bluuebunny/crossref_metadata_2025 huggingface dataset:
Atrophy responses to muscle inactivity. I. Cellular markers of protein deficits
Authors: Haddad F. , Roy R. R. , Zhong H. , Edgerton V. R. , Baldwin K. M.
Published: March 2015

The goal of this study was to use the model of spinal cord isolation (SI), which blocks nearly all neuromuscular activity while leaving the motoneuron muscle-fiber connections intact, to characterize the cellular processes linked to marked muscle atrophy. Rats randomly assigned to normal control and SI groups were studied at 0, 2, 4, 8, and 15 days after SI surgery. The slow soleus muscle atrophied by ∼50%, with the greatest degree of loss occurring during the first 8 days. Throughout the SI duration, muscle protein concentration was maintained at the control level, whereas myofibrillar protein concentration steadily decreased between 4 and 15 days of SI, and this was associated with a 50% decrease in myosin heavy chain (MHC) normalized to total protein. Actin relative to the total protein was maintained at the control level. Marked reductions occurred in total RNA and DNA content and in total MHC and actin mRNA expressed relative to 18S ribosomal RNA. These findings suggest that two key factors contributing to the muscle atrophy in the SI model are 1) a reduction in ribosomal RNA that is consistent with a reduction in protein translational capacity, and 2) insufficient mRNA substrate for translating key sarcomeric proteins comprising the myofibril fraction, such as MHC and actin. In addition, the marked selective depletion of MHC protein in the muscles of SI rats suggests that this protein is more vulnerable to inactivity than actin protein. This selective MHC loss could be a major contributor for the previously reported loss in the functional integrity of SI muscles. Collectively, these data are consistent with the involvement of pretranslational and translational processes in muscle atrophy due to SI.
Angiopoietin-2 and rat brain capillary remodeling during adaptation and deadaptation to prolonged mild hypoxia
Authors: Pichiule Paola , LaManna Joseph C.
Published: March 2015

Angiogenesis is a crucial component of rat brain adaptation to prolonged hypoxia, but it is not known whether this structural change is permanent or reversed on return to normoxia. Also, the intrinsic mechanisms controlling brain microvascular plasticity in response to oxygen availability remains unclear. Our results indicate that capillary density in the rat cerebral cortex increased by 60% after 3 wk of hypoxia and that it progressively decreased to prehypoxic values after 3 wk of normoxic recovery (deadaptation). Angiopoietin-2 (Ang2) expression in the capillary endothelium was induced between 6 h and 14 days of hypoxia but fell to control levels at 21 days of hypoxia. During deadaptation, Ang2 levels were elevated at 1–14 days but decreased to baseline at 21 days. In contrast, the constitutive expression of Ang1 and Tie2 was not affected during hypoxia or deadaptation. TUNEL-positive endothelial cells and caspase-3 activation were observed at 7 and 14 days of deadaptation. These data suggest that Ang2 might modulate both angiogenesis and vascular regression in the rat brain and that capillary regression occurring during deadaptation involves activation of apoptosis.
CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults
Authors: Givens Raymond C. , Lin Yvonne S. , Dowling Amy L. S. , Thummel Kenneth E. , Lamba Jatinder K. , Schuetz Erin G. , Stewart Paul W. , Watkins Paul B.
Published: March 2015

A single-nucleotide polymorphism (A6986G) in the cytochrome P-450 3A5 ( CYP3A5) gene distinguishes an expressor ( *1) and a reduced-expressor ( *3) allele and largely predicts CYP3A5 content in liver and intestine. CYP3A5 is the prevailing CYP3A isoform in kidney. We report that, among renal microsomes from 21 organ donors, those from *1/ *3 individuals had at least eightfold higher mean kidney microsomal CYP3A5 content and 18-fold higher mean CYP3A catalytic activity than did those from *3/ *3 individuals ( P = 0.0001 and P = 0.0137, respectively). We also report significant associations between the A6986G polymorphism and systolic blood pressure ( P = 0.0007), mean arterial pressure ( P = 0.0075), and creatinine clearance ( P = 0.0035) among 25 healthy African-American adults. These associations remained significant when sex, age, and body mass index were taken into account. The mean systolic blood pressure of homozygous CYP3A5 expressors ( *1/ *1) exceeded that of homozygous nonexpressors ( *3/ *3) by 19.3 mmHg. We speculate whether a high CYP3A5 expressor allele frequency among African-Americans may contribute to a high prevalence of sodium-sensitive hypertension in this population.
Vestibulosympathetic reflex during mental stress
Authors: Carter Jason R. , Ray Chester A. , Cooke William H.
Published: March 2015

Increases in sympathetic neural activity occur independently with either vestibular or mental stimulation, but it is unknown whether sympathetic activation is additive or inhibitive when both stressors are combined. The purpose of the present study was to investigate the combined effects of vestibular and mental stimulation on sympathetic neural activation and arterial pressure in humans. Muscle sympathetic nerve activity (MSNA), arterial pressure, and heart rate were recorded in 10 healthy volunteers in the prone position during 1) head-down rotation (HDR), 2) mental stress (MS; using arithmetic), and 3) combined HDR and MS. HDR significantly ( P< 0.05) increased MSNA (9 ± 2 to 13 ± 2 bursts/min). MS significantly increased MSNA (8 ± 2 to 13 ± 2 bursts/min) and mean arterial pressure (87 ± 2 to 101 ± 2 mmHg). Combined HDR and MS significantly increased MSNA (9 ± 1 to 16 ± 2 bursts/min) and mean arterial pressure (89 ± 2 to 100 ± 3 mmHg). Increases in MSNA (7 ± 1 bursts/min) during the combination trial were not different from the algebraic sum of each trial performed alone (8 ± 2 bursts/min). We conclude that the interaction for MSNA and arterial pressure is additive during combined vestibular and mental stimulation. Therefore, vestibular- and stress-mediated increases of MSNA appear to occur independently in humans.
Influence of head position on thermal stress in newborns: simulation using a thermal mannequin
Authors: Elabbassi Elmountacer Billah , Chardon Karen , Telliez Frédéric , Bach Véronique , Libert Jean-Pierre
Published: March 2015

The influence of head position on thermal stress was assessed by using a heavily clothed thermal mannequin in three different body positions [supine, face straight up (FSU); supine, face to the side (FTS); prone, FTS] and with or without the head covered by a bonnet. The mannequin was exposed to air temperatures of 29, 32, 34, and 36°C. When the head is uncovered, body or head position has no impact on heat loss. When the head is covered, dry heat loss from the mannequin as a whole (and that from the head in particular) is lower (−0.35 to −0.40 W) in the FTS position than in the FSU position as a result of decreased heat loss from the surface area of the face in contact with the mattress. In the FTS position and with the head covered, there was no difference in heat loss between the prone and supine positions. The results suggest that in heavily clothed newborns whose head is covered by a bonnet, thermal stress depends on the head position.
Effect of rhythmic tetanic skeletal muscle contractions on peak muscle perfusion
Authors: Dobson John L. , Gladden L. Bruce
Published: March 2015

The purpose of this investigation was to examine the effect of rhythmic tetanic skeletal muscle contractions on peak muscle perfusion by using spontaneously perfused canine gastrocnemii in situ. Simultaneous pulsatile blood pressures were measured by means of transducers placed in the popliteal artery and vein, and pulsatile flow was measured with a flow-through-type transit-time ultrasound probe placed in the venous return line. Two series of experiments were performed. In series 1, maximal vasodilation of the muscles' vascular beds was elicited by infusing a normal saline solution containing adenosine (29.3 mg/min) and sodium nitroprusside (180 μg/min) for 15 s and then simultaneously occluding both the popliteal artery and vein for 5 min. The release of occlusion initiated a maximal hyperemic response, during which time four tetanic contractions were induced with supramaximal voltage (6–8 V, 0.2-ms stimuli for 200-ms duration at 50 Hz, 1/s). In series 2, the muscles were stimulated for 3 min before the muscle contractions were stopped for a period of 3 s; stimulation was then resumed. The results of series 1 indicate that, although contractions lowered venous pressure, muscle blood flow was significantly reduced from 2,056 ± 246 to 1,738 ± 225 ml · kg−1 · min−1when contractions were initiated and then increased significantly to 1,925 ± 225 ml · kg−1 · min−1during the first 5 s after contractions were stopped. In series 2, blood flow after 3 min of contractions averaged 1,454 ± 149 ml · kg−1 · min−1. Stopping the contractions for 3 s caused blood flow to increase significantly to 1,874 ± 172 ml · kg−1 · min−1; blood flow declined significantly to 1,458 ± 139 ml · kg−1 · min−1when contractions were resumed. We conclude that the mechanical action of rhythmic, synchronous, maximal isometric tetanic skeletal muscle contractions inhibits peak muscle perfusion during maximal and near-maximal vasodilation of the muscle's vascular bed. This argues against a primary role for the muscle pump in achieving peak skeletal muscle blood flow.
Hindlimb unloading alters ligament healing
Authors: Provenzano Paolo P. , Martinez Daniel A. , Grindeland Richard E. , Dwyer Kelley W. , Turner Joanne , Vailas Arthur C. , Vanderby Ray
Published: March 2015

We investigated the hypothesis that hindlimb unloading inhibits healing in fibrous connective tissue such as ligament. Male rats were assigned to 3- and 7-wk treatment groups with three subgroups each: sham control, ambulatory healing, and hindlimb-suspended healing. Ambulatory and suspended animals underwent surgical rupture of their medial collateral ligaments, whereas sham surgeries were performed on control animals. After 3 or 7 wk, mechanical and/or morphological properties were measured in ligament, muscle, and bone. During mechanical testing, most suspended ligaments failed in the scar region, indicating the greatest impairment was to ligament and not to bone-ligament insertion. Ligament testing revealed significant reductions in maximum force, ultimate stress, elastic modulus, and low-load properties in suspended animals. In addition, femoral mineral density, femoral strength, gastrocnemius mass, and tibialis anterior mass were significantly reduced. Microscopy revealed abnormal scar formation and cell distribution in suspended ligaments with extracellular matrix discontinuities and voids between misaligned, but well-formed, collagen fiber bundles. Hence, stress levels from ambulation appear unnecessary for formation of fiber bundles yet required for collagen to form structurally competent continuous fibers. Results support our hypothesis that hindlimb unloading impairs healing of fibrous connective tissue. In addition, this study provides compelling morphological evidence explaining the altered structure-function relationship in load-deprived healing connective tissue.
Paradoxical absence of M lines and downregulation of creatine kinase in mouse extraocular muscle
Authors: Andrade Francisco H. , Merriam Anita P. , Guo Wei , Cheng Georgiana , McMullen Colleen A. , Hayeß Katrin , van der Ven Peter F. M. , Porter John D.
Published: March 2015

The M lines are structural landmarks in striated muscles, necessary for sarcomeric stability and as anchoring sites for the M isoform of creatine kinase (CK-M). These structures, especially prominent in fast skeletal muscles, are missing in rodent extraocular muscle, a particularly fast and active muscle group. In this study, we tested the hypotheses that 1) myomesin and M protein (cytoskeletal components of the M lines) and CK-M are downregulated in mouse extraocular muscle compared with the leg muscles, gastrocnemius and soleus; and 2) the expression of other cytosolic and mitochondrial CK isoforms is correspondingly increased. As expected, mouse extraocular muscles expressed lower levels of myomesin, M protein, and CK-M mRNA than the leg muscles. Immunocytochemically, myomesin and M protein were not detected in the banding pattern typically seen in other skeletal muscles. Surprisingly, message abundance for the other known CK isoforms was also lower in the extraocular muscles. Moreover, total CK activity was significantly decreased compared with that in the leg muscles. Based on these data, we reject our second hypothesis and propose that other energy-buffering systems may be more important in the extraocular muscles. The downregulation of major structural and metabolic elements and relative overexpression of two adenylate kinase isoforms suggest that the extraocular muscle group copes with its functional requirements by using strategies not seen in typical skeletal muscles.
Psoas muscle attenuation measurement with computed tomography indicates intramuscular fat accumulation in patients with the HIV-lipodystrophy syndrome
Authors: Torriani Martin , Hadigan Colleen , Jensen Megan E. , Grinspoon Steven
Published: March 2015

The human immunodeficiency virus (HIV)-lipodystrophy syndrome is characterized by abnormalities of lipid metabolism, glucose homeostasis, and fat distribution. Overaccumulation of intramuscular lipid may contribute to insulin resistance in this population. We examined 63 men: HIV positive with lipodystrophy ( n = 22), HIV positive without lipodystrophy ( n = 20), and age- and body mass index-matched HIV-negative controls ( n = 21). Single-slice computed tomography was used to determine psoas muscle attenuation and visceral fat area. Plasma free fatty acids (FFA), lipid profile, and markers of glucose homeostasis were measured. Muscle attenuation was significantly decreased in subjects with lipodystrophy [median (interquartile range), 55.0 (51.0-58.3)] compared with subjects without lipodystrophy [57.0 (55.0-59.0); P = 0.05] and HIV-negative controls [59.5 (57.3-64.8); P < 0.01]. Among HIV-infected subjects, muscle attenuation correlated significantly with FFA ( r = -0.38; P = 0.02), visceral fat ( r = -0.49; P = 0.002), glucose ( r = -0.38; P = 0.02) and insulin ( r = -0.60; P = 0.0001) response to a 75-g oral glucose tolerance test. In forward stepwise regression analysis with psoas attenuation as the dependent variable, visceral fat ( P = 0.02) and FFA ( P < 0.05), but neither body mass index, subcutaneous fat, nor antiretroviral use, were strong independent predictors of muscle attenuation ( r2= 0.39 for model). Muscle attenuation ( P = 0.02) and visceral fat ( P = 0.02), but not BMI, subcutaneous fat, FFA, or antiretroviral use, were strong independent predictors of insulin response (area under the curve) to glucose challenge ( r2= 0.47 for model). These data demonstrate that decreased psoas muscle attenuation due to intramuscular fat accumulation may contribute significantly to hyperinsulinemia and insulin resistance in HIV-lipodystrophy patients. Further studies are needed to assess the mechanisms and consequences of intramuscular lipid accumulation in HIV-infected patients.
Estrogen attenuates the exercise pressor reflex in female cats
Authors: Schmitt Petra M. , Kaufman M. P.
Published: March 2015

In humans, the pressor and muscle sympathetic nerve responses to static exercise are less in women than in men. The difference has been attributed to the effect of estrogen on the exercise pressor reflex. Estrogen receptors are abundant in areas of the dorsal horn receiving input from group III and IV muscle afferents, which comprise the sensory limb of the exercise pressor reflex arc. These findings prompted us to investigate the effect of estrogen on the spinal pathway of the exercise pressor reflex arc. Previously, we found that the threshold concentration of 17β-estradiol needed to attenuate the exercise pressor reflex in male decerebrate cats was 10 μg/ml (Schmitt PM and Kaufman MP. J Appl Physiol 94: 1431-1436, 2003). The threshold concentration for female cats, however, is not known. Consequently, we applied 17β-estradiol to a well covering the L6-S1 spinal cord in decerebrate female cats. The exercise pressor reflex was evoked by electrical stimulation of the L7 or S1 ventral root, a maneuver that caused the hindlimb muscles to contract statically. We found that the pressor response to contraction averaged 38 ± 7 mmHg before the application of 17β-estradiol (0.01 μg/ml) to the spinal cord, whereas it averaged only 23 ± 4 mmHg 30 min after application ( P < 0.05). Recovery of the pressor response to contraction was not obtained for 2 h after application of 17β-estradiol. Application of 17β-estradiol in a dose of 0.001 μg/ml had no effect on the exercise pressor reflex ( n = 5). We conclude that the concentration of 17β-estradiol required to attenuate the exercise pressor reflex is 1,000 times more dilute in female cats than that needed to attenuate this reflex in male cats.
Time- and dose-dependent differential upregulation of three genes by 17β-estradiol in endothelial cells
Authors: Villablanca Amparo C. , Lewis Kristine A. , Rutledge John C.
Published: March 2015

The purpose of this study was to identify genetic targets in the vasculature for estrogen by profiling genes expressed in female human aortic endothelial cells exposed to various doses of 17β-estradiol at differing concentrations and for differing periods of time. Our approach employed a RT-PCR-based cloning strategy of DNA differential display analysis, with differential expression verified by semiquantitative PCR performed with gene-specific primers. A significant increase in mRNA expression in response to 17β-estradiol was observed for the following three genes: aldose reductase (3.4-fold), caspase homologue-α protein (4.2-fold), and plasminogen activator inhibitor-1 intron e (2.3-fold). For all three upregulated genes, estradiol-induced upregulation occurred with a similar time course and temporally clustered to the first 24 h after hormone treatment. In addition, the effect of estradiol dose on gene expression was consistent and occurred at physiological concentrations. Our results describe previously uncharacterized estradiol-sensitive time- and dose-dependent regulation of genes with potential importance to vascular function in human endothelial cells.
Selected Contribution: Intermittent hypoxia induces phrenic long-term facilitation in carotid-denervated rats
Authors: Bavis Ryan W. , Mitchell Gordon S.
Published: March 2015

Episodic hypoxia elicits a long-lasting augmentation of phrenic inspiratory activity known as long-term facilitation (LTF). We investigated the respective contributions of carotid chemoafferent neuron activation and hypoxia to the expression of LTF in urethane-anesthetized, vagotomized, paralyzed, and ventilated Sprague-Dawley rats. One hour after three 5-min isocapnic hypoxic episodes [arterial Po 2(PaO2 ) = 40 ± 5 Torr], integrated phrenic burst amplitude was greater than baseline in both carotid-denervated ( n = 8) and sham-operated ( n = 7) rats ( P < 0.05), indicating LTF. LTF was reduced in carotid-denervated rats relative to sham ( P < 0.05). In this and previous studies, rats were ventilated with hyperoxic gas mixtures (inspired oxygen fraction = 0.5) under baseline conditions. To determine whether episodic hyperoxia induces LTF, phrenic activity was recorded under normoxic (PaO2 = 90–100 Torr) conditions before and after three 5-min episodes of isocapnic hypoxia (PaO2 = 40 ± 5 Torr; n = 6) or hyperoxia (PaO2 > 470 Torr; n= 6). Phrenic burst amplitude was greater than baseline 1 h after episodic hypoxia ( P < 0.05), but episodic hyperoxia had no detectable effect. These data suggest that hypoxia per se initiates LTF independently from carotid chemoafferent neuron activation, perhaps through direct central nervous system effects.
Comparison of body composition methods in overweight and obese children
Authors: Gately P. J. , Radley D. , Cooke C. B. , Carroll S. , Oldroyd B. , Truscott J. G. , Coward W. A. , Wright A.
Published: March 2015

The objective of the present study was to investigate the accuracy of percent body fat (%fat) estimates from dual-energy X-ray absorptiometry, air-displacement plethysmography (ADP), and total body water (TBW) against a criterion four-compartment (4C) model in overweight and obese children. A volunteer sample of 30 children (18 male and 12 female), age of (mean ± SD) 14.10 ± 1.83 yr, body mass index of 31.6 ± 5.5 kg/m, and %fat (4C model) of 41.2 ± 8.2%, was assessed. Body density measurements were converted to %fat estimates by using the general equation of Siri (ADPSiri) (Siri WE. Techniques for Measuring Body Composition. 1961) and the age- and gender-specific constants of Lohman (ADPLoh) (Lohman TG. Exercise and Sport Sciences Reviews. 1986). TBW measurements were converted to %fat estimates by assuming that water accounts for 73% of fat-free mass (TBW73) and by utilizing the age- and gender-specific water contents of Lohman (TBWLoh). All estimates of %fat were highly correlated with those of the 4C model ( r ≥ 0.95, P < 0.001; SE ≤ 2.14). For %fat, the total error and mean difference ± 95% limits of agreement compared with the 4C model were 2.50, 1.8 ± 3.5 (ADPSiri); 1.82, -0.04 ± 3.6 (ADPLoh); 2.86, -2.0 ± 4.1 (TBW73); 1.90, -0.3 ± 3.8 (TBWLoh); and 2.74, 1.9 ± 4.0 DXA (dual-energy X-ray absorptiometry), respectively. In conclusion, in overweight and obese children, ADPLoh and TBWLoh were the most accurate methods of measuring %fat compared with a 4C model. However, all methods under consideration produced similar limits of agreement.
Role of TGF-β1 in relation to exercise-induced type I collagen synthesis in human tendinous tissue
Authors: Heinemeier Katja , Langberg Henning , Olesen Jens L. , Kjaer Michael
Published: March 2015

Mechanical loading of tissue is known to influence local collagen synthesis, and microdialysis studies indicate that mechanical loading of human tendon during exercise elevates tendinous type I collagen production. Transforming growth factor-β1 (TGF-β1), a potent stimulator of type I collagen synthesis, is released from cultured tendon fibroblasts in response to mechanical loading. Thus TGF-β1 could link mechanical loading and collagen synthesis in tendon tissue in vivo. Tissue levels of TGF-β1 and type I collagen metabolism markers [procollagen I COOH-terminal propeptide (PICP) and COOH-terminal telopeptide of type I collagen (ICTP)] were measured by microdialysis in peritendinous tissue of the Achilles' tendon in six male volunteers before and after treadmill running (1 h, 12 km/h, 3% uphill). In addition, blood levels of TGF-β1, PICP, and ICTP were obtained. PICP levels increased 68 h after exercise ( P < 0.05). Dialysate levels of TGF-β1 changed from 303 ± 46 pg/ml (at rest) to 423 ± 86 pg/ml 3 h postexercise. This change was nonsignificant, but the decay of tissue TGF-β1 after catheter insertion was markedly delayed by exercise compared with the decay seen in resting subjects. Plasma concentrations of TGF-β1 rose 30% in response to exercise ( P < 0.05 vs. pre). Our observations indicate an increased local production of type I collagen in human peritendinous tissue in response to uphill running. Although not conclusive, changes in circulating and local TGF-β1, in response to exercise, suggest a role for TGF-β1 in mechanical regulation of local collagen type I synthesis in tendon-related connective tissue in vivo.
Facial cooling-induced bradycardia does not slow pulmonary V̇o2kinetics at the onset of high-intensity exercise
Authors: Endo Masako , Tauchi Shinko , Hayashi Naoyuki , Koga Shunsaku , Rossiter Harry B. , Fukuba Yoshiyuki
Published: March 2015

The mechanism(s) underlying the attenuation of the slow component of pulmonary O2uptake (V̇o2) by prior heavy-intensity exercise is (are) poorly understood but may be ascribed to either an intramuscular-metabolic or a circulatory modification resulting from “priming” exercise. We investigated the effects of altering the circulatory dynamics by delayed vagal withdrawal to the circulation induced by the cold face stimulation (CFS) on the V̇o2kinetics during repeated bouts of heavy-intensity cycling exercise. Five healthy subjects (aged 21-43 yr) volunteered to participate in this study and initially performed two consecutive 6-min leg cycling exercise bouts (work rate: 50% of the difference between lactate threshold and maximal V̇o2) separated by 6-min baseline rest without CFS as a control (N1 and N2). CFS was then applied separately, by gel-filled cold compresses to the face for 2-min spanning the rest-exercise transition, to each of the first bout (CFS1) or second bout (CFS2) of repeated heavy-intensity exercise. In the control protocol, V̇o2responses in N2 showed a facilitated adaptation compared with those in N1, mainly attributable to the reduction of slow component. CFS application successfully slowed and delayed the heart rate (HR) kinetics ( P < 0.05) on transition to exercise [HR time constant; N1: 55.6 ± 16.0 (SD) vs. CFS1: 69.0 ± 12.8 s and N2: 55.5 ± 11.8 vs. CFS2: 64.0 ± 17.5 s]; however, it did not affect the “primary” V̇o2kinetics [V̇o2time constant; N1: 23.7 ± 7.9 (SD) vs. CFS1: 20.9 ± 3.8 s, and N2: 23.3 ± 10.3 vs. CFS2: 17.4 ± 6.3 s]. In conclusion, increased vagal withdrawal delayed and slowed the circulatory response but did not alter the V̇o2kinetics at the onset of supra-lactate threshold cycling exercise. As the facilitation of V̇o2subsequent to prior heavy leg cycling exercise is not attenuated by slowing the central circulation, it seems unlikely that this facilitation is exclusively determined by a blood flow-related mechanism.
Mucosal afferents mediate laryngeal adductor responses in the cat
Authors: Andreatta Richard D. , Mann Eric A. , Poletto Christopher J. , Ludlow Christy L.
Published: March 2015

Laryngeal adductor responses (LAR) close the airway in response to stimulation of peripheral afferents in the superior laryngeal nerve. Although both mucosal afferents and proprioceptive receptors are present in the larynx, their relative contribution for reflex elicitation is unknown. Our purpose was to determine which receptor types are of importance in eliciting the LAR. A servomotor with displacement feedback was used to deliver punctate displacements to the body of the arytenoid cartilage and overlying mucosa on each side of the larynx in eight anesthetized cats. The same displacements were delivered both before and after surgical excision of the overlying mucosa. With the mucosa intact, early short-latency component R1 LAR responses recorded from the thyroarytenoid muscles were frequent (ipsilateral > 92%, contralateral > 95%). After the mucosa was removed, the LAR became infrequent (<3%) and was reduced in amplitude in both the ipsilateral and contralateral thyroarytenoid muscle recording sites ( P < 0.0005). These findings demonstrate that mucosal mechanoreceptors and not proprioceptive afferents contribute to the elicitation of LAR responses in the cat.
Rapid effects of 17β-estradiol and progesterone on sheep visceral and parietal pleurae via a nitric oxide pathway
Authors: Hatzoglou C. , Gourgoulianis K. I. , Hatzoglou A. , Castanas E. , Molyvdas P. A.
Published: March 2015

We investigated the effects of 17β-estradiol and progesterone on transepithelial electrical resistance ( RTE) in sheep visceral and parietal pleurae. Specimens of intact pleurae from adult female sheep were used. The samples were transferred to the laboratory within 30 min after death of the animal in a Krebs-Ringer solution at 4°C. The pleura was then mounted as a planar sheet in Ussing-type chambers, and electrical measurements were made. There was an increase in RTEin all of the samples examined after addition of 17β-estradiol and progesterone in visceral and parietal pleurae. This increase was rapid within 1 min, lasted for ∼15 min, returned to the basal level within 30–45 min, and was dose dependent. Tamoxifen, an estrogen receptor antagonist, did not significantly eliminate the effect of 17β-estradiol. Furthermore, no steroid receptors were identified in cytosolic preparations of visceral and parietal pleura with ligand binding assays. The estrogen- and progesterone-induced increase in RTEin both visceral and parietal pleurae was affected by addition of an inhibitor of nitric oxide synthase. Indeed, previous administration of Nω-nitro-l-arginine methyl ester prevented the increase in RTEby 17β-estradiol and progesterone. These results suggest that 17β-estradiol and progesterone induce an increase in RTEin both visceral and parietal pleura and thus alter the transepithelial permeability. The effect of steroids may be accounted for by rapid release of nitric oxide in pleura.
Invited Review: Role of mechanophysiology in aging of ECM: effects of changes in mechanochemical transduction
Authors: Silver Frederick H. , DeVore Dale , Siperko Lorraine M.
Published: March 2015

Mechanical forces play a role in the development and evolution of extracellular matrices (ECMs) found in connective tissue. Gravitational forces acting on mammalian tissues increase the net muscle forces required for movement of vertebrates. As body mass increases during development, musculoskeletal tissues and other ECMs are able to adapt their size to meet the increased mechanical requirements. However, the control mechanisms that allow for rapid growth in tissue size during development are altered during maturation and aging. The purpose of this mini-review is to examine the relationship between mechanical loading and cellular events that are associated with downregulation of mechanochemical transduction, which appears to contribute to aging of connective tissue. These changes result from decreases in growth factor and hormone levels, as well as decreased activation of the phosphorelay system that controls cell division, gene expression, and protein synthesis. Studies pertaining to the interactions among mechanical forces, growth factors, hormones, and their receptors will better define the relationship between mechanochemical transduction processes and cellular behavior in aging tissues.
Modeling pulmonary and CNS O2 toxicity and estimation of parameters for humans
Authors: Arieli R. , Yalov A. , Goldenshluger A.
Published: March 2015

10.1152/japplphysiol.00434.2001.—The power expression for cumulative oxygen toxicity and the exponential recovery were successfully applied to various features of oxygen toxicity. From the basic equation, we derived expressions for a protocol in which Po 2 changes with time. The parameters of the power equation were solved by using nonlinear regression for the reduction in vital capacity (ΔVC) in humans:  %ΔVC  = 0.0082 × t 2(Po 2/101.3)4.57, where t is the time in hours and Po 2is expressed in kPa. The recovery of lung volume is  ΔVC t  = ΔVCe × e −(−0.42 + 0.00379Po 2 ) t , where ΔVC t is the value at time tof the recovery, ΔVCe is the value at the end of the hyperoxic exposure, and Po 2 is the prerecovery oxygen pressure. Data from different experiments on central nervous system (CNS) oxygen toxicity in humans in the hyperbaric chamber ( n = 661) were analyzed along with data from actual closed-circuit oxygen diving ( n = 2,039) by using a maximum likelihood method. The parameters of the model were solved for the combined data, yielding the power equation for active diving: K = t 2(Po 2/101.3)6.8, where tis in minutes. It is suggested that the risk of CNS oxygen toxicity in diving can be derived from the calculated parameter of the normal distribution: Z = [ln( t) − 9.63 +3.38 × ln(Po 2/101.3)]/2.02. The recovery time constant for CNS oxygen toxicity was calculated from the value obtained for the rat, taking into account the effect of body mass, and yielded the recovery equation: Kt = K e × e −0.079 t , where Kt and K e are the values of K at time t of the recovery process and at the end of the hyperbaric oxygen exposure, respectively, and tis in minutes.
Left ventricular diastolic filling and systolic function of young and older trained and untrained men
Authors: Baldi James C. , McFarlane Kendra , Oxenham Helen C. , Whalley Gillian A. , Walsh Helen J. , Doughty Robert N.
Published: March 2015

Aging is associated with impaired early diastolic filling; however, the effect of endurance training on resting diastolic function in older subjects is unclear. Heart rate and ventricular loading conditions affect mitral inflow velocities measured by Doppler echocardiography; therefore, tissue Doppler imaging of mitral annular velocity, which is relatively preload independent, was combined with mitral inflow velocity and maximal oxygen consumption (V̇o2 max) in young (20-35 yr) and older (60-80 yr) trained and untrained men to determine whether endurance training is associated with an attenuation of age-associated changes in diastolic filling. As expected, V̇o2 max was higher in trained men ( P < 0.01) and lower in older men ( P < 0.01). Peak early mitral inflow velocity (E) and early-to-late mitral inflow velocity ratios were lower in older vs. young men ( P < 0.01); however, there was no training effect ( P > 0.05). Peak early mitral annular velocity (E′) was higher and peak late mitral annular velocity (A′) was lower in young vs. older men ( P < 0.01). A significant interaction effect was found for A′, E′/A′, and peak systolic mitral annular velocity (S′). Training was associated with lower A′ in young and higher A′ in older men. S′ was greater in trained vs. untrained older men ( P < 0.05), but it was similar in trained and untrained young men. These findings suggest that early diastolic filling is not affected by training in older men, and the effect of training on A′ and S′ is different in young and older men.
Targeted disruption of the Fgf2 gene does not affect vascular growth in the mouse ischemic hindlimb
Authors: Sullivan Chris J. , Doetschman Thomas , Hoying James B.
Published: March 2015

Ischemic revascularization involves extensive structural adaptation of the vasculature, including both angiogenesis and arteriogenesis. Previous studies suggest that fibroblast growth factor (FGF)-2 participates in both angiogenesis and arteriogenesis. Despite this, the specific role of endogenous FGF-2 in vascular adaptation during ischemic revascularization is unknown. Therefore, we used femoral artery ligation in Fgf2 +/+ and Fgf2 −/− mice to test the hypothesis that endogenous FGF-2 is an important regulator of angiogenesis and arteriogenesis in the setting of hindlimb ischemia. Femoral ligation increased capillary and arteriole density in the ischemic calf in both Fgf2 +/+and Fgf2 −/− mice. The level of angiographically visible arteries in the thigh was increased in the ischemic hindlimb in all mice, and no significant differences were observed between Fgf2 +/+ and Fgf2 −/− mice. Additionally, limb perfusion progressively improved to peak values at day 35postsurgery in both genotypes. Given the equivalent responses observed in Fgf2 +/+ and Fgf2 −/− mice, we demonstrate that endogenous FGF-2 is not required for revascularization in the setting of peripheral ischemia. Vascular adaptation, including both angiogenesis and arteriogenesis, was not affected by the absence of FGF-2 in this model.
Middle cerebral artery blood velocity during intense static exercise is dominated by a Valsalva maneuver
Authors: Pott Frank , Van Lieshout Johannes J. , Ide Kojiro , Madsen Per , Secher Niels H.
Published: March 2015

Lifting of a heavy weight may lead to “blackout” and occasionally also to cerebral hemorrhage, indicating pronounced consequences for the blood flow through the brain. We hypothesized that especially strenuous respiratory straining (a Valsalva-like maneuver) associated with intense static exercise would lead to a precipitous rise in mean arterial and central venous pressures and, in turn, influence the middle cerebral artery blood velocity (MCA V mean) as a noninvasive indicator of changes in cerebral blood flow. In 10 healthy subjects, MCA V mean was evaluated in response to maximal static two-legged exercise performed either with a concomitantly performed Valsalva maneuver or with continued ventilation and also during a Valsalva maneuver without associated exercise ( n = 6). During static two-legged exercise, the largest rise for mean arterial pressure and MCA V meanwas established at the onset of exercise performed with a Valsalva-like maneuver (by 42 ± 5 mmHg and 31 ± 3% vs. 22 ± 6 mmHg and 25 ± 6% with continued ventilation; P < 0.05). Profound reductions in MCA V mean were observed both after exercise with continued ventilation (−29 ± 4% together with a reduction in the arterial CO2 tension by −5 ± 1 Torr) and during the maintained Valsalva maneuver (−21 ± 3% together with an elevation in central venous pressure to 40 ± 7 mmHg). Responses to performance of the Valsalva maneuver with and without exercise were similar, reflecting the deterministic importance of the Valsalva maneuver for the central and cerebral hemodynamic response to intense static exercise. Continued ventilation during intense static exercise may limit the initial rise in arterial pressure and may in turn reduce the risk of hemorrhage. On the other hand, blackout during and after intense static exercise may reflect a reduction in cerebral blood flow due to expiratory straining and/or hyperventilation.
Plasma corticosterone response to acute and chronic voluntary exercise in female house mice
Authors: Girard I. , Garland T.
Published: March 2015

Plasma levels of corticosterone (B) respond acutely to exercise in all mammals that have been studied, but the literature contains conflicting reports regarding how chronic activity alters this response. We measured acute and chronic effects of voluntary activity on B in a novel animal model, mice selectively bred for high voluntary wheel running. Female mice were housed with or without wheels for 8 wk beginning at 26 days of age. Wheel-access selection mice had significantly higher B at night 8, day 15, and night 29, compared with wheel-access controls. Elevation of B was an acute effect of voluntary exercise. When adjusted for running in the previous 20 min, no difference between wheel-access selection and control animals remained. No training effect on B response was observed. These results are among the strongest evidence that, in some animals, the acute B response is unaffected by chronic voluntary exercise. In mice without wheels, selection mice had significantly higher B than controls at day 15, night 29, and night 50, suggesting that selection resulted in a modulation of the hypothalamic-pituitary-adrenal axis. Growth over the first 4 wk of treatment was significantly and inversely related to average night B levels within each of the four treatment groups.
Transient mechanical benefits of a deep inflation in the injured mouse lung
Authors: Allen Gilman , Lundblad Lennart K. A. , Parsons Polly , Bates Jason H. T.
Published: March 2015

The lasting effects of a recruitment maneuver (RM) in the injured lung are not well characterized. We speculated that the reduction in respiratory elastance ( H) after a deep inflation (DI) is transient in nature and should be sustained longer at higher positive end-expiratory pressure (PEEP). Thirteen ventilated mice were given 2 DIs at various levels of PEEP before and after saline lavage. Forced oscillations were used to measure H periodically over 7 min after the DIs. Time constants (τ) were estimated for the post-DI recovery in H. Values for τ before lavage (80–115 s) were reduced after lavage (13–30 s) at all levels of PEEP ( P = 0.0001). PEEP did not significantly influence τ before or after lavage. The plateau level and total recovery in H after a DI were significantly influenced by PEEP and lavage ( P < 0.0001). Our results suggest that for a DI to be beneficial in the injured mouse lung, it may have to be applied several times a minute.
Determinants of long-term facilitation in humans during NREM sleep
Authors: Babcock Mark , Shkoukani Mahdi , Aboubakr Salah E. , Badr M. Safwan
Published: March 2015

Long-term facilitation (LTF) is a prolonged increase in ventilatory motor output after episodic peripheral chemoreceptor stimulation. We have previously shown that LTF is activated during sleep following repetitive hypoxia in snorers (Babcock MA and Badr MS. Sleep 21: 709–716, 1998). The purpose of this study was 1) to ascertain the relative contribution of inspiratory flow limitation to the development of LTF and 2) to determine the effect of eliminating inspiratory flow limitation by nasal CPAP on LTF. We studied 25 normal subjects during stable non-rapid eye movement sleep. We induced 10 episodes of brief repetitive isocapnic hypoxia (inspired O2 fraction = 8%; 3 min) followed by 5 min of room air. Measurements were obtained during control and at 20 min of recovery (R20). During the episodic hypoxia study, inspiratory minute ventilation (V˙i) increased from 6.7 ± 1.9 l/min during the control period to 8.2 ± 2.7 l/min at R20 (122% of control; P < 0.05). Linear regression analysis confirmed that inspiratory flow limitation during control was the only independent determinant of the presence of LTF ( P = 0.005). Six subjects were restudied by using nasal continuous positive airway pressure to ascertain the effect of eliminating inspiratory flow limitation on LTF.V˙i during the recovery period was 97 ± 10% ( P > 0.05). In conclusion, 1) repetitive hypoxia in sleeping humans is followed by increasedV˙i in the recovery period, indicative of development of LTF; 2) inspiratory flow limitation is the only independent determinant of posthypoxic LTF in sleeping human; 3) elimination of inspiratory flow limitation abolished the ventilatory manifestations of LTF; and 4) we propose that increased V˙i in the recovery period was a result of preferential recruitment of upper airway dilators by repetitive hypoxia.
Selected Contribution: Chronic intermittent hypoxia enhances respiratory long-term facilitation in geriatric female rats
Authors: Zabka A. G. , Mitchell G. S. , Olson E. B. , Behan M.
Published: March 2015

Age and the estrus cycle affect time-dependent respiratory responses to episodic hypoxia in female rats. Respiratory long-term facilitation (LTF) is enhanced in middle-aged vs. young female rats ( 72 ). We tested the hypothesis that phrenic and hypoglossal (XII) LTF are diminished in acyclic geriatric rats when fluctuating sex hormone levels no longer establish conditions that enhance LTF. Chronic intermittent hypoxia (CIH) enhances LTF ( 41 ); thus we further predicted that CIH would restore LTF in geriatric female rats. LTF was measured in young (3-4 mo) and geriatric (20-22 mo) female Sasco Sprague-Dawley rats and in a group of geriatric rats exposed to 1 wk of nocturnal CIH (11 vs. 21% O2 at 5-min intervals, 12 h/night). In anesthetized, paralyzed, vagotomized, and ventilated rats, time-dependent hypoxic phrenic and XII responses were assessed. The short-term hypoxic response was measured during the first of three 5-min episodes of isocapnic hypoxia (arterial Po2 35-45 Torr). LTF was assessed 15, 30, and 60 min postepisodic hypoxia. Phrenic and XII short-term hypoxic response was not different among groups, regardless of CIH treatment ( P > 0.05). LTF in geriatric female rats was smaller than previously reported for middle-aged rats but comparable to that in young female rats. CIH augmented phrenic and XII LTF to levels similar to those of middle-aged female rats without CIH ( P < 0.05). The magnitude of phrenic and XII LTF in all groups was inversely related to the ratio of progesterone to estradiol serum levels ( P < 0.05). Thus CIH and sex hormones influence the magnitude of LTF in geriatric female rats.
Heat stress increases muscle glycogen use but reduces the oxidation of ingested carbohydrates during exercise
Authors: Jentjens Roy L. P. G. , Wagenmakers Anton J. M. , Jeukendrup Asker E.
Published: March 2015

The aim of the present study was to test the hypothesis that the oxidation rate of ingested carbohydrate (CHO) is impaired during exercise in the heat compared with a cool environment. Nine trained cyclists (maximal oxygen consumption 65 ± 1 ml · kg body wt−1 · min−1) exercised on two different occasions for 90 min at 55% maximum power ouptput at an ambient temperature of either 16.4 ± 0.2°C (cool trial) or 35.4 ± 0.1°C (heat trial). Subjects received 8% glucose solutions that were enriched with [U-13C]glucose for measurements of exogenous glucose, plasma glucose, liver-derived glucose and muscle glycogen oxidation. Exogenous glucose oxidation during the final 30 min of exercise was significantly ( P < 0.05) lower in the heat compared with the cool trial (0.76 ± 0.06 vs. 0.84 ± 0.05 g/min). Muscle glycogen oxidation during the final 30 min of exercise was increased by 25% in the heat (2.07 ± 0.16 vs. 1.66 ± 0.09 g/min; P < 0.05), and liver-derived glucose oxidation was not different. There was a trend toward a higher total CHO oxidation and a lower plasma glucose oxidation in the heat although this did not reach statistical significance ( P = 0.087 and P = 0.082, respectively). These results demonstrate that the oxidation rate of ingested CHO is reduced and muscle glycogen utilization is increased during exercise in the heat compared with a cool environment.
Dose-response relationship of the cardiovascular adaptation to endurance training in healthy adults: how much training for what benefit?
Authors: Iwasaki Ken-ichi , Zhang Rong , Zuckerman Julie H. , Levine Benjamin D.
Published: March 2015

Occupational or recreational exercise reduces mortality from cardiovascular disease. The potential mechanisms for this reduction may include changes in blood pressure (BP) and autonomic control of the circulation. Therefore, we conducted the present long-term longitudinal study to quantify the dose-response relationship between the volume and intensity of exercise training, and regulation of heart rate (HR) and BP. We measured steady-state hemodynamics and analyzed dynamic cardiovascular regulation by spectral and transfer function analysis of cardiovascular variability in 11 initially sedentary subjects during 1 yr of progressive endurance training sufficient to allow them to complete a marathon. From this, we found that 1) moderate exercise training for 3 mo decreased BP, HR, and total peripheral resistance, and increased cardiovascular variability and arterial baroreflex sensitivity; 2) more prolonged and intense training did not augment these changes further; and 3) most of these changes returned to control values at 12 mo despite markedly increased training duration and intensity equivalent to that routinely observed in competitive athletes. In conclusion, increases in R-wave-R-wave interval and cardiovascular variability indexes are consistent with an augmentation of vagal modulation of HR after exercise training. It appears that moderate doses of training for 3 mo are sufficient to achieve this response as well as a modest hypotensive effect from decreasing vascular resistance. However, more prolonged and intense training does not necessarily lead to greater enhancement of circulatory control and, therefore, may not provide an added protective benefit via autonomic mechanisms against death by cardiovascular disease.