis of neutrophils. Moreover, the increased neutrophil oxidant production and apoptosis by normoxic SE and hypoxic ME were ameliorated by treating neutrophils with diphenylene iodonium (a NADPH oxidase inhibitor). Therefore, we conclude that ME at 12–15% O₂ enhances bactericidal capacity and facilitates the subsequent apoptosis of neutrophils.

Maturation and long-term hypoxia alters Ca2+-induced Ca2+ release in sheep cerebrovascular sympathetic neurons

Thu, 15 Oct 2009 07:50:23 PDT

The contribution of sympathetic nerves arising from the superior cervical ganglia (SCG) toward the growth and function of cerebral blood vessels is pertinent throughout maturation as well as in response to cardiovascular stress imposed by high-altitude long-term hypoxia (LTH). The function of SCG sympathetic neurons is dependent on intracellular Ca²⁺ concentration ([Ca²⁺]_i) signaling, which is strongly influenced by a process known as Ca²⁺-induced Ca²⁺ release (CICR) from the smooth endoplasmic reticulum (SER). In this study, we used the sheep SCG neuronal model to test the hypotheses that maturation decreases CICR and high-altitude LTH depresses CICR in fetal SCG neurons but not in those of the adult. We found that the contribution of CICR to electric field stimulation (EFS)-evoked [Ca²⁺]_i transients was greatest in SCG cells from normoxic fetuses and was abolished by LTH. The decline in CICR was associated with a reduction in sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) function in fetal SCG cells during LTH, reducing SER Ca²⁺ levels below the threshold needed for the coupling of Ca²⁺ influx and CICR. With respect to the maturation from the fetus to adult, the decrease in CICR may reflect both a reduction in the levels of ryanodine receptor isoforms 2 and 3 and SERCA function. In response to LTH and in contrast to the fetus, CICR function in adult SCG cells is maintained and may reflect alterations in other mechanisms that modulate the CICR process. As CICR is instrumental in the function of sympathetic neurons within the cerebrovasculature, the loss of this signaling mechanism in the fetus may have consequences for the adaptation to LTH in terms of fetal susceptibility to vascular insults.

CNTF 1357 G -> A polymorphism and the muscle strength response to resistance training

Thu, 15 Oct 2009 07:50:23 PDT

The present study examined associations between the ciliary neurotrophic factor (CNTF) 1357 G -> A polymorphism and the muscle strength response to a unilateral, upper arm resistance-training (RT) program among healthy, young adults. Subjects were 754 Caucasian men (40%) and women (60%) who were genotyped and performed a training program of the nondominant (trained) arm with the dominant (untrained) arm as a comparison. Peak elbow flexor strength was measured with one repetition maximum, isometric strength with maximum voluntary contraction, and bicep cross-sectional area with MRI in the trained and untrained arms before and after training. Women with the CNTF GG genotype gained more absolute isometric strength, as measured by MVC (6.5 ± 0.3 vs. 5.2 ± 0.5 kg), than carriers of the CNTF A1357 allele in the trained arm pre- to posttraining (P < 0.05). No significant associations were seen in men. Women with the CNTF GG genotype gained more absolute dynamic (1.0 ± 0.1 vs. 0.6 ± 0.1 kg) and allometric (0.022 ± 0.0 vs. 0.015 ± 0.0 kg/kg^–0.67) strength, as measured by 1 RM, than carriers of the CNTF A1357 allele in the untrained arm pre- to posttraining (P < 0.05). No significant associations were seen in men. No significant associations, as measured by cross-sectional area, were seen in men or women. The CNTF 1357 G -> A polymorphism explains only a small portion of the variability in the muscle strength response to training in women.

The phenotype and potential origin of nestin+ cardiac myocyte-like cells following infarction

Thu, 15 Oct 2009 07:50:23 PDT

Nestin⁺ cardiac myocyte-like cells were detected in the peri-infarct/infarct region of the ischemically damaged heart. The present study was undertaken to elucidate the phenotype and potential origin of nestin⁺ cardiac myocyte-like cells and identify stimuli implicated in their appearance. In the infarcted human and rat heart, nestin⁺ cardiac myocyte-like cells were morphologically and structurally immature, exhibited a desmin-immunoreactive striated phenotype, expressed the β₁-adrenergic receptor, and associated with an aberrant pattern of connexin-43 expression and/or organization. Nestin⁺ cardiac myocyte-like cells were detected 24 h postischemic injury and persisted in the infarcted rat heart for 9 mo. In the normal rat heart, cardiac progenitor transcriptional factors Nkx2.5/GATA4 were detected in a subpopulation of nestin⁺ neural stem cells. Following an ischemic insult, nestin⁺/Nkx2.5⁺ neural stem cells migrated to the peri-infarct/infarct region and appeared to be in a primordial state of differentiation to a nestin⁺ cardiac myocyte-like cell. The exposure of adult male rats to normobaric hypoxia (12% O₂) for 10 days failed to promote the appearance of nestin⁺ cardiac myocyte-like cells. Following osmotic pump delivery of isoproterenol to normal adult rats, nestin⁺ cardiac myocyte-like cells were detected, albeit the response was modest and secondary to tissue loss. Thus ischemia-induced appearance of nestin⁺ cardiac myocyte-like cells apparently represents an adaptive response to heal the infarcted heart. Nkx2.5/GATA4 expression in a subpopulation of resident neural stem cells provides the appropriate phenotype for their potential differentiation to a nestin⁺ cardiac myocyte-like cell.

Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats

Thu, 15 Oct 2009 07:50:23 PDT

There is increasing evidence that upregulation of arginase contributes to impaired endothelial function in aging. In this study, we demonstrate that arginase upregulation leads to endothelial nitric oxide synthase (eNOS) uncoupling and that in vivo chronic inhibition of arginase restores nitroso-redox balance, improves endothelial function, and increases vascular compliance in old rats. Arginase activity in old rats was significantly increased compared with that shown in young rats. Old rats had significantly lower nitric oxide (NO) and higher superoxide (O₂^–) production than young. Acute inhibition of both NOS, with N^G-nitro-l-arginine methyl ester, and arginase, with 2(S)-amino- 6-boronohexanoic acid (ABH), significantly reduced O₂^– production in old rats but not in young. In addition, the ratio of eNOS dimer to monomer in old rats was significantly decreased compared with that shown in young rats. These results suggest that eNOS was uncoupled in old rats. Although the expression of arginase 1 and eNOS was similar in young and old rats, inducible NOS (iNOS) was significantly upregulated. Furthermore, S-nitrosylation of arginase 1 was significantly elevated in old rats. These findings support our previously published finding that iNOS nitrosylates and activates arginase 1 (Santhanam et al., Circ Res 101: 692–702, 2007). Chronic arginase inhibition in old rats preserved eNOS dimer-to-monomer ratio and significantly reduced O₂^– production and enhanced endothelial-dependent vasorelaxation to ACh. In addition, ABH significantly reduced vascular stiffness in old rats. These data indicate that iNOS-dependent S-nitrosylation of arginase 1 and the increase in arginase activity lead to eNOS uncoupling, contributing to the nitroso-redox imbalance, endothelial dysfunction, and vascular stiffness observed in vascular aging. We suggest that arginase is a viable target for therapy in age-dependent vascular stiffness.

Quantification of lung microstructure with hyperpolarized 3He diffusion MRI

Thu, 15 Oct 2009 07:50:23 PDT

The structure and integrity of pulmonary acinar airways and their changes in different diseases are of great importance and interest to a broad range of physiologists and clinicians. The introduction of hyperpolarized gases has opened a door to in vivo studies of lungs with MRI. In this study we demonstrate that MRI-based measurements of hyperpolarized ³He diffusivity in human lungs yield quantitative information on the value and spatial distribution of lung parenchyma surface-to-volume ratio, number of alveoli per unit lung volume, mean linear intercept, and acinar airway radii—parameters that have been used by lung physiologists for decades and are accepted as gold standards for quantifying emphysema. We validated our MRI-based method in six human lung specimens with different levels of emphysema against direct unbiased stereological measurements. We demonstrate for the first time MRI images of these lung microgeometric parameters in healthy lungs and lungs with different levels of emphysema (mild, moderate, and severe). Our data suggest that decreases in lung surface area per volume at the initial stages of emphysema are due to dramatic decreases in the depth of the alveolar sleeves covering the alveolar ducts and sacs, implying dramatic decreases in the lung's gas exchange capacity. Our novel methods are sufficiently sensitive to allow early detection and diagnosis of emphysema, providing an opportunity to improve patient treatment outcomes, and have the potential to provide safe and noninvasive in vivo biomarkers for monitoring drug efficacy in clinical trials.

Muscle apoptosis is induced in pressure-induced deep tissue injury

Thu, 15 Oct 2009 07:50:23 PDT

Pressure ulcer is a complex and significant health problem. Although the factors including pressure, shear, and ischemia have been identified in the etiology of pressure ulcer, the cellular and molecular mechanisms that contribute to the development of pressure ulcer are unclear. This study tested the hypothesis that the early-onset molecular regulation of pressure ulcer involves apoptosis in muscle tissue. Adult Sprague-Dawley rats were subjected to an in vivo protocol to mimic pressure-induced deep tissue injury. Static pressure was applied to the tibialis region of the right limb of the rats for 6 h each day on two consecutive days. The compression force was continuously monitored by a three-axial force transducer equipped in the compression indentor. The contralateral uncompressed limb served as intra-animal control. Tissues underneath the compressed region were collected for histological analysis, terminal dUTP nick-end labeling (TUNEL), cell death ELISA, immunocytochemical staining, and real-time RT-PCR gene expression analysis. The compressed muscle tissue generally demonstrated degenerative characteristics. TUNEL/dystrophin labeling showed a significant increase in the apoptotic muscle-related nuclei, and cell death ELISA demonstrated a threefold elevation of apoptotic DNA fragmentation in the compressed muscle tissue relative to control. Positive immunoreactivities of cleaved caspase-3, Bax, and Bcl-2 were evident in compressed muscle. The mRNA contents of Bax, caspase-3, caspase-8, and caspase-9 were found to be higher in the compressed muscle tissue than control. These results demonstrated that apoptosis is activated in muscle tissue following prolonged moderate compression. The data are consistent with the hypothesis that muscle apoptosis is involved in the underlying mechanism of pressure-induced deep tissue injury.

In vivo intramuscular fascicle-aponeuroses dynamics of the human medial gastrocnemius during plantarflexion and dorsiflexion of the foot

Shin, D. D., Hodgson, J. A., Edgerton, V. R., Sinha, S. — Thu, 15 Oct 2009 07:50:24 PDT

Velocity-encoded phase-contrast magnetic resonance (MR) imaging techniques and a computer-controlled MR-compatible foot pedal device were used to investigate the medial gastrocnemius muscle and aponeurosis deformations during passive and active eccentric movements of the plantarflexors. Intrafascicular strain, measured as the ratio of strain in the fascicle segment at its insertion to strain at its origin, was nonuniform along the proximodistal axis of the muscle (P < 0.01), progressively increasing from the proximal to distal direction. The high intrafascicular strain regions appeared to correlate with the muscle regions that are likely to encounter high stress concentrations, i.e., the regions where the muscle physiological cross section decreases close to the tendons. The architectural gear ratio, i.e., the mechanical amplification ratio of fascicle length displacement to that of tendon/aponeuroses in a pennate muscle, also exhibited significant regional differences, with the highest ratios in the proximal region of the muscle accompanied by a higher initial pennation angle and a larger range of fascicular rotation about the origin. Values close to unity in the distal region of the muscle suggest that the aponeurosis separation may decrease in this region. Fascicle length and pennation angle changes were significantly influenced by force generation in the muscle, probably due to a shortening of the loaded muscle fibers relative to a passive condition. Overall, our data illustrate significant proximodistal intramuscular heterogeneity as supported by a regionally variable end-to-end strain ratio of fascicles and angle changes in the medial gastrocnemius muscle during passive and active ankle movements. These observations emphasize the need to reassess current conceptual models of muscle-tendon mechanics.

Effects of vitamin E on mitochondrial dysfunction and asthma features in an experimental allergic murine model

Thu, 15 Oct 2009 07:50:24 PDT

We showed recently that IL-4 causes mitochondrial dysfunction in allergic asthma. IL-4 is also known to induce 12/15-lipoxygenase (12/15-LOX), a potent candidate molecule in asthma. Because vitamin E (Vit-E) reduces IL-4 and inhibits 12/15-LOX in vitro, here we tested the hypothesis that Vit-E may be effective in restoring key mitochondrial dysfunctions, thus alleviating asthma features in an experimental allergic murine model. Ovalbumin (OVA)-sensitized and challenged male BALB/c mice showed the characteristic features of asthma such as airway hyperresponsiveness (AHR), airway inflammation, and airway remodeling. In addition, these mice showed increase in the expression and metabolites of 12/15-LOX, reduction in the activity and expression of the third subunit of mitochondrial cytochrome-c oxidase, and increased cytochrome c in lung cytosol, which indicate that OVA sensitization and challenge causes mitochondrial dysfunction. Vit-E was administered orally to these mice, and 12/15-LOX expression, key mitochondrial functions, ultrastructural changes of mitochondria in bronchial epithelia, and asthmatic parameters were determined. Vit-E treatment reduced AHR, Th2 response including IL-4, IL-5, IL-13, and OVA-specific IgE, eotaxin, transforming growth factor-β1, airway inflammation, expression and metabolites of 12/15-LOX in lung cytosol, lipid peroxidation, and nitric oxide metabolites in the lung, restored the activity and expression of the third subunit of cytochrome-c oxidase in lung mitochondria and bronchial epithelia, respectively, reduced the appearance of cytochrome c in lung cytosol, and also restored mitochondrial ultrastructural changes of bronchial epithelia. In summary, these findings show that Vit-E reduces key mitochondrial dysfunctions and alleviates asthmatic features.

Breath-by-breath measurement of particle deposition in the lung of spontaneously breathing rats

Karrasch, S., Eder, G., Bolle, I., Tsuda, A., Schulz, H. — Thu, 15 Oct 2009 07:50:24 PDT

A number of deposition models for humans, as well as experimental animals, have been described. However, no breath-by-breath deposition measurement in rats has been reported to date. The objective of this study is to determine lung deposition of micrometer-sized particles as a function of breathing parameters in the adult rat lung. A new aerosol photometry system was designed to measure deposition of nonhygroscopic, 2-µm sebacate particles in anesthetized, intubated, and spontaneously breathing 90-day-old Wistar-Kyoto rats placed in a size-adjusted body plethysmograph box. Instrumental dead space of the system was minimized down to 310 µl (i.e., ~20% of respiratory dead space). The system allows continuous monitoring of particle concentration in the respired volume. Breathing parameters, such as respiratory rate (f), tidal volume (Vt), as well as inspiration/expiration times, were also monitored at different levels of anesthesia. The results showed that Vt typically varied between 1.5 and 4.0 ml for regular breathing and between 4.0 and 10.0 ml for single-sigh breaths; f ranged from 40 to 200 breaths/min. Corresponding deposition values varied between 5 and 50%, depending on breath-by-breath breathing patterns. The best fit of deposition (D) was achieved by a bilinear function of Vt and f and found to be D = 11.0 – 0.09·f + 3.75·Vt. We conclude that our approach provides more realistic conditions for the measurement of deposition than conventional models using ventilated animals and allows us to analyze the correlation between breath-specific deposition and spontaneous breathing patterns.

An artificial neural network to estimate physical activity energy expenditure and identify physical activity type from an accelerometer

Staudenmayer, J., Pober, D., Crouter, S., Bassett, D., Freedson, P. — Thu, 15 Oct 2009 07:50:24 PDT

The aim of this investigation was to develop and test two artificial neural networks (ANN) to apply to physical activity data collected with a commonly used uniaxial accelerometer. The first ANN model estimated physical activity metabolic equivalents (METs), and the second ANN identified activity type. Subjects (n = 24 men and 24 women, mean age = 35 yr) completed a menu of activities that included sedentary, light, moderate, and vigorous intensities, and each activity was performed for 10 min. There were three different activity menus, and 20 participants completed each menu. Oxygen consumption (in ml·kg^–1·min^–1) was measured continuously, and the average of minutes 4–9 was used to represent the oxygen cost of each activity. To calculate METs, activity oxygen consumption was divided by 3.5 ml·kg^–1·min^–1 (1 MET). Accelerometer data were collected second by second using the Actigraph model 7164. For the analysis, we used the distribution of counts (10th, 25th, 50th, 75th, and 90th percentiles of a minute's second-by-second counts) and temporal dynamics of counts (lag, one autocorrelation) as the accelerometer feature inputs to the ANN. To examine model performance, we used the leave-one-out cross-validation technique. The ANN prediction of METs root-mean-squared error was 1.22 METs (confidence interval: 1.14–1.30). For the prediction of activity type, the ANN correctly classified activity type 88.8% of the time (confidence interval: 86.4–91.2%). Activity types were low-level activities, locomotion, vigorous sports, and household activities/other activities. This novel approach of applying ANNs for processing Actigraph accelerometer data is promising and shows that we can successfully estimate activity METs and identify activity type using ANN analytic procedures.

No major sex differences in muscle protein synthesis rates in the postabsorptive state and during hyperinsulinemia-hyperaminoacidemia in middle-aged adults

Thu, 15 Oct 2009 07:50:24 PDT

Men have more muscle than women, but most studies evaluating sex differences in muscle protein metabolism have been unable to discern sexual dimorphism in basal muscle protein turnover rates in young and middle-aged adults. We hypothesized that the anabolic response to nutritional stimuli (i.e., amino acids and insulin) would be greater in young/middle-aged men than women. We therefore measured the rates of muscle protein synthesis (MPS) in 16 healthy individuals [8 men and 8 women, matched for age (mean ± SE: 37.7 ± 1.5 yr) and body mass index (25.2 ± 0.7 kg/m²)] after an overnight fast (plasma insulin ~5 µU/ml and plasma phenylalanine ~60 µM) and during a hyperinsulinemic-hyperaminoacidemic-euglycemic clamp (plasma insulin ~28 µU/ml; plasma phenylalanine ~110 µM; plasma glucose ~5.4 mM). The rates of MPS were not different between men and women (ANOVA main effect for sex; P = 0.49). During the clamp, the rate of MPS increased by ~50% (P = 0.003) with no difference in the increases from basal values between men and women (+0.019 ± 0.004 vs. +0.018 ± 0.010%/h, respectively; P = 0.93). There were also no differences between men and women in the basal concentrations of muscle phosphorylated Akt^Ser473, Akt^Thr308, mTOR^Ser2448, and p70s6k^Thr389 or in the hyperinsulinemia-hyperaminoacidemia-induced increases in phosphorylation of those signaling elements (P ≥ 0.25). We conclude that there are no major differences in the rate of MPS and its intracellular control during basal conditions and during hyperinsulinemia-hyperaminoacidema between young and middle-aged adult men and women.

The role of clock genes in cardiometabolic disease

Esser, K. A., Young, M. E. — Thu, 15 Oct 2009 07:50:24 PDT

Diurnal physiology: core principles with application to the pathogenesis, diagnosis, prevention, and treatment of myocardial hypertrophy and failure

Sole, M. J., Martino, T. A. — Thu, 15 Oct 2009 07:50:24 PDT

The circadian system has been shown to be fundamentally important in human health and disease. Recently, there have been major advances in our understanding of daily rhythmicity, and its relevance to human physiology, and to the pathogenesis and treatment of cardiac hypertrophy and heart failure. Cardiovascular tissues, such as heart and blood vessels, show remarkable daily variation in gene expression, metabolism, growth, and remodeling. Moreover, synchrony of daily molecular and physiological rhythms is integral to healthy organ growth and renewal. Disruption of these rhythms adversely affects normal growth, also the remodeling mechanisms in disease, leading to gross abnormalities in heart and vessels. These observations provide new insights into the pathogenesis, diagnosis, treatment, and prevention of heart disease. In this review, we focus on the recent advances in circadian biology and cardiovascular function, with particular emphasis on how this applies to human myocardial hypertrophy and heart failure, and the implications and importance for translational medicine.

Pressed for time: the circadian clock and hypertension

Rudic, R. D., Fulton, D. J. — Thu, 15 Oct 2009 07:50:24 PDT

Hypertension is a major risk factor for cardiovascular disease and death. The "silent" rise of blood pressure that occurs over time is largely asymptomatic. However, its impact is deafening—causing and exacerbating cardiovascular disease, end-organ damage, and death. The present article addresses recent observations from human and animal studies that provide new insights into how the circadian clock regulates blood pressure, contributes to hypertension, and ultimately evolves vascular disease. Further, the molecular components of the circadian clock and their relationship with locomotor activity, metabolic control, fluid balance, and vascular resistance are discussed with an emphasis on how these novel, circadian clock-controlled mechanisms contribute to hypertension.

Anticipating anticipation: pursuing identification of cardiomyocyte circadian clock function

Young, M. E. — Thu, 15 Oct 2009 07:50:25 PDT

Diurnal rhythms in myocardial physiology (e.g., metabolism, contractile function) and pathophyiology (e.g., sudden cardiac death) are well establish and have classically been ascribed to time-of-day-dependent alterations in the neurohumoral milieu. Existence of an intramyocellular circadian clock has recently been exposed. Circadian clocks enable the cell to anticipate environmental stimuli, facilitating a timely and appropriate response. Generation of genetically modified mice with a targeted disruption of the cardiomyocyte circadian clock has provided an initial means for deciphering the functions of this transcriptionally based mechanism and allowed predictions regarding which environmental stimuli the heart anticipates (i.e., "anticipating anticipation"). Recent studies show that the cardiomyocyte circadian clock influences myocardial gene expression, β-adrenergic signaling, transcriptional responsiveness to fatty acids, triglyceride metabolism, heart rate, and cardiac output, as well as ischemia-reperfusion tolerance. In addition to reviewing current knowledge regarding the roles of the cardiomyocyte circadian clock, this article highlights putative frontiers in this field. The latter includes establishing molecular links between the cardiomyocyte circadian clock with identified functions, understanding the pathophysiological consequences of disruption of this mechanism, targeting resynchronization of the cardiomyocyte circadian clock for prevention/treatment of cardiovascular disease, linking the circadian clock with the cardiobeneficial effects of caloric restriction, and determining whether circadian clock genes are subject to epigenetic regulation. Information gained from studies investigating the cardiomyocyte circadian clock will likely translate to extracardiac tissues, such as skeletal muscle, liver, and adipose tissue.

Effects of acute hypoxia and hyperthermia on the permeability of the blood-brain barrier in adult rats

Natah, S. S., Srinivasan, S., Pittman, Q., Zhao, Z., Dunn, J. F. — Thu, 15 Oct 2009 07:50:25 PDT

Acute mountain sickness (AMS) develops within a few hours after arrival at high altitude and includes headache, anorexia, nausea, vomiting, and malaise. This afflicts 15–25% of the general tourist population at moderate altitudes. High-altitude cerebral edema (HACE) is considered to be the end stage of severe AMS and has been suggested to be a vasogenic edema, raising the possibility that acute hypoxia may increase blood-brain barrier (BBB) permeability. At present, there are no good small-animal models to study this syndrome. We hypothesize 1) that acute hypoxia can damage the BBB and 2) that rat can be used as a model to study hypoxia-induced changes in BBB permeability, especially if hypoxia-induced hypothermia could be minimized with high ambient temperature (HAT). Male Wistar rats were exposed to 1, 2, and 7 days of hypobaric hypoxia (equivalent to 0.5 atm), and changes in the temperature and BBB permeability were studied. The extravasation of endogenous immunoglobulin G, a large molecule, did not increase during room temperature hypoxia but did increase when hypoxia was combined with HAT. Hypoxia caused a significant increase in the leakage of sodium fluorescein (mol wt 376 Da). The expression of endothelial barrier antigen (EBA), a protein associated with the BBB, was reduced to 50% between 24 and 48 h after exposure to hypoxia, and the loss was exacerbated by HAT. The values almost returned to control levels by 7 days, showing adaptation to hypoxia. Hypoxic rats exhibited sodium fluorescein leakage mainly in focal areas in the brain parenchyma. In conclusion, it is possible to have transient BBB damage through exposure to acute hypoxia, and this damage is exacerbated by increasing body temperature to more of a normothermic value.

Pick your Poiseuille: normalizing the shear stimulus in studies of flow-mediated dilation

Parker, B. A., Trehearn, T. L., Meendering, J. R. — Thu, 15 Oct 2009 07:50:25 PDT

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Thu, 15 Oct 2009 07:50:25 PDT

Last Word on Viewpoint: Pick your Poiseuille: normalizing the shear stimulus in studies of flow-mediated dilation

Parker, B. A., Trehearn, T. L., Meendering, J. R. — Thu, 15 Oct 2009 07:50:25 PDT