Journal of Applied Physiology current issue

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