bluuebunny/crossref_metadata_2025 huggingface dataset:
Adeno-associated virus mediated gene delivery into coronary microvessels of chronically instrumented dogs
Authors: Post Heiner , Kajstura Jan , Lei Biao , Sessa William C. , Byrne Barry , Anversa Piero , Hintze Thomas H. , Recchia Fabio A.
Published: March 2015

The objective of this study was to assess the potential of adeno-associated virus (AAV)-mediated gene delivery into coronary microvessels in vivo in a large animal. Ten mongrel dogs were chronically instrumented and allowed to recover for 10 days. Dogs were reanesthetized, and the aorta was constricted by a hydraulic occluder, whereby left ventricular (LV) pressure increased by 30% and left circumflex coronary artery blood flow by 50%. Recombinant AAV (serotype 2, CMV enhancer/chicken β-actin promoter) encoding for green fluorescent protein (GFP) was injected as a bolus into the left atrium during aortic constriction at total titers of 1010or 1012infectious units. Dogs were followed for 2 ( n = 4)or4wk( n = 6). Hemodynamics or body weight did not change. In LV tissue slices, a fluorescein-labeled antibody to GFP stained endothelial and smooth muscle cells but was absent in myocytes. To quantify transduction, slices were then stained with antibodies against α-smooth muscle actin or von Willebrand factor. Approximately 4% of arterioles and 2% of microvessels stained positive for anti-GFP independent from viral titer or duration. By regression analyses, the percent of vessels transfected was proportional to the increase in LV systolic pressure during occlusion. AAV is a potential vector for gene transfer into the coronary microcirculation in large animals, including perhaps humans.
Mechanisms of sympathoexcitation: single-unit analysis of muscle vasoconstrictor neurons in awake OSAS subjects
Authors: Elam Mikael , McKenzie David , Macefield Vaughan
Published: March 2015

In congestive heart failure (CHF), muscle sympathetic activity (MSNA) is greatly elevated, but our laboratory has shown that single muscle vasoconstrictor neurons primarily fire only once per cardiac interval, as in normal subjects (Elam M and Macefield VG. J Appl Physiol 91: 717–724, 2001; Macefield VG, Rundqvist B, Sverrisdottir YB, Wallin BG, and Elam M. Circulation 100: 1708–1713, 1999). In this study, we used patients with obstructive sleep apnea syndrome (OSAS) to test the hypothesis that this firing pattern is maintained in other states of sympathoexcitation. Unitary recordings were made from muscle vasoconstrictor neurons in eight awake OSAS patients. The average firing frequency of 12 units was 0.96 Hz and the firing probability 51%, similar to previous observations in CHF patients (0.98 Hz, 55%) but higher than in healthy subjects (0.40 Hz, 31%). However, the percentages of cardiac intervals in which neurons generated one, two, three, or four spikes were 59, 27, 10, and 3% in OSAS, compared with 71, 18, 7, and 2% in CHF and 73, 18, 5, and 3% in healthy subjects. Thus the firing pattern is different in OSAS and CHF, leading to rejection of the hypothesis: although in both conditions individual neurons show an increase in firing probability, in OSAS patients they also fire more often within a cardiac interval. It is likely that differences may also be apparent in other states of sympathoexcitation.
Drastic reduction of calsequestrin-like proteins and impaired calcium binding in dystrophicmdxmuscle
Authors: Culligan Kevin , Banville Niamh , Dowling Paul , Ohlendieck Kay
Published: March 2015

Although the reduction in dystrophin-associated glycoproteins is the primary pathophysiological consequence of the deficiency in dystrophin, little is known about the secondary abnormalities leading to x-linked muscular dystrophy. As abnormal Ca2+handling may be involved in myonecrosis, we investigated the fate of key Ca2+regulatory membrane proteins in dystrophic mdx skeletal muscle membranes. Whereas the expression of the ryanodine receptor, the dihydropyridine receptor, the Ca2+-ATPase, and calsequestrin was not affected, a drastic decline in calsequestrin-like proteins of 150–220 kDa was observed in dystrophic microsomes using one-dimensional immunoblotting, two-dimensional immunoblotting with isoelectric focusing, diagonal two-dimensional blotting technique, and immunoprecipitation. In analogy, overall Ca2+binding was reduced in the sarcoplasmic reticulum of dystrophic muscle. The reduction in Ca2+binding proteins might be directly involved in triggering impaired Ca2+sequestration within the lumen of the sarcoplasmic reticulum. Thus disturbed sarcolemmal Ca2+fluxes seem to influence overall Ca2+homeostasis, resulting in distinct changes in the expression profile of a subset of Ca2+handling proteins, which might be an important factor in the progressive functional decline of dystrophic muscle fibers.
Resistance exercise alters MRF and IGF-I mRNA content in human skeletal muscle
Authors: Psilander Niklas , Damsgaard Rasmus , Pilegaard Henriette
Published: March 2015

Increasing evidence suggests that the myogenic regulatory factors (MRFs) and IGF-I have important roles in the hypertrophy response observed after mechanical loading. We, therefore, hypothesized that a bout of heavy-resistance training would affect the MRF and IGF-I mRNA levels in human skeletal muscle. Six male subjects completed four sets of 6-12 repetitions on a leg press and knee extensor machine separated by 3 min. Myogenin, MRF4, MyoD, IGF-IEabc (isoforms a, b, and c) and IGF-IEbc (isoform b and c) mRNA levels were determined in the vastus lateralis muscle by RT-PCR before exercise, immediately after, and 1, 2, 6, 24, and 48 h postexercise. Myogenin, MyoD, and MRF4 mRNA levels were elevated ( P < 0.005) by 100-400% 0-24 h postexercise. IGF-IEabc mRNA content decreased ( P < 0.005) by ∼44% after 1 and 6 h of recovery. The IGF-IEbc mRNA level was unaffected. The present study shows that myogenin, MyoD, and MRF4 mRNA levels are transiently elevated in human skeletal muscle after a single bout of heavy-resistance training, supporting the idea that the MRFs may be involved in regulating hypertrophy and/or fiber-type transitions. The results also suggest that IGF-IEa expression may be downregulated at the mRNA level during the initial part of recovery from resistance exercise.
Influence of varying degrees of malnutrition on IGF-I expression in the rat diaphragm
Authors: Lewis Michael I. , Li Hongyan , Huang Zhi-Shen , Biring Manmohan S. , Cercek Bojan , Fournier Mario
Published: March 2015

This study evaluated the impact of varying degrees of prolonged malnutrition on the local insulin-like growth factor-I (IGF-I) system in the costal diaphragm muscle. Adult rats were provided with either 60 or 40% of usual food intake over 3 wk. Nutritionally deprived (ND) animals (i.e., ND60 and ND40) were compared with control (Ctl) rats fed ad libitum. Costal diaphragm fiber types and cross-sectional areas were determined histochemically. Costal diaphragm muscle IGF-I mRNA levels were determined by RT-PCR. Serum and muscle IGF-I peptide levels were determined by using a rat-specific radioimmunoassay. The body weights of Ctl rats increased by 5%, whereas those of ND60 and ND40 animals decreased by 16 and 26%, respectively. Diaphragm weights were reduced by 17 and 27% in ND60 and ND40 animals, respectively, compared with Ctl. Diaphragm fiber proportions were unaffected by either ND regimen. Significant atrophy of both type IIa and IIx fibers was noted in the ND60 group, whereas atrophy of all three fiber types was observed in the diaphragm of ND40 rats. Serum IGF-I levels were reduced by 62 and 79% in ND60 and ND40 rats, respectively, compared with Ctl. Diaphragm muscle IGF-I mRNA levels in both ND groups were similar to those noted in Ctl. In contrast, IGF-I concentrations were reduced by 36 and 42% in the diaphragm muscle of ND60 and ND40 groups, respectively, compared with Ctl. We conclude that the local (autocrine/paracrine) muscle IGF-I system is affected in our models of prolonged ND. We propose that this contributes to disordered muscle protein turnover and muscle cachexia with atrophy of muscle fibers. This is particularly so in view of recent data demonstrating the importance of the autocrine/paracrine system in muscle growth and maintenance of fiber size.
High-speed running performance: a new approach to assessment and prediction
Authors: Bundle Matthew W. , Hoyt Reed W. , Weyand Peter G.
Published: March 2015

We hypothesized that allout running speeds for efforts lasting from a few seconds to several minutes could be accurately predicted from two measurements: the maximum respective speeds supported by the anaerobic and aerobic powers of the runner. To evaluate our hypothesis, we recruited seven competitive runners of different event specialties and tested them during treadmill and overground running on level surfaces. The maximum speed supported by anaerobic power was determined from the fastest speed that subjects could attain for a burst of eight steps (∼3 s or less). The maximum speed supported by aerobic power, or the velocity at maximal oxygen uptake, was determined from a progressive, discontinuous treadmill test to failure. All-out running speeds for trials of 3-240 s were measured during 10-13 constant-speed treadmill runs to failure and 4 track runs at specified distances. Measured values of the maximum speeds supported by anaerobic and aerobic power, in conjunction with an exponential constant, allowed us to predict the speeds of all-out treadmill trials to within an average of 2.5% ( R2 = 0.94; n = 84) and track trials to within 3.4% ( R2 = 0.86; n = 28). An algorithm using this exponent and only two of the all-out treadmill runs to predict the remaining treadmill trials was nearly as accurate (average = 3.7%; R2 = 0.93; n = 77). We conclude that our technique 1) provides accurate predictions of high-speed running performance in trained runners and 2) offers a performance assessment alternative to existing tests of anaerobic power and capacity.
Assessment of upper airway stabilizing forces with the use of phrenic nerve stimulation in conscious humans
Authors: Sériès Frédéric , Éthier Germain
Published: March 2015

Phrenic nerve stimulation (PNS) applied at end-expiration allows the investigation of passive upper airway (UA) dynamic during wakefulness. Assuming that phasic UA dilating/stabilizing forces should modify the UA properties when twitches are applied during inspiration, we compared the UA dynamic responses to expiratory and inspiratory twitches (2 s and 200 ms after expiratory and inspiratory onset, respectively) in nine men (mean age 28 yr). This procedure was repeated with a 2-cm mouth opening provided with a closed mouthpiece. The percentage of flow-limited (FL) twitches was significantly higher when PNS was realized during expiration than during inspiration. Maximal inspiratory flow (V˙i max) of FL twitches was significantly higher for inspiratory twitches (1,383 ± 42 and 1,185 ± 40 ml/s). With mouth aperture,V˙i max decreased with an increase in the corresponding pharyngeal resistance values, and the percentage of twitch with a FL regimen increased but only for inspiratory twitches. We conclude that 1) UA dynamics are significantly influenced by the inspiratory/expiratory timing at which PNS is applied, 2) the improvement in UA dynamic properties observed from expiratory to inspiratory PNS characterizes the overall inspiratory stabilizing effects, and 3) mouth aperture alters the stability of UA structures during inspiration.
Acute ethanol increases angiogenic growth factor gene expression in rat skeletal muscle
Authors: Gavin Timothy P. , Wagner Peter D.
Published: March 2015

Moderate ethanol consumption demonstrates a protective effect against cardiovascular disease and improves insulin sensitivity, possibly through angiogenesis. We investigated whether 1) ethanol would increase skeletal muscle growth factor gene expression and 2) the effects of ethanol on skeletal muscle growth factor gene expression were independent of exercise-induced growth factor gene expression. Female Wistar rats were used. Four groups (saline + rest; saline + exercise; 17 mmol/kg ethanol + rest; and 17 mmol/kg ethanol + exercise) were used to measure the growth factor response to acute exercise and ethanol administration. Vascular endothelial growth factor (VEGF), transforming growth factor-β1(TGF-β1), basic fibroblast growth factor (bFGF), Flt-1, and Flk-1 mRNA were analyzed from the left gastrocnemius by quantitative Northern blot. Ethanol increased VEGF, TGF-β1, bFGF, and Flt-1 mRNA at rest and after acute exercise. Ethanol increased resting Flk-1 mRNA. Ethanol increased bFGF mRNA independently of exercise. These findings suggest that 1) ethanol can increase skeletal muscle angiogenic growth factor gene expression and 2) the mechanisms responsible for the ethanol-induced increases in VEGF, TGFβ1, and Flt-1 mRNA appear to be different from those responsible for exercise-induced regulation. Therefore, these results provide evidence in adult rat tissue that the protective cardiovascular effects of moderate ethanol consumption may result in part through the increase of angiogenic growth factors.
Long-term (6-wk) hindlimb suspension inhibits spermatogenesis in adult male rats
Authors: Tash Joseph S. , Johnson Donald C. , Enders George C.
Published: March 2015

The International Space Station will allow extended habitation in space and long-term exposure to microgravity (μG). A concern is the impact of long-term μG exposure on the ability of species to reproduce. The model often used to simulate μG is rat hindlimb suspension (HLS), where the hindlimbs are elevated above the cage floor with a tail harness. Experiments described here are the first to examine the effect of long-term HLS on testicular function in adult male rats. Free-roaming (controls), animals with only the tail harnessed but hindlimbs in contact with the cage floor (TO), and HLS animals were tested for 6 wk. Cryptorchidism was prevented in TO and HLS animals by partial constriction of the inguinal canal with sutures. All parameters were compared at the end of the 6-wk experiment. Testicular weights and spermatogenesis were significantly reduced by HLS, such that no spermatogenic cells beyond round spermatids were present and epididymides were devoid of mature sperm. In many tubules, loss of all germ cells, except a few spermatogonia, resulting in histopathology similar to the Sertoli cell, was observed. Spermatogenesis appeared unaffected in control and TO animals. Sertoli and Leydig cell appearance, testosterone, luteinizing hormone, and follicle-stimulating hormone levels, and epididymal and seminal vesicle weight were unchanged by HLS. Cortisone was not elevated by HLS; thus stress may not be a factor. These results demonstrate that spermatogenesis is severely inhibited by long-term HLS, whereas testicular androgen production is not. These results have significant implications regarding serious effects of long-term exposure to μG on the reproductive capability of scrotal mammals, including humans.
Fiber capillarization relative to mitochondrial volume in diaphragm of shrew
Authors: Mathieu-Costello O. , Morales S. , Savolainen J. , Vornanen M.
Published: March 2015

The objective was to examine fiber capillarization in relation to fiber mitochondrial volume in the highly aerobic diaphragm of the shrew, the smallest mammal. The diaphragms of four common shrews [ Sorex araneus; body mass, 8.2 ± 1.3 (SE) g] and four lesser shrews ( Sorex minutus, 2.6 ± 0.1 g) were perfusion fixed in situ, processed for electron microscopy, and analyzed by morphometry. Capillary length per fiber volume was extremely high, at values of 8,008 ± 1,054 and 12,332 ± 625 mm−2in S. araneus and S. minutus, respectively ( P= 0.012), with no difference in capillary geometry between the two species. Fiber mitochondrial volume density was 28.5 ± 2.3% ( S. araneus) and 36.5 ± 1.4% ( S. minutus; P = 0.025), yielding capillary length per milliliter mitochondria values ( S. araneus, 27.8 ± 1.5 km; S. minutus, 33.9 ± 2.2 km; P = 0.06) as high as in the flight muscle of the hummingbird and small bats. The size of the capillary-fiber interface (i.e., capillary surface per fiber surface ratio) per fiber mitochondrial volume in shrew diaphragm was also as high as in bird and bat flight muscles, and it was about two times greater than in rat hindlimb muscle. Thus, whereas fiber capillary and mitochondrial volume densities decreased with increased body mass in S. araneus compared with S. minutusSoricinae shrews, fiber capillarization per milliliter mitochondria in both species was much higher than previously reported for shrew diaphragm, and it matched that of the intensely aerobic flight muscles of birds and mammals.
Hypoxemia and low Crs in vagally denervated lambs result from reduced lung volume and not pulmonary edema
Authors: Lalani Salim , Remmers John E. , MacKinnon Yolanda , Ford Gordon T. , Hasan Shabih U.
Published: March 2015

Vagal denervation performed in the intrathoracic region in newborn lambs leads to hypoxemia and decreased respiratory system compliance (Crs), which could result from atelectasis and/or pulmonary edema. The objective of the present study was to quantify the relative roles of alveolar derecruitment and pulmonary edema as underlying cause(s) of respiratory failure. Vagal denervation was performed in the intrathoracic region and below the recurrent laryngeal nerves in six newborn lambs within 24 h of birth, whereas six were sham operated. Pre- and postinflation Crs was measured to investigate the presence of alveolar derecruitment. Pulmonary edema was assessed with lung wet-dry-to-wet and lung tissue wet-to-dry ratios, total protein, and FITC-BSA recovery in lung tissue and bronchoalveolar lavage. Compared with that in the sham-operated animals, Crs was significantly lower in vagally denervated animals. However, postinflation, pulmonary system compliance obtained by quasi-static lung inflation and deflation to 30 cmH2O showed no significant difference between the sham-operated and denervated lambs. The lung wet-dry-to-wet and lung tissue wet-to-dry ratios, total protein, and FITC-BSA recovery in lung tissue and bronchoalveolar lavage were similar in denervated and sham-operated groups. We provide evidence that reduced lung volume and not pulmonary edema is associated with intrathoracic vagal denervation and is the likely underlying mechanism for hypoxemia and low Crs.
Altered myocardial Gsprotein and adenylyl cyclase signaling in rats exposed to chronic hypoxia and normoxic recovery
Authors: Hrbasová Markéta , Novotny Jiri , Hejnová Lucie , Kolář František , Neckář Jan , Svoboda Petr
Published: March 2015

The present work has analyzed the consequences of chronic intermittent high-altitude hypoxia for functioning of the G protein-mediated adenylyl cyclase (AC) signaling system in the right (RV) and left ventricular (LV) myocardium in rats. Adaptation to hypoxia did not appreciably affect the number of β-adrenoceptors and the content of predominantly membrane-bound α-subunit (Gsα) of the stimulatory G protein, but it raised the amount of cytosolic Gsα in RV. The levels of myocardial inhibitory Gα protein were not altered. Activity of AC stimulated by GTP, fluoride, forskolin, or isoprotertenol was reduced by ∼50% in RV from chronically hypoxic rats, and a weaker depression was also found in LV. In addition, hypoxia significantly diminished a functional activity of membrane-bound Gsα in both RV and LV. The RV baseline contractile function was markedly increased in chronically hypoxic animals, and its sensitivity to β-adrenergic stimulation was decreased. Animals recovering from hypoxia for 5 wk still exhibited markedly elevated levels of cytosolic Gsα and significantly lower activity of AC in RV than did age-matched controls, but contractile responsiveness to β-agonists was normal.
Effects of human pregnancy on fluid regulation responses to short-term exercise
Authors: Heenan Aaron P. , Wolfe Larry A. , Davies Gregory A. L. , McGrath Michael J.
Published: March 2015

This study tested the hypothesis that human pregnancy alters fluid and electrolyte regulation responses to acute short-term exercise. Responses of 22 healthy pregnant women (PG; gestational age, 37.0 ± 0.2 wk) and 17 nonpregnant controls (CG) were compared at rest and during cycling at 70 and 110% of the ventilatory threshold (VT). At rest, ANG II concentration was significantly ( P < 0.05) higher in PG vs. CG, whereas plasma osmolality and concentrations of AVP, sodium, and potasium were significantly lower. Atrial natriuretic peptide concentration at rest was similar between groups. ANG II and AVP concentrations increased significantly from rest to 110% VT in CG only, whereas increases in atrial natriuretic peptide concentration were similar between groups. Increases in osmolality, and total protein and albumin concentrations from rest to both work rates were similar between the two groups. PG and CG exhibited similar shifts in fluid during acute short-term exercise, but the increases in ANG II and AVP were absent and attenuated, respectively, during pregnancy. This was attributed to the significantly augmented fluid volume state already present at rest in late gestation.
Invited Review: Uncoupling proteins and thermoregulation
Authors: Argyropoulos George , Harper Mary-Ellen
Published: March 2015

Energy balance in animals is a metabolic state that exists when total body energy expenditure equals dietary energy intake. Energy expenditure, or thermogenesis, can be subcategorized into groups of obligatory and facultative metabolic processes. Brown adipose tissue (BAT), through the activity of uncoupling protein 1 (UCP1), is responsible for nonshivering thermogenesis, a major component of facultative thermogenesis in newborn humans and in small mammals. UCP1, found in the mitochondrial inner membrane in BAT, uncouples energy substrate oxidation from mitochondrial ATP production and hence results in the loss of potential energy as heat. Mice that do not express UCP1 (UCP1 knockouts) are markedly cold sensitive. The recent identification of four new homologs to UCP1 expressed in BAT, muscle, white adipose tissue, brain, and other tissues has been met by tremendous scientific interest. The hypothesis that the novel UCPs may regulate thermogenesis and/or fatty acid metabolism guides investigations worldwide. Despite several hundred publications on the new UCPs, there are a number of significant controversies, and only a limited understanding of their physiological and biochemical properties has emerged. The discovery of UCP orthologs in fish, birds, insects, and even plants suggests the widespread importance of their metabolic functions. Answers to fundamental questions regarding the metabolic functions of the new UCPs are thus pending and more research is needed to elucidate their physiological functions. In this review, we discuss recent findings from mammalian studies in an effort to identify potential patterns of function for the UCPs.
Clenbuterol prevents epinephrine from antagonizing insulin-stimulated muscle glucose uptake
Authors: Hunt Desmond G. , Ding Zhenping , Ivy John L.
Published: March 2015

In the present study, we investigated the effects of chronic clenbuterol treatment on insulin-stimulated glucose uptake in the presence of epinephrine in isolated rat skeletal muscle. Insulin (50 μU/ml) increased glucose uptake in both fast-twitch (epitrochlearis) and slow-twitch (soleus) muscles. In the presence of 24 nM epinephrine, insulin-stimulated glucose uptake was completely suppressed. This suppression of glucose uptake by epinephrine was accompanied by an increase in the intracellular concentration of glucose 6-phosphate and a decrease in insulin-receptor substrate-1-associated phosphatidylinositol 3-kinase (IRS-1/PI3-kinase) activity. Clenbuterol treatment had no direct effect on insulin-stimulated glucose uptake. However, after clenbuterol treatment, epinephrine was ineffective in attenuating insulin-stimulated muscle glucose uptake. This ineffectiveness of epinephrine to suppress insulin-stimulated glucose uptake occurred in conjunction with its inability to increase the intracellular concentration of glucose 6-phosphate and attenuate IRS-1/PI3-kinase activity. Results of this study indicate that the effectiveness of epinephrine to inhibit insulin-stimulated glucose uptake is severely diminished in muscle from rats pretreated with clenbuterol.
Metabolic determinants of the onset of acidosis in exercising human muscle: a 31P-MRS study
Authors: Roussel M. , Mattei J. P. , Le Fur Y. , Ghattas B. , Cozzone P. J. , Bendahan D.
Published: March 2015

Onset of intracellular acidosis during muscular exercise has been generally attributed to activation or hyperactivation of nonoxidative ATP production but has not been analyzed quantitatively in terms of H+ balance, i.e., production and removal mechanisms. To address this issue, we have analyzed the relation of intracellular acidosis to H+balance during exercise bouts in seven healthy subjects. Each subject performed a 6-min ramp rhythmic exercise (finger flexions) at low frequency (LF, 0.47 Hz), leading to slight acidosis, and at high frequency (HF, 0.85 Hz), inducing a larger acidosis. Metabolic changes were recorded using 31P-magnetic resonance spectroscopy. Onset of intracellular acidosis was statistically identified after 3 and 4 min of exercise for HF and LF protocols, respectively. A detailed investigation of H+ balance indicated that, for both protocols, nonoxidative ATP production preceded a change in pH. For HF and LF protocols, H+ consumption through the creatine kinase equilibrium was constant in the face of increasing H+ generation and efflux. For both protocols, changes in pH were not recorded as long as sources and sinks for H+approximately balanced. In contrast, a significant acidosis occurred after 4 min of LF exercise and 3 min of HF exercise, whereas the rise in H+ generation exceeded the rise in H+ efflux at a nearly constant H+ uptake associated with phosphocreatine breakdown. We have clearly demonstrated that intracellular acidosis in exercising muscle does not occur exclusively as a result of nonoxidative ATP production but, rather, reflects changes in overall H+ balance.
Effects of chronic sympathectomy on vascular function in the human forearm
Authors: Eisenach John H. , Clark Erin S. , Charkoudian Nisha , Dinenno Frank A. , Atkinson John L. D. , Fealey Robert D. , Dietz Niki M. , Joyner Michael J.
Published: March 2015

To determine whether endothelial function is altered by chronic surgical sympathectomy, we infused ACh, isoproterenol, nitroprusside (NTP), and the nitric oxide synthase inhibitor N G-mono-methyl-l-arginine (l-NMMA) into the brachial arteries of nine patients 5–64 mo after thoracic sympathectomy for hyperhidrosis. Age- and gender-matched controls were also studied. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Lower body negative pressure was used to assess reflex vasoconstrictor responses. Tyramine, which acts locally and causes norepinephrine release from sympathetic nerves, was also administered via the brachial artery. FBF at rest was 2.5 ± 0.4 ml · dl−1 · min−1 in the patients and 2.5 ± 0.3 ml · dl−1 · min−1 in the controls ( P = 0.95). The normal vasoconstrictor responses to lower body negative pressure were abolished in the patients. By contrast, tyramine produced dose-dependent vasoconstriction in the patients that was identical to that of controls. The dose-response curves to ACh were similar in patients and controls, with maximum values of 19.3 ± 4.4 vs. 25.5 ± 2.8 ml · dl−1 · min−1, respectively. l-NMMA reduced baseline FBF similarly and reduced the maximal FBF response to ACh in both groups (patients 8.9 ± 3.5 vs. controls 9.7 ± 2.5 ml · dl−1 · min−1). The vasodilation to isoproterenol was similar and blunted to the same extent in both groups by l-NMMA. The responses to NTP in patients and controls were similar and not affected byl-NMMA. We conclude that, in humans, chronic surgical sympathectomy does not cause major disruptions in vascular function in the forearm. The normal vasoconstrictor responses to tyramine indicate that there were viable sympathetic nerves in the forearm that were not engaged by LBNP.
Peri-OVLT E-series prostaglandins and core temperature do not increase after intravenous IL-1β in pregnant rats
Authors: Fewell James E. , Eliason Heather L. , Auer Roland N.
Published: March 2015

Rats have an attenuated febrile response to endogenous pyrogen near the term of pregnancy. Given the fundamental role of E-series prostaglandins (PGEs) in mediating the febrile response to blood-borne endogenous pyrogen, the present experiments were carried out to determine whether PGEs increase in the area surrounding the organum vasculosum laminae terminalis (peri-OVLT) of near-term pregnant (P) rats as in nonpregnant (NP) rats after intravenous (iv) administration of recombinant rat interleukin-1β (rrIL-1β). Core temperature was measured by telemetry and peri-OVLT interstitial fluid was sampled in 12 NP and 12 P chronically instrumented, Sprague-Dawley rats by microdialysis for determination of total PGEs by radioimmunoassay. Basal core temperatures were higher in NP compared with P rats (NP 37.9°C ± 0.5, P 36.9°C ± 0.4; P < 0.05), but basal peri-OVLT PGEs were similar in both groups (NP 260 ± 153 pg/ml, P 278 ± 177 pg/ml; P =not significant). Intravenous administration of rrIL-1β to NP rats produced a significant increase in core temperature with a latency, magnitude, and duration of 10 min, 0.87°C, and at least 170 min, respectively; peri-OVLT PGEs were increased significantly by 30 min and averaged 270% above basal levels throughout the experiment. In P rats, however, neither core temperature nor peri-OVLT PGEs increased significantly after iv administration of rrIL-1β. Intravenous administration of vehicle did not significantly alter core temperature or peri-OVLT PGEs in either group of rats. Thus peri-OVLT PGEs do not increase in P rats as they do in NP rats after iv administration of rrIL-1β. The mechanism of this interesting component of the maternal adaptation to pregnancy, which likely plays a major role in mediating the attenuated febrile response to endogenous pyrogen near the term of pregnancy, warrants further investigation.
Genetic variability in forced and voluntary endurance exercise performance in seven inbred mouse strains
Authors: Lerman Imanuel , Harrison Brooke C. , Freeman Kalev , Hewett Timothy E. , Allen David L. , Robbins Jeffrey , Leinwand Leslie A.
Published: March 2015

The goal of this study was to characterize the genetic contribution to both forced and voluntary exercise performance and to determine whether performance in these two paradigms is controlled by similar genetic influences. There were marked strain differences in treadmill exercise performance, with Swiss Webster (SW) and FVB/NJ mice showing elevated performance and C57BL/6J animals showing decreased performance compared with all other strains. There was no apparent relationship between treadmill performance and voluntary wheel performance, with the exception of SW mice, which demonstrated high performances on both the treadmill and the voluntary wheel. Numerous properties were measured to attempt to understand the basis for these differences in exercise performance. DBA/1J and SW mice exhibited significantly greater cardiac contractility than all other analyzed strains. Conversely, BALB/cByJ mice exhibited significantly reduced cardiac contractility compared with all other strains. Expression of molecular indicators of hypertrophy (atrial natriuretic factor and β-myosin heavy chain) was significantly elevated in DBA/2J myocardium compared with all other analyzed strains.
Metabolic and appetite responses to prolonged walking under three isoenergetic diets
Authors: Ainslie P. N. , Abbas K. , Campbell I. T. , Frayn K. N. , Harvie M. , Keegan M. A. , MacLaren D. P. M. , Macdonald I. A. , Paramesh K. , Reilly T.
Published: March 2015

The effects of three isoenergetic diets on metabolic and appetite responses to prolonged intermittent walking were investigated. Eight men undertook three 450-min walks at intensities varying between 25–30 and 50–55% of maximal O2 uptake. In a balanced design, the subjects were given breakfast, snacks, and lunch containing total carbohydrate (CHO), protein (P), and fat (F) in the following amounts (g/70 kg body mass): mixed diet, 302 CHO, 50 P, 84 F; high-CHO diet, 438 CHO, 46 P, 35 F; high-fat diet, 63 CHO, 44 P, 196 F. Substrate balance was calculated by indirect calorimetry over the 450-min exercise period. Blood samples were taken before exercise and every 45 min during the exercise period. The high-fat diet resulted in a negative total CHO balance (−140 ± 1 g) and a lower negative fat balance (−110 ± 33 g) than the other two diets ( P < 0.05). Plasma glucagon, nonesterified fatty acids, glycerol, and 3-hydroxybutyrate were higher with the high-fat diet ( P < 0.05 vs. high CHO), whereas plasam insulin was lower after high fat ( P < 0.05 vs. mixed and high CHO). Subjective ratings of fatigue and appetite showed no differences between the three trials. Although diet influenced the degree of total CHO and fat oxidation, fat was the main source of enery in all trials.
Measurement of gluconeogenesis in exercising men by mass isotopomer distribution analysis
Authors: Trimmer Jeff K. , Schwarz Jean-Marc , Casazza Gretchen A. , Horning Michael A. , Rodriguez Nestor , Brooks George A.
Published: March 2015

We evaluated the hypothesis that coordinated adjustments in absolute rates of gluconeogenesis (GNGab) and hepatic glycogenolysis (Gly) would maintain euglycemia and match glucose production (GP) to peripheral utilization during rest and exercise. Specifically, we evaluated the extent to which gradations in exercise power output would affect the contribution of GNGabto GP. For these purposes, we employed mass isotopomer distribution analysis (MIDA) and isotope-dilution techniques on eight postabsorptive (PA) endurance-trained men during 90 min of leg cycle ergometry at 45 and 65% peak O2consumption (V˙o2 peak; moderate and hard intensities, respectively) and the preceding rest period. GP was constant in resting subjects, whereas the fraction from GNG (fGNG) increased over time during rest (22.3 ± 0.9% at 11.25 h PA vs. 25.6 ± 0.9% at 12.0 h PA, P < 0.05). In the transition from rest to exercise, GP increased in an intensity-dependent manner (rest, 2.0 ± 0.1; 45%, 4.0 ± 0.4; 65%, 5.84 ± 0.64 mg · kg−1· min−1, P < 0.05), although glucose rate of disappearance exceeded rate of appearance during the last 30 min of exercise at 65%V˙o2 peak. Compared with rest, increases in GP were sustained by 92 and 135% increments in GNGabduring moderate- and hard-intensity exercises, respectively. Correspondingly, Gly (calculated as the difference between GP and MIDA-measured GNGab) increased 100 and 203% over rest during the two exercise intensities. During moderate-intensity exercise, fGNGwas the same as at rest; however, during the harder exercise fGNGdecreased significantly to account for only 21% of GP. The highest sustained GNGabobserved in these trials on PA men was 1.24 ± 0.3 mg · kg−1· min−1. We conclude that, after an overnight fast, 1) absolute GNG rates increased with intensity of effort despite a reduced fGNGat 65% V˙o2 peak, 2) during exercise Gly is more responsible than GNGabfor maintaining GP, and 3) in 12-h fasted men, neither increased Gly or GNGabnor was their combination able to maintain euglycemia during prolonged hard (65%V˙o2 peak) exercise.
Ventilatory response of the cat to hypoxia in sleep and wakefulness
Authors: Lovering Andrew T. , Dunin-Barkowski Witali L. , Vidruk Edward H. , Orem John M.
Published: March 2015

This study characterized ventilation, the airflow waveform, and diaphragmatic activity in response to hypoxia in the intact adult cat during sleep and wakefulness. Exposure to hypoxia for up to 3 h caused sustained hyperventilation during both wakefulness and sleep. Hyperventilation resulted from significant increases in minute ventilation due to increases in both tidal volume and frequency. Diaphragmatic activity changed significantly from augmenting activity with little postinspiratory-inspiratory activity (PIIA) in normoxia to augmenting activity with increased PIIA in hypoxia. The increase in PIIA was least in rapid eye movement sleep. These changes in diaphragmatic activity were associated with changes in airflow waveforms in inspiration and expiration. We conclude that the ventilatory response to hypoxia involves a change in the output of the central pattern generator and that the change is dependent in part on the state of consciousness.
On the respiratory function of the ribs
Authors: Cappello Matteo , De Troyer André
Published: March 2015

To assess the respiratory function of the ribs, we measured the changes in airway opening pressure (Pao) induced by stimulation of the parasternal and external intercostal muscles in anesthetized dogs, first before and then after the bony ribs were removed from both sides of the chest. Stimulating either set of muscles with the rib cage intact elicited a fall in Pao in all animals. After removal of the ribs, however, the fall in Pao produced by the parasternal intercostals was reduced by 60% and the fall produced by the external intercostals was eliminated. The normal outward curvature of the rib cage was also abolished in this condition, and when the curvature was restored by a small inflation, external intercostal stimulation consistently elicited a rise rather than a fall in Pao. These findings thus confirm that the ribs play a critical role in the act of breathing by converting intercostal muscle shortening into lung volume expansion. In addition, they carry the compression that is required to balance the pressure difference across the chest wall.
Reduced amount of mitochondrial DNA in aged human muscle
Authors: Welle Stephen , Bhatt Kirti , Shah Bharati , Needler Nancy , Delehanty Joseph M. , Thornton Charles A.
Published: March 2015

Muscle concentrations of mRNAs encoded by mitochondrial DNA (mtDNA) decline with aging. To determine whether this can be explained by diminished mtDNA levels, we measured the relative concentrations of mtDNA and a representative mtDNA transcript [encoding cytochrome- coxidase, subunit 2 (COX-2)] in muscle of young (21–27 yr) and older subjects (65–75 yr). The amount of COX-2 mRNA (relative to 28S rRNA) was 22% lower ( P = 0.04) in older muscle, and the amount of mtDNA (relative to nuclear DNA) was 38% lower ( P = 0.0002). The average level of mitochondrial transcription factor A (Tfam), a protein essential for mtDNA replication, was similar in younger and older muscle. Tfam mRNA, nuclear respiratory factor-1 mRNA, and several mRNAs encoding proteins required for mtDNA replication were expressed at similar levels in younger and older muscle. The mtDNA concentrations were only weakly related to age-adjusted aerobic fitness (maximal oxygen consumption) and self-reported physical activity levels. We conclude that the lower concentration of mitochondrial mRNAs in older muscle can be explained by a reduced concentration of mtDNA.
Temporal relation between leukocyte accumulation in muscles and halted recovery 10–20 h after strength exercise
Authors: Raastad Truls , Risøy Bjørn Audun , Benestad Haakon Breien , Fjeld Jan Gunnar , Hallén Jostein
Published: March 2015

Effects of normal strength exercise on leukocyte accumulation were examined in 10 well-trained male subjects (27.2 ± 2.7 yr). The workout, consisting of five maximal sets of three repetitions of leg press exercise and five maximal sets of six repetitions of knee extension exercise, was performed with the dominant leg, and the other leg served as control. Repeated maximal isokinetic knee extensions at 60°/s were performed to evaluate neuromuscular fatigue and recovery after the workout. Accumulation of leukocytes was assessed with 99mTc-labeled cells, and repeated images of the thighs were taken 1–24 h after the workout. Maximal force-generating capacity in the exercised leg was reduced by 17 ± 2% ( P < 0.01) after the workout. The course of recovery followed a biphasic pattern characterized by halted recovery 10–23 h after exercise. The presence of leukocytes was ∼10% higher in the exercised than in the control thigh 10 h after exercise ( P < 0.05). This difference increased to ∼15% at 20 h after exercise ( P < 0.05). The retarded recovery of maximal force-generating capacity 10–20 h after exercise, together with a significant infiltration of leukocytes in exercised muscle during the same time interval, shows a temporal relation between leukocyte infiltration and impaired recovery.
Effect of creatine supplementation on oxygen uptake kinetics during submaximal cycle exercise
Authors: Jones Andrew M. , Carter Helen , Pringle Jamie S. M. , Campbell Iain T.
Published: March 2015

The purpose of this study was to test the effect of oral creatine (Cr) supplementation on pulmonary oxygen uptake (V˙o 2) kinetics during moderate [below ventilatory threshold (VT)] and heavy (above VT) submaximal cycle exercise. Nine subjects (7 men; means ± SD: age 28 ± 3 yr, body mass 73.2 ± 5.6 kg, maximalV˙o 2 46.4 ± 8.0 ml · kg−1 · min−1) volunteered to participate in this study. Subjects performed transitions of 6-min duration from unloaded cycling to moderate (80% VT; 8–12 repeats) and heavy exercise (50% change; i.e., halfway between VT and maximal V˙o 2; 4–6 repeats), both in the control condition and after Cr loading, in a crossover design. The Cr loading regimen involved oral consumption of 20 g/day of Cr monohydrate for 5 days, followed by a maintenance dose of 5 g/day thereafter. V˙o 2 was measured breath by breath and modeled by using two (moderate) or three (heavy) exponential terms. For moderate exercise, there were no differences in the parameters of the V˙o 2 kinetic response between control and Cr-loaded conditions. For heavy exercise, the time-based parameters of the V˙o 2response were unchanged, but the amplitude of the primary component was significantly reduced with Cr loading (means ± SE: control 2.00 ± 0.12 l/min; Cr loaded 1.92 ± 0.10 l/min; P < 0.05) as was the end-exerciseV˙o 2 (control 2.19 ± 0.13 l/min; Cr loaded 2.12 ± 0.14 l/min; P < 0.05). The magnitude of the reduction in submaximalV˙o 2 with Cr loading was significantly correlated with the percentage of type II fibers in the vastus lateralis ( r = 0.87; P < 0.01; n = 7), indicating that the effect might be related to changes in motor unit recruitment patterns or the volume of muscle activated.
Experimental and calculated parameters on particle phagocytosis by alveolar macrophages
Authors: Camner Per , Lundborg Margot , Låstbom Lena , Gerde Per , Gross Norma , Jarstrand Connie
Published: March 2015

Phagocytosis of three types of fluorescein-labeled test particles by rat alveolar macrophages (AM) were studied: spherical silica (3.2 μm), heat-killed Candida albicans (3.8 μm), and heat-killed Cryptococcus neoformans (6.1 μm) opsonized with specific IgG. These particles should attach to scavenger, mannose, and Fc receptors, respectively. Both control AM and AM pretreated for 20 h with interferon-γ (12.5 or 50 U/ml) were studied. The sum of the number of attached and ingested particles per AM (accumulated attachment) was used as a measure of the attachment process, and the number of ingested particles per AM divided by the accumulated attachment (ingested fraction) was used as a measure of the ingestion process. The average ingestion time (IT), which is also a measure of the ingestion process, was calculated from the experimental data. The ingestion process was independent of the attachment process. IT increased with the time of observation. This is explained by the fact that IT determined from observation times shorter than the whole distribution of IT for a certain particle results in a shorter IT than the real average IT. C. albicans (mannose receptor) had the fastest ingestion process, C. neoformans opsonized with specific IgG (Fc receptor) had ingestion that was nearly as fast, and the silica particles (scavenger receptors) had the slowest ingestion process. Treatment with interferon-γ markedly impaired the attachment process for all three types of particles (and three types of receptors) but clearly impaired the ingestion process only for silica particles (scavenger receptors).
Changes in MCT 1, MCT 4, and LDH expression are tissue specific in rats after long-term hypobaric hypoxia
Authors: McClelland Grant B. , Brooks George A.
Published: March 2015

Little is known about the effect of chronic hypobaric hypoxia on the enzymes and transporters involved in lactate metabolism. We looked at the protein expression of monocarboxylate transporters MCT 1, MCT 2, and MCT 4, along with total lactate dehydrogenase (LDH) and LDH isozymes in skeletal muscle, cardiac muscle, and liver. Expression of these components of the lactate shuttle affects the ability to transport and oxidize lactate. We hypothesized that the expression of MCTs and LDH would increase after acclimation to high altitude (HA). The response to acclimation to HA was, however, tissue specific. In addition, the response was different in whole muscle (Mu) and mitochondria-enriched (Mi) fractions. Heart, soleus, and plantaris muscles showed the greatest response to HA. Acclimation resulted in a 34% increase in MCT 4 in heart and a decrease in MCT 1 (−47%) and MCT 4 (−47%) in plantaris Mu. In Mi fractions, the heart had an increase (+40%) and soleus a decrease (−40%) in LDH. HA also had a significant effect on the LDH isozyme composition of both the Mu and Mi fractions. Mitochondrial density was decreased in both the soleus (−17%) and plantaris (−44%) as a result of chronic hypoxia. We conclude that chronic hypoxia had a tissue-specific effect on MCTs and LDH (that form the lactate shuttle) but did not produce a consistent increase in these components in all tissues.
Selected Contribution: Merosin deficiency leads to alterations in passive and active skeletal muscle mechanics
Authors: Jannapureddy Suneal R. , Patel Nisha D. , Hwang Willy , Boriek Aladin M.
Published: March 2015

The role of extracellular elements on the mechanical properties of skeletal muscles is unknown. Merosin is an essential extracellular matrix protein that forms a mechanical junction between the sarcolemma and collagen. Therefore, it is possible that merosin plays a role in force transmission between muscle fibers and collagen. We hypothesized that deficiency in merosin may alter passive muscle stiffness, viscoelastic properties, and contractile muscle force in skeletal muscles. We used the dy/dy mouse, a merosin-deficient mouse model, to examine changes in passive and active muscle mechanics. After mice were anesthetized and the diaphragm or the biceps femoris hindlimb muscle was excised, passive length-tension relationships, stress-relaxation curves, or isometric contractile properties were determined with an in vitro biaxial mechanical testing apparatus. Compared with controls, extensibility was smaller in the muscle fiber direction and the transverse fiber direction of the mutant mice. The relaxed elastic modulus was smaller in merosin-deficient diaphragms compared with controls. Interestingly, maximal muscle tetanic stress was depressed in muscles from the mutant mice during uniaxial loading but not during biaxial loading. However, presence of transverse passive stretch increases maximal contractile stress in both the mutant and normal mice. Our data suggest that merosin contributes to muscle passive stiffness, viscoelasticity, and contractility and that the mechanism by which force is transmitted between adjacent myofibers via merosin possibly in shear.