Physiological Reports

Autonomic nervous system (ANS) activity causes acute variations in the blood pressure. Blood pressure responds to high intensity interval exercise (HIIE) repeatedly during alternating intensities, however, ANS response to the changing intensities of HIIE is unknown. We characterized the response of beat-to-beat blood pressure variability (BTB BPV) to an acute bout of HIIE using coefficient of variation (CoV) and spectral low frequency [LF], and high frequency [HF] domains. Our hypotheses were mean arterial pressure BTB BPV, would increase during 1) high intensity and 2) active recovery of HIIE compared to baseline (BL). BTB BPV would reduce during 1) cool down 2) post HIIE 3) 30 minutes post HIIE compared to BL in young adults. HIIE included bouts of 1-minute high-intensity separated by 1-minute recovery ({square}70% and 10% estimated Wattmax) for total of 10 minutes on a recumbent stepper. A secondary analysis was performed using twenty-one datasets of young individuals (age 25{+/-}1.5, 48% female). During high intensity, LF and HF increased compared to BL (p < 0.05) indicating increased sympathetic activity and breathing. During active recovery, LF and HF remained elevated above BL and were greater than during high intensity (p [&le;] 0.02). Sympathetic activity reduced back to BL immediately post HIIE but returned to being higher than BL at 30 minutes after HIIE (p=0.001). BTB BPV CoV also increased during HIIE compared to BL (p<0.05). Results suggest that young healthy individuals have increased BTB BPV during HIIE suggesting cardiovascular system responds to ANS fluctuations during changing exercise intensity. New and NoteworthyThis novel study analyzed beat -to-beat blood pressure variability during high intensity interval exercise (HIIE) in young healthy adults. We found that blood pressure variability was highest during active recovery compared to resting or high intensity exercise. Moreover, variability increased during HIIE but returned to resting post-exercise. These findings provide valuable insights into the blood pressure and ANS responses to HIIE, contributing to our understanding of their impact on overall cardiovascular health in young adults.

The increase in plasma volume [~]24 hours post-exercise may act as an erythropoietic signal, but this mechanisms responsiveness to different exercise prescription variables is poorly understood. The purpose of this study was to determine the impact of high-intensity interval exercise duration on plasma volume and related responses. On separate days, 16 healthy, recreationally active participants (n=8 males; n=8 females) performed four (4x4) or eight intervals (8x4) consisting of 4 min at 105% critical power with 3 min recovery. Venous blood samples collected before, immediately after, and 24 hours after each HIIT session were used to measure hemoglobin concentration and hematocrit to calculate plasma volume changes. Erythropoietic and plasma volume regulating hormone concentrations were measured using ELISA kits. Plasma volume decreased immediately after both protocols (4x4: -4.4{+/-}3.5%, p<0.05; 8x4: -4.4{+/-}3.6%, p<0.05) but was only significantly elevated above baseline 24 hours after the 8x4 protocol (4x4: +1.0{+/-}7.1%, p>0.05; 8x4: +5.6{+/-}4.6%, p<0.05). Erythropoietin concentration ([EPO]) was higher than baseline 24 hours after the HIIT protocols (4x4: Pre vs 24 h post: 6.5{+/-}3.1 vs. 7.1{+/-}3.3 mIU/mL; 8x4: 6.9{+/-}3.7 vs. 7.3{+/-}3.7 mIU/mL; main effect of time, p<0.05) with no difference between protocols (p>0.05). [Aldosterone] was elevated immediately post-exercise after both protocols (4x4: Pre vs 0 h post: 295{+/-}151 vs. 544{+/-}259 pg/mL; 8x4: 335{+/-}235 vs. 821{+/-}553 pg/mL), but the 8x4 protocol caused a larger increase (interaction effect, p<0.05). That post-exercise hypervolemia may be exercise duration-dependent but is not required for increases in circulating EPO has important implications for endurance training aiming to increase oxygen delivery to active tissues. NEWS AND NOTEWORTHYThis study is the first to show that both a common HIIT protocol length (4 x 4 min) and an extended HIIT protocol (8 x 4 min) similarly increased [erythropoietin] 24 h after exercise, despite only the extended protocol transiently increasing plasma volume. Previous works have investigated plasma volume regulation following different HIIT durations, but not explored links to erythropoietic signalling. This studys findings have relevance for understanding the physiology of exercise-induced erythropoiesis.

The short-term scaling exponent of detrended fluctuation analysis (DFA1) applied to interbeat intervals may provide a method to identify ventilatory thresholds and indicate systemic perturbation during prolonged exercise. The purposes of this study were to i) confirm whether DFA1 values of 0.75 and 0.5 coincide with the gas exchange threshold (GET) and respiratory compensation point (RCP), ii) quantify DFA1 during constant-speed running near the maximal lactate steady state (MLSS), and iii) assess the repeatability of DFA1 between MLSS trials. Seventeen runners performed an incremental running test, and eleven and ten runners also performed constant-speed running 5% below, at, and 5% above the MLSS, and a repeat trial at MLSS, respectively. GET (bias [LOA]: -3.6 [-9.1 to 1.9] mL{middle dot}kg-1{middle dot}min-1) and RCP (-3.5 [-14.1 to 7.2] mL{middle dot}kg-1{middle dot}min-1) were overestimated using DFA1. DFA1 responses during 30-min running trials near MLSS were variable (i.e., 0.27 to 1.24), and affected by intensity (p=0.019) and duration (p=0.001). No difference in DFA1 was detected between MLSS trials (p=0.926). These results question whether DFA1 values can accurately delineate exercise thresholds, but the dependency of DFA1 on intensity and duration support its potential use to quantify systemic perturbations imposed by continuous exercise.

Calcium ion concentration modulates the function of pyruvate dehydrogenase, isocitrate dehydrogenase, and -ketoglutarate dehydrogenase. Previous studies have shown that despite its ability to affect the function of these dehydrogenases, [Ca2+] does not substantially alter mitochondrial ATP synthesis in vitro under physiological sub-strate conditions. We hypothesize that, rather than contributing to respiratory control, [Ca2+] governs fuel selection. Specifically, cardiac mitochondria are able to use different primary carbon substrates to synthesize ATP aerobically. To determine if and how [Ca2+] affects the relative use of carbohydrates versus fatty acids we measured oxygen consumption and tricarboxylic acid cycle intermediate concentrations in suspensions of cardiac mitochondria with different combinations of pyruvate and palmitoyl-L-carnitine in the media at various [Ca2+] and ADP infusion rates. Results reveal that when both fatty acid and carbohydrate substrates are available, fuel selection is sensitive to both calcium and ATP synthesis rate. When no Ca2+ is added under low ATP-demand conditions, {beta}-oxidation provides roughly half of acetyl-CoA for the citrate synthase reaction with the rest coming from the pyruvate dehydrogenase reaction. Under low demand conditions with increasing [Ca2+], the fuel utilization ratio shifts to increased fractional consumption of pyruvate, with 83{+/-}10% of acetyl-CoA derived from pyruvate at the highest [Ca2+] evaluated. With high ATP demand, the majority of acetyl-CoA is derived from pyruvate, regardless of the Ca2+ level. Our results suggest that changes in work rate alone are enough to effect a switch to carbohydrate use while in vivo the rate at which this switch happens may depend on mitochondrial calcium.\n\nKey PointsO_LIDespite its effects on activity of mitochondrial dehydrogenases, Ca2+ does not substantially alter mitochondrial ATP synthesis in vitro under physiological substrate conditions. Nor does is appear to play an important role in respiratory control in vivo in the myocardium.\nC_LIO_LIWe hypothesize that Ca2+ plays a role mediating the switch in fuel selection to increasing carbohydrate oxidation and decreasing fatty acid oxidation with increasing work rate.\nC_LIO_LITo determine if and how Ca2+ affects the relative use of carbohydrates versus fatty acids in vitro we measured oxygen consumption and TCA cycle intermediate concentrations in suspensions of purified rat ventricular mitochondria with carbohydrate, fatty acid, and mixed substrates at various [Ca2+] and ATP demand rates.\nC_LIO_LIOur results suggest that changes in work rate alone are enough to effect a switch to carbohydrate use in vitro while in vivo the rate at which this switch happens may depend on mitochondrial calcium.\nC_LI

We measured plasma levels of fibrinogen, plasminogen, tissue plasminogen activator (t-PA) and plasminogen activation inhibitor 1 (PAI-1) in blood from 37 patients with severe coronavirus disease-19 (COVID-19) and 23 controls. PAI-1, t-PA and fibrinogen levels were significantly higher in the COVID-19 group. Increased levels of PAI-1 likely result in lower plasmin activity and hence decreased fibrinolysis. These observations provide a partial explanation for the fibrin- mediated increase in blood viscosity and hypercoagulability that has previously been observed in COVID-19. Our data suggest that t-PA administration may be problematic, but that other interventions designed to enhance fibrinolysis might prove useful in the treatment of the coagulopathy that is often associated with severe COVID-19.

Systolic and diastolic blood pressures are reported as single point values by the non-invasive techniques used in clinical practice, while, in fact, they are highly varying signals. The objective of this study was to document the magnitude of variation of systolic and diastolic pressures over a few minutes by analysing intra-arterial pressure recordings made in 51 haemodynamically stable patients in an intensive care unit. Intra-arterial pressure data were acquired by a validated data acquisition system. Fast-Flush test was performed and the dynamic characteristics of the catheter transducer system namely natural frequency and damping co-efficient were calculated. Only those recordings with acceptable dynamic characteristics were included in the analysis. Power spectral calculation using the Discrete Fourier transform (DFT) of the pressure recording revealed two frequency peaks below the peak at heart rate. The lower and higher frequency peaks below the heart rate peak are referred to as Mayer and Traube waves in this study. Mayer wave peaks were observed in DFT spectra of 49 out of 51 patients. The Mayer wave frequency peaks ranged between 0.045 Hz to 0.065 Hz in 41 out of 51 patients. The frequency of Traube waves or the respiratory variations was more than 0.14 Hz. Three categories of systolic and diastolic pressure variabilities namely beat-to-beat variability, Respiratory variability (Traube wave amplitude) and Total magnitude of variation are reported for all 51 patients. The mean systolic and diastolic pressure variations (in a period of about 10 minutes) in the study sample were 21 {+/-} 9 mm Hg and 14 {+/-} 5 mm Hg respectively. Given the magnitude of systolic and diastolic pressure variations over a few minutes, the validity of reporting single point values for these pressures and using single point cut-offs for diagnosis and treatment of hypertension must be re-evaluated.

Advances in early cancer detection and treatment have significantly improved survival rates, resulting in over 18.1 million cancer survivors in the United States. Many of these survivors experience chronic pain, fatigue, and neuropathic symptoms related to cancer or its treatments. Emerging evidence suggests that autonomic nervous system dysfunction plays a crucial role in these symptoms. Heart rate variability (HRV), a measure of autonomic function, has shown potential in predicting the onset of somatic symptoms in cancer patients. This systematic review aimed to assess the association of HRV with pain, fatigue, and neuropathy in cancer patients and survivors. A comprehensive search was conducted across multiple databases, yielding 19 studies that met inclusion criteria. These studies varied in cancer types, stages, and HRV measurement methods. Most studies focused on breast cancer and reported a predominant female population. Fatigue was the most studied symptom, followed by pain. HRV measures included both time and frequency domain variables, with significant variability in measurement duration and control for confounding factors. Findings suggest that decreased HRV is associated with increased fatigue and pain, providing potential support for a bidirectional relationship between autonomic dysfunction and these symptoms. However, the heterogeneity in HRV measurement methods and the high risk of bias in many studies highlight the need for standardized HRV protocols in cancer research. Further large-scale studies with low risk of bias are necessary to validate HRV as a reliable tool for phenotyping and managing cancer-related symptoms.

In the United States, cardiovascular disease is the leading cause of death, and the rate of maternal mortality remains among the highest of any industrialized nation. Maternal cardiometabolic health throughout gestation and postpartum is representative of placental health and physiology. Both proper placental functionality and placental microRNA expression are essential to successful pregnancy outcomes, and both are highly sensitive to genetic and environmental sources of variation. While placental pathologies, such as preeclampsia, are associated with maternal cardiovascular health and may contribute to the developmental programming of cardiovascular disease, the role of more subtle alterations to placental function and microRNA expression in this relationship remains poorly understood. To develop a more comprehensive understanding of how cardiometabolic health influences placental microRNA expression, and how this shapes placental functionality, we performed small RNA sequencing to investigate microRNA in the placentae from the Rhode Island Child Health Study (n=230). We modeled microRNA counts on maternal family history of cardiovascular disease using negative binomial generalized linear models, and identified microRNAs that were differential expressed (DEmiRs) at a false discovery rate (FDR) less than 0.10. Utilizing parallel mRNA sequencing data and bioinformatic target prediction software, we identified potential mRNA targets of these DEmiRs. We identified 9 DEmiRs, with predicted targets of those miRNA enriched overwhelmingly in the TGF{beta} signaling pathway but also in pathways involving cellular metabolism and immunomodulation. Overall, we identified a robust association existing between familial cardiovascular disease and placental microRNA expression which may be implicated in both placental insufficiencies and the developmental programming of cardiovascular disease.

Ventilatory thresholds (VT1 and VT2) are critical in exercise prescription and athletic training, delineating the transitions from aerobic to anaerobic metabolism. More specifically, VT1 signifies the onset of lactate accumulation whilst VT2 signifies the onset of metabolic acidosis. Accurate determination of these thresholds is vital for optimizing training intensity. Fractal correlation properties of heart rate variability (HRV), particularly the short-term scaling exponent alpha 1 of Detrended Fluctuation Analysis (DFA-1), have demonstrated potential for this purpose. This study validates the accuracy of commercial ventilatory threshold estimation algorithm (VT-algorithm) developed by Kubios. The VT-algorithm employs instantaneous heart rate (HR) relative to HR reserve and respiratory rate (RF), along with the DFA-1. Sixty-four physically active participants underwent an incremental cardiopulmonary exercise test (CPET) with inter-beat interval (RR) measurements. DFA-1 and the Kubios VT-algorithm were used to assess HR and oxygen uptake (VO2) at ventilatory thresholds. On average VO2 at true VT, DFA-1, and VT-algorithm derived ventilatory thresholds were 1.74, 2.00 and 1.89 l/min (VT1) and 2.40, 2.41 and 2.40 l/min (VT2), respectively. Correspondingly, average HRs at the true VT, DFA-1, and VT-algorithm thresholds were 141, 151 and 142 bpm (VT1) and 169, 168 and 170 bpm (VT2), respectively. When compared to the true thresholds, Bland-Altman error statistics (bias {+/-} standard deviation of error) for the DFA-1 thresholds were -0.26{+/-}0.41 l/min or -10{+/-}16 bpm at VT1 and 0.00{+/-}0.34 l/min or 1{+/-}10 bpm at VT2, whereas the VT-algorithm errors were - 0.15{+/-}0.28 l/min or -1{+/-}11 bpm at VT1 and 0.01{+/-}0.20 l/min or -1{+/-}7 bpm at VT2. HRV based VT determination algorithms accurately estimate ventilatory thresholds, offering insights into training zones, internal loading, and metabolic transitions during exercise without the need of laboratory equipment. The Kubios VT-algorithm, which incorporates instantaneous HR and RF along with DFA-1, provided higher accuracy for VO2 and HR values for both VT1 and VT2.

Fructose high-salt (FHS) diets increase blood pressure (BP) in an angiotensin II (Ang II)-dependent manner. Ang II stimulates aldosterone release, which, by acting on the mineralocorticoid receptor (MR), regulates Na+ reabsorption by the aldosterone-sensitive distal nephron (ASDN). The MR can be transactivated by glucocorticoids, including those locally produced by 11{beta}-HSD1. The epithelial sodium channel (ENaC) is a key transporter regulated by MRs. We hypothesized that fructose-induced salt-sensitive hypertension depends in part on abnormal activation of MRs in the ASDN with consequent increases in ENaC expression. We found that aldosterone-upregulated genes in mice ASDN, significantly overlapped with 74 genes upregulated by FHS in the rat kidney cortex (13/74; p[&le;]1x10-8), and that these 74 genes are prominently expressed in rat ASDN cells. Additionally, the average z-score expression of mice-aldosterone-upregulated genes is highly correlated with FHS compared to glucose high-salt (GHS) in the rat kidney cortex (Pearson correlation; r=0.66; p[&le;]0.005). There were no significant differences in plasma aldosterone concentrations between the FHS and GHS. However, 11{beta}-HSD1 transcripts were upregulated by FHS (log2FC=0.26, p[&le;]0.02). FHS increased BP by 23{+/-}6 mmHg compared to GHS, and blocking MRs with eplerenone prevented this increase. Additionally, inhibiting ENaC with amiloride significantly reduced BP in FHS from 148{+/-}6 to 134{+/-}5 mmHg (p[&le;]0.019). Compared to GHS, FHS increased total and cleaved ENaC protein by 89{+/-}14 % (p[&le;]0.03) and 47{+/-}16 % (p[&le;]0.01) respectively. FHS did not change {beta}- or {gamma}-subunit expression. These results suggest that fructose-induced salt-sensitive hypertension depends, in part, on abnormal Na+ retention by ENaC, resulting from the activation of MRs by glucocorticoids.

Under stressful or exciting conditions, athletes can perform beyond their typical capabilities during a so-called "adrenaline rush." In the preliminary study by one sub-elite runner, we found that even in the fasted state, hyperglycemia occurs during high loaded running by the fact that both blood glucose and interstitial fluid glucose levels rose rapidly to 11-12 mM. This suggests that glycogen in the liver is degraded by anti-stress hormones, leading to an increase in glucose concentration. In the next, we analyzed the temporal changes in interstitial glucose concentration before, during, and after races using continuous glucose monitoring (CGM) data obtained from a total of 36 elite long-distance athletes including walking race (non-fasting state). We found that even healthy subjects recorded high glucose levels (mean 8.3 {+/-} 1.5 mM) before the start of the race and the glucose fluctuations during the race were also recorded at 11.2 {+/-} 2.2 mM, suggesting not only blood glucose level fluctuation due to supplementation before the races, but also due to the effects of stress hormones such as epinephrine, cortisol and glucagon. Furthermore, the mean glucose level during the daytime for the three days before the race event was significantly different by 0.3 mM (p<0.001) compared to the mean during the daytime for the three days after the race. These results suggested that efficient utilization of liver glycogen is important to keep high performance throughout the race, since the liver glycogen also consumed under stress.

BackgroundAnemia is one of the very common complications in Chronic Kidney Disease (CKD) and often included among patients who undergo hemodialysis. A very important aspect of anemia is that erythropoietin (EPO) resistance plays a very major role, whereas the role of inflammation to EPO resistance and impaired erythropoiesis is still poorly understood. ObjectiveThe objective of this study research therefore was to measure the effects of inflammation assessed by C-reactive protein (CRP) on anemia and in response to EPO in CKD patients undergoing hemodialysis here. MethodsThis is a cross-sectional study involving 120 CKD patients undergoing maintenance hemodialysis. Based on their CRP levels, participants were divided into two groups: High Inflammation (CRP [&ge;] 10 mg/L) and Low Inflammation (CRP < 10 mg/L). The hematological parameters such as hematocrit, serum ferritin, transferrin saturation, and EPO dose are evaluated. Statistical Analysis: Group comparisons and correlation analysis to study the relationships between CRP levels, iron status, and EPO resistance. ResultsIn the high inflammation group, hematocrit levels (29.6 {+/-} 4.8%) were significantly lower than in the low inflammation group in a comparison of (34.2 {+/-} 5.2%, p < 0.001). The EPO dose was higher in the high inflammation group (3,200 {+/-} 800 IU/week vs. 2,200 {+/-} 700 IU/week, p < 0.001). Different parameters regarding iron, like serum ferritin and transferrin saturation, were significantly lesser in the high inflammation group. CRP levels had a negative correlation with hematocrit (r = -0.42, p < 0.001) and transferrin saturation (r = -0.36, p < 0.001), while they were found to have a positive correlation with the EPO dose administered (r = 0.48, p < 0.001). ConclusionsInflammation as measured by CRP has an important effect on anemia management in CKD patients undergoing hemodialysis.

Renal hemodynamics, renal transporter expression levels, and urine excretion all exhibit circadian variations. Disturbance of these diurnal patterns is associated with hypertension and chronic kidney disease. Renal hemodynamics determines oxygen delivery, whereas renal transport and metabolism determines oxygen consumption. The balance between oxygen delivery and consumption then yields renal oxygenation. We hypothesized that kidney oxygenation also demonstrates 24-h periodicity. Another notable modulator of kidney function is sex, which has impacts on renal hemodynamics and transport function that are regulated by as well as independent of the circadian clock. The goal of this study was to investigate the diurnal and sexual variations in renal oxygen consumption and oxygenation. For this purpose, we developed computational models of rat kidney function that represent sexual dimorphism and circadian variation in renal hemodynamics and transporter activities. Model simulations predicted substantial differences in tubular Na+ transport and oxygen consumption among different nephron segments. We also simulated the effect of loop diuretics, which are used in the treatment of renal hypoxia, on the outer medullary oxygen tension. Our model predicted a significantly higher effect of loop diuretics on renal oxygenation in female rats compared to male rats. In addition, loop diuretics were more effective when administered during the active phase.

The response of hemodynamic parameters in healthy volunteers to changes in alveolar pressure and lung volume was studied by noninvasive methods during respiratory maneuvers similar to Valsalva and Muller maneuvers (in a sitting position and lying on the back horizontally). The following lung volumes and values of pressure (relative to atmospheric pressure) were considered in various combinations: total lung capacity, functional residual capacity, residual volume, -30, -15, 0, +15, +30 mmHg. Changes in hemodynamic parameters averaged over the duration of a maneuver were studied (the duration of a maneuver was 30 s). Changes in alveolar and, accordingly, intrathoracic pressure influenced hemodynamic more strongly than changes in lung volume or body position. Stroke volume decreased with increasing alveolar pressure and increased with decreasing pressure regardless of lung volume and body position; changes ranged from -35 to +15 ml. The effect of changes in alveolar pressure was more pronounced in a sitting position. Heart rate increased with increasing alveolar pressure (up to +20 bpm) but changed little with decrease in pressure. Mean arterial pressure decreased with decreasing alveolar pressure regardless of lung volume and body position; with increasing alveolar pressure, the result depended on lung volume. When performing maneuvers at total lung capacity, mean arterial pressure remained below baseline values, in other cases it increased. Changes in mean arterial pressure were within {+/-}20 mmHg. Regardless of lung volume and body position, total peripheral resistance decreased with decreasing alveolar pressure and increased with increasing alveolar pressure; the range of changes in total peripheral resistance was -0.3 to +0.7 mmHg{middle dot}s/ml.

In white fat adipocytes voltage-gated Ca2+ channels are constitutively active. Since the adipocyte membrane potential (Vm) is controlled by Cl- we investigated if changes in [Cl-]o can affect the activity of voltage-gated Ca2+ channels and intracellular calcium, [Ca2+]i. Adipocytes were isolated from epididymal fat of CD-1 mice. [Ca2+]i was imaged with epifluorescent microscopy at 28{degrees}C. Constitutive voltage-gated channel activity was confirmed by the ability of verapamil to decrease [Ca2+]i. Substitution of [Cl-]o to 113, 53 and 18 mM with the membrane impermeant gluconate anion decreased [Ca2+]i from 114{+/-}8.7 to 106{+/-}7.5, 101{+/-}7.1 and 97{+/-}6 nM respectively. Substitution of [Cl-]o with glutamate mimicked the ability of gluconate to decrease [Ca2+]i. To explore if anions affected [Ca2+]i via chelation of external Ca2+, [Ca2+]o was analyzed by potentiometry. Gluconate, glutamate, aspartate and methylsulphonate had Ca2+ association constants of 17{+/-}1.8, 12{+/-}1, 8.2{+/-}4.1 and 3.3{+/-}0.5 L-1 M respectively. Substitution of 134 mM [Cl-]o with gluconate decreased [Ca2+]o from 2.6 mM to 200 M; the effect of this anion on [Ca2+]i was mimicked by a decrease of [Ca2+]o to 200 M in standard [Cl-]o solution. Conversely, titration of [Ca2+]o from 200 M back to 2.6 mM in 134 mM gluconate solutions abolished the effect of this anion on [Ca2+]i. Substitution of [Cl-]o with methylsulphonate to affect Vm did not affect [Ca2+]i. Whereas, growth hormone at 10-20 nM increased [Ca2+]i, an effect blocked by verapamil or absence of [Ca2+]o. In conclusion, growth hormone, but not changes in Vm, can increase voltage-gated Ca2+ channel activity and [Ca2+]i in white fat adipocytes. Key pointsO_LI[Ca2+]i plays a key role in the metabolic and endocrine functions of white fat adipocytes. C_LIO_LIIn adipocytes basal [Ca2+]i is maintained by voltage-gated Ca2+ channels constitutively active at their resting membrane potential, Vm, which is predominantly controlled by Cl- permeability. C_LIO_LISubstitution of [Cl-]o to depolarize Vm with gluconate or glutamate, did not increase but decreased [Ca2+]i. an action due to chelation of extracellular Ca2+. This effect was not seen with methylsulphonate, which did no chelate Ca2+ but did not affect [Ca2+]i. C_LIO_LIGrowth hormone elevated, [Ca2+]i an effect blocked by inhibitors of voltage-gated Ca2+ channels C_LIO_LIIn adipocytes, voltage-gated Ca2+ channel activity appear recalcitrant to changes in Vm, but are however gated by growth hormone. C_LI

Intracellular accumulation of hydrogen ions (H+) and inorganic phosphate (Pi) have temperature-dependent effects on single fiber contractile function between 10-30{degrees}C. In vivo, human skeletal muscle temperatures range between 35-38{degrees}C, and although contractile function is highly dependent on temperature, the effects of fatigue-inducing [H+] and [Pi] on contractile mechanics at 37{degrees}C is unknown. Using sinusoidal analysis, the independent and combined effects of these metabolites on cellular and molecular contractile function were determined at 37{degrees}C in slow-contracting myosin heavy chain (MHC) I and fast-contracting MHC IIA fibers from vastus lateralis muscle of 13 older adults (8 females), under four conditions: maximal calcium activation ("control"; 5 mM Pi, pH 7.0), high Pi (30 mM), low pH (6.2), and fatigue (30 mM Pi and pH 6.2). Specific tension (force/cross-sectional area, mN/mm2) in both fiber types was reduced only under fatigue conditions (20-26%). MHC I fibers had slower cross-bridge kinetics with fewer or less stiff strongly-bound myosin-actin cross-bridges in high Pi, low pH, and fatigue. In contrast, fatigued MHC IIA fibers had faster cross-bridge kinetics with increased myofilament and/or cross-bridge viscosity. Single fiber oscillatory work was reduced in both fiber types when Pi or pH alone was altered. However, fatigue conditions returned oscillatory work values toward control through alterations to cross-bridge kinetics in MHC I fibers and changes to work absorption and production processes in MHC IIA fibers. These findings quantify fiber-type specific mechanical and kinetic mechanisms of fatigue in human skeletal muscle at 37{degrees}C, thus advancing our understanding of metabolite-based muscle fatigue in vivo. KEY POINTS SUMMARYO_LIWorking skeletal muscle increases intracellular concentrations of hydrogen ion and inorganic phosphate, leading to fatigue, or loss of force-generating capacity C_LIO_LITemperature plays a well-established role in the muscle response to hydrogen ion and/or inorganic phosphate accumulation, but has not previously been studied at human body temperature (37{degrees}C) C_LIO_LIAt 37{degrees}C, reduced force generation only occurs when high phosphate and hydrogen ions are combined, not when changed individually C_LIO_LIIn slow-contracting fibers, fatigue slowed myosin-actin cross-bridge kinetics and reduced the number or stiffness of strongly-bound cross-bridges. In fast-contracting fibers, fatigue increased myosin-actin cross-bridge kinetics and increased myofilament viscosity. C_LIO_LIThe distinct responses by fiber type to fatigue provides new insight into its mechanisms and advances our understanding of the whole muscle and body responses to fatigue C_LI Abstract Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/672942v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@e4ece3org.highwire.dtl.DTLVardef@17c62eforg.highwire.dtl.DTLVardef@1434e30org.highwire.dtl.DTLVardef@1c2446c_HPS_FORMAT_FIGEXP M_FIG C_FIG

Heart rate variability, or the variation in the time interval between consecutive beats, is a non-invasive dynamic metric of the autonomic nervous system and an independent risk factor for cardiovascular death. Prior limitations of use include requirements for continuous electrocardiography and lack of reference standards. Consumer wrist-worn tracking devices using photoplethysmography now provide the unique potential of continuously measuring surrogates of sympathetic and parasympathetic activity through the analysis of interbeat intervals. Here we leverage wrist-worn trackers to present the largest, to our knowledge, analysis of heart rate variability in humans across the time, frequency, and graphical domains. We derive diurnal parasympathetic and sympathetic measures and provide scaling parameters by age, sex, and time of day. Poincare plots graphically summarize heart rate variability metrics and may detect common arrhythmias. Lastly, we observe a strong dose-dependent correlation between daily steps and optimal heart rate variability metrics. Our results provide the ability to interpret continuous heart rate variability for tens of millions of wrist-worn trackers already in use.

Recent studies have emphasized the importance of the nitric oxide synthase (NOS)-independent, nitrate (NO3-) [-&gt;] nitrite (NO2-) [-&gt;] nitric oxide (NO) pathway in skeletal muscle. In particular, it has been hypothesized that this pathway is especially active in type II, or fast-twitch, muscle fibers, necessitating greater NO3- and NO2- storage. We therefore measured NO3- and NO2- concentrations in the predominantly fast-twitch vastus lateralis and predominantly slow-twitch soleus muscles of rats. Contrary to the above hypothesis, we found that NO3- and NO2- concentrations were 3.4-fold and 1.8-fold higher, respectively, in the soleus. On the other hand, NO signaling (i.e., cyclic guanosine monophosphate (cGMP) level) was comparable in the two muscles. Although the physiological significance of these observations remains to be determined, we speculate that NO production via the NO3- [-&gt;] NO2- [-&gt;] NO pathway is normally higher in slow-twitch muscles, thus helping compensate for their inherently lower NOS activity.

BackgroundVariables that influence mean corpuscular volume (MCV) in HFE p.C282Y (rs1800562)/p.H63D (rs1799945) compound heterozygotes are inadequately defined. MethodsWe retrospectively studied self-reported non-Hispanic white adult compound heterozygotes with transferrin saturation (TS) >50% and serum ferritin (SF) >300 g/L (men) or TS >45% and SF >200 g/L (women) who participated in primary care-based screening. In post-screening evaluations, we excluded participants with anemia, pregnancy, or medication use that increases MCV. We defined heavy alcohol intake as >28 g/d men and >14 g/d women. We determined associations of MCV with 11 clinical and laboratory variables. ResultsThere were 74 participants (37 men, 37 women) of mean age 59{+/-}12 (SD) y. Mean screening TS and SF were 65{+/-}13% and 529{+/-}169 {micro}g/L (men) and 59{+/-}14% and 376{+/-}195 {micro}g/L (women). Post-screening values did not differ significantly. Mean MCV was 95.7{+/-}4.0 fL. There was a negative correlation of MCV with body mass index (p=0.0488) and positive correlations of MCV with age (p=0.0098), daily heme iron intake (p=0.0333), and daily alcohol intake (p=0.0113). Mean MCVs of 19 participants with and 55 without heavy alcohol intake were 97.8{+/-}3.8 g/d and 95.0{+/-}3.9 g/d, respectively; p=0.0074). Linear regression on MCV confirmed positive associations with age (p=0.0064) and daily alcohol intake (p=0.0151). MCV was not significantly associated with sex, diabetes, daily intakes of non-heme and supplemental iron, swollen or tender 2nd/3rd metacarpophalangeal joints, TS, or SF. ConclusionMCV in HFE p.C282Y/p.H63D compound heterozygotes with high iron phenotypes is positively associated with age and daily alcohol intake, after adjustment for other variables.

Incidence and outcomes of systemic inflammatory diseases, such as sepsis, differ between men and women, but the underlying mechanisms remain unclear. We examined systemic inflammatory responses in 56 male and 54 female healthy volunteers challenged with 1 ng/kg bacterial lipopolysaccharide (LPS) twice, with an interval of one week. Sex hormones, inflammatory markers, and monocyte RNA expression were determined. Women exhibited higher levels of several proinflammatory mediators than men during the first LPS challenge (TNF +45%, p=0.002; IL-6 +43%, p=0.0009; IP-10 +58%, p<0.0001; G-CSF +60%, p=0.02). Among women, use of hormonal contraceptives was associated with a more pronounced pro-inflammatory response (TNF +60%, p=0.001; IL-8 +30%, p=0.008; IP-10 +37%, p<0.0001). Endogenous concentrations of estrogens and testosterone inversely correlated with the extent of cytokine responses in women, while estrone positively correlated with these responses among men. The magnitude of endotoxin tolerance, exemplified by a significantly blunted cytokine response upon the second LPS challenge, was similar between the sexes, as were monocyte RNA expression patterns. In conclusion, our data indicate that there is considerable sexual dimorphism in systemic inflammation and implicate an important role for sex hormones in regulating immunity.