Journal of Applied Physiology

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ISSN / EISSN : 8750-7587 / 1522-1601
Published by: American Physiological Society (10.1152)
Total articles ≅ 32,547
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Philip J. Peyton
Journal of Applied Physiology; https://doi.org/10.1152/japplphysiol.00597.2021

Abstract:
Under the three-compartment model of ventilation-perfusion (VA/Q) scatter, Bohr-Enghoff calculation of alveolar deadspace fraction (VDA/VA) uses arterial CO2 partial pressure measurement as an approximation of "ideal" alveolar CO2(ideal PACO2). However, this simplistic model suffers from several inconsistencies. Modelling of realistic physiological distributions of VA and Q instead suggests an alternative concept of "ideal" alveolar gas at the VA/Q ratio where uptake or elimination rate of a gas is maximal. The alveolar-capillary partial pressure at this "modal" point equals the mean of expired alveolar and arterial partial pressures, regardless of VA/Q scatter severity or overall VA/Q. For example, modal ideal PACO2 can be estimated from Estimated modal ideal PACO2 = (PACO2+PaCO2)/2 Using a multicompartment computer model of log normal distributions of VA and Q, agreement of this estimate with the modal ideal PACO2 located at the VA/Q ratio of maximal compartmental VCO2 was assessed across a wide range of severity of VA/Q scatter and overall VA/Q ratio. Agreement of VDA/VA for CO2 from the Bohr equation using modal idealPCO2 with that using the estimated value was also assessed. Estimated modal ideal PACO2 agreed closely with modal ideal PACO2, intraclass correlation (ICC) > 99.9%. There was no significant difference between VDA/VACO2 using either value for ideal PACO2. Modal ideal PACO2 reflects a physiologically realistic concept of ideal alveolar gas where there is maximal gas exchange effectiveness in a physiological distribution of VA/Q, which is generalizable to any inert gas, and is practical to estimate from arterial and end-expired CO2 partial pressures.
Brian A. Hain, Haifang Xu, Ashley M. VanCleave, Bradley S. Gordon, Scot R. Kimball, David L. Waning
Journal of Applied Physiology; https://doi.org/10.1152/japplphysiol.00536.2021

Abstract:
Cancer cachexia is a wasting disorder associated with advanced cancer that contributes to mortality. Cachexia is characterized by involuntary loss of body weight and muscle weakness that affects physical function. Regulated in DNA damage and development 1 (REDD1) is a stress-response protein that is transcriptionally upregulated in muscle during wasting conditions and inhibits mechanistic target of rapamycin complex 1 (mTORC1). C2C12 myotubes treated with Lewis lung carcinoma (LLC)-conditioned media increased REDD1 mRNA expression and decreased myotube diameter. To investigate the role of REDD1 in cancer cachexia, we inoculated 12-week old male wild-type or global REDD1 knockout (REDD1 KO) mice with LLC cells and euthanized 28-days later. Wild-type mice had increased skeletal muscle REDD1 expression, and REDD1 deletion prevented loss of body weight and lean tissue mass, but not fat mass. We found that REDD1 deletion attenuated loss of individual muscle weights and loss of myofiber cross sectional area. We measured markers of the Akt/mTORC1 pathway and found that, unlike wild-type mice, phosphorylation of both Akt and 4E-BP1 was maintained in the muscle of REDD1 KO mice after LLC inoculation, suggesting that loss of REDD1 is beneficial in maintaining mTORC1 activity in mice with cancer cachexia. We measured Foxo3a phosphorylation as a marker of the ubiquitin proteasome pathway and autophagy and found that REDD1 deletion prevented dephosphorylation of Foxo3a in muscles from cachectic mice. Our data provides evidence that REDD1 plays an important role in cancer cachexia through the regulation of both protein synthesis and protein degradation pathways.
Katie M. Harris, Tobias Weber, Danielle K. Greaves, David Andrew Green, Nandu Goswami, Lonnie Grove Petersen
Journal of Applied Physiology; https://doi.org/10.1152/japplphysiol.00425.2021

Taylor S. Thurston, Joshua C. Weavil, Thomas J. Hureau, Jayson R. Gifford, Vincent P. Georgescu, Hsuan-Yu Wan, D. Taylor La Salle, Russell S. Richardson, Markus Amann
Journal of Applied Physiology; https://doi.org/10.1152/japplphysiol.00400.2021

Abstract:
This study investigated the impact of dietary nitrate supplementation on peripheral hemodynamics, the development of neuromuscular fatigue, and time to task failure during cycling exercise. Eleven recreationally active male participants (27±5 years, VO2max: 42±2ml/kg/min) performed two experimental trials following 3 days of either dietary nitrate-rich beetroot juice (4.1mmol NO3 -/day; DNS) or placebo (PLA) supplementation in a blinded, counterbalanced order. Exercise consisted of constant-load cycling at 50, 75, and 100 W (4-min each) and, at ~80% of peak power output (218±12W), to task-failure. All participants returned to repeat the shorter of the two trials performed to task-failure, but with the opposite supplementation regime (ISO-time comparison). Mean arterial pressure (MAP), leg blood flow (QL; Doppler ultrasound), leg vascular conductance (LVC), and pulmonary gas exchange were continuously assessed during exercise. Locomotor muscle fatigue was determined by the change in pre- to post-exercise quadriceps twitch-torque (∆Qtw) and voluntary activation (∆VA; electrical femoral nerve stimulation). Following DNS, plasma [nitrate] (~670 vs ~180 nmol) and [nitrite] (~775 vs ~11 nmol) were significantly elevated compared to PLA. Unlike PLA, DNS lowered both QL and MAP by ~8% (P<0.05), but did not alter LVC (P=0.31). VO2 across work rates, as well as cycling time to task-failure (~7min) and locomotor muscle fatigue following the ISO-time comparison were not different between the two conditions (∆Qtw ~42%, ∆VA ~4%). Thus, despite significant hemodynamic changes, DNS did not alter the development of locomotor muscle fatigue and, ultimately, cycling time to task failure.
Jeremy E. Orr, Bradley Allan Edwards, Christopher N. Schmickl, Maile Karris, Pamela N. DeYoung, Chantal Darquenne, Rebecca Theilmann, Sonia Jain, Atul Malhotra, Charles B. Hicks, et al.
Journal of Applied Physiology; https://doi.org/10.1152/japplphysiol.00591.2021

Abstract:
Obstructive sleep apnea (OSA) is highly prevalent in people living with HIV (PLWH), and might contribute to frequently reported symptoms and co-morbidities. Traditional risk factors for OSA are often absent in PLWH, suggesting that HIV or HIV medications might predispose to OSA. Therefore, we measured the anatomical and non-anatomical traits important for OSA pathogenesis in those with and without HIV. We recruited virally-suppressed PLWH who had been previously diagnosed with OSA (PLWH+OSA) adherent to positive airway pressure (PAP) therapy, along with age, gender and body mass index (BMI) matched OSA controls. All participants underwent a baseline polysomnogram to assess OSA severity, and a second overnight research sleep study during which the airway pressure was adjusted slowly or rapidly to measure the OSA traits. Seventeen PLWH+OSA and 17 OSA control participants were studied (median age 58 IQR[54, 65] years, BMI 30.7 [28.4, 31,8] kg/m2, apnea-hypopnea index 46 [24, 74]/h. The groups were similar, although PLWH+OSA demonstrated greater sleepiness (despite PAP) and worse sleep efficiency on baseline polysomnography. On physiological testing during sleep, there were no statistically significant differences in OSA traits (including Veupnea, Varousal, Vpassive, Vactive, and loop gain) between PLWH+OSA and OSA controls, using mixed-effects modeling to account for age, gender, and BMI, and incorporating each repeated measurement (range 72-334 measures/trait). Our data suggest that well treated HIV does not substantially impact the pathogenesis of OSA. Given similar underlying physiology, existing available therapeutic approaches are likely to be adequate to manage OSA in PLWH, which might improve symptoms and co-morbidities.
Weiyu Li, Amy G. Tsai, Marcos Intaglietta, Daniel M. Tartakovsky
Journal of Applied Physiology; https://doi.org/10.1152/japplphysiol.00524.2021

Abstract:
­­ ­Although some of the cardiovascular responses to changes in hematocrit (Hct) are not fully quantified experimentally, available information is sufficient to build a mathematical model of the consequences of treating anemia by introducing RBCs into the circulation via blood transfusion. We present such a model, which describes how the treatment of normovolemic anemia with blood transfusion impacts oxygen (O2) delivery (DO2, the product of blood O2 content and arterial blood flow) by the microcirculation. Our analysis accounts for the differential response of the endothelium to the wall shear stress (WSS) stimulus, changes in nitric oxide (NO) production due to modification of blood viscosity caused by alterations of both hematocrit (Hct) and cell free layer thickness, as well as for their combined effects on microvascular blood flow and DO2. Our model shows that transfusions of 1- and 2-unit of blood have a minimal effect on DO2 if the microcirculation is unresponsive to the WSS stimulus for NO production that causes vasodilatation increasing blood flow and DO2. Conversely, in a fully WSS responsive organism, blood transfusion significantly enhances blood flow and DO2, because increased viscosity stimulates endothelial NO production causing vasodilatation. This finding suggests that evaluation of a patients' pre-transfusion endothelial WSS responsiveness should be beneficial in determining the optimal transfusion requirements for treating anemic patients.
Tsubasa Tomoto, Justin Repshas, Rong Zhang, Takashi Tarumi
Journal of Applied Physiology; https://doi.org/10.1152/japplphysiol.00243.2021

Abstract:
Midlife aerobic exercise may significantly impact age-related changes in the cerebro- and cardiovascular regulations. This study investigated the associations of midlife aerobic exercise with dynamic cerebral autoregulation (dCA), cardiovagal baroreflex sensitivity (BRS), and central arterial stiffness. Twenty middle-aged athletes (MA) who had aerobic training for >10 years were compared with 20 young (YS) and 20 middle-aged sedentary (MS) adults. Beat-to-beat cerebral blood flow velocity, blood pressure (BP), and heart rate were measured at rest and during forced BP oscillations induced by repeated sit-stand maneuvers at 0.05 Hz. Transfer function analysis was used to calculate dCA and BRS parameters. Carotid distensibility was measured by ultrasonography. MA had the highest peak oxygen uptake (VO2peak) among all groups. During forced BP oscillations, MS showed lower BRS gain than YS, but this age-related reduction was absent in MA. Conversely, dCA was similar among all groups. At rest, BRS and dCA gains at low frequency (~0.1 Hz) were higher in the MA compared with MS and YS groups. Carotid distensibility was similar between MA and YS groups, but it was lower in the MS. Across all subjects, VO2peak was positively associated with BRS gains at rest and during forced BP oscillations (r=0.257~0.382, p=0.003~0.050) and carotid distensibility (r=0.428~0.490, p=0.001). Furthermore, dCA gain at rest and carotid distensibility were positively correlated with BRS gain at rest in YS and MA groups (all p<0.05). These findings suggest that midlife aerobic exercise improves central arterial elasticity and BRS which may contribute to CBF regulation through dCA.
Yuan Wang, Ruide Liu, Rui Jin, Zijun He, Yanyan Chen, Zuchang Ma, Yining Sun
Journal of Applied Physiology; https://doi.org/10.1152/japplphysiol.00554.2021

Abstract:
Objectives: The aim of this study is to propose a new wave protocol to identify low-frequency oscillations for evaluating resting energy expenditure (REE) and compare its performance with the 5-minute interval abbreviated protocol and standard protocol. Research methods & procedures: Consecutive 20-minute indirect calorimetry (IC) was used to collect metabolic data from 23 women and 37 men (between 23 and 43 years old). Sliding window filter algorithms were used to eliminate noise. Three protocols were used to evaluate REE: averaging the data between two consecutive waves (wave protocol), averaging the second 5-minute intervals (interval protocol), and averaging the last 15-minute REE (standard protocol). Results: Based on 60 healthy participants' metabolic data, compared with the interval protocol, the wave protocol showed better consistency with the standard protocol. The mean bias (limits of agreement) using the wave protocol was 0.3458% (-7.817% to 8.509%), and that using the interval protocol was -1.720% (-16.06% to 12.62%). The time required to evaluate REE with the wave protocol and interval protocol was measured. The measurement time for the interval protocol was 10 minutes, while the average measurement time for the wave protocol was 9.75 minutes. Conclusions: We recommend the wave protocol for estimating REE in healthy people. This abbreviated protocol can identify low-frequency oscillations and consider individual differences to more accurately reflect the baseline REE compared to the interval protocol. Compared with the standard protocol, the measurement time of the wave protocol was reduced by nearly half (from 20 minutes (standard protocol) to 9.75 minutes).
Sydnee A. Hyman, Isabella T. Wu, Laura S. Vasquez-Bolanos, Mackenzie B. Norman, Mary C. Esparza, Shannon N. Bremner, Shanelle N. Dorn, Ivan Ramirez, Donald C. Fithian, John G. Lane, et al.
Journal of Applied Physiology; https://doi.org/10.1152/japplphysiol.01119.2020

Abstract:
Chronic rotator cuff tears can cause severe functional deficits. Addressing the chronic fatty and fibrotic muscle changes is of high clinical interest; however, the architectural and physiological consequences of chronic tear and repair are poorly characterized. We present a detailed architectural and physiological analysis of chronic tear and repair (both over 8 and 16 weeks) compared to age-matched control rabbit supraspinatus (SSP) muscles. Using female New Zealand White Rabbits (N=30, n=6/group) under 2% isofluorane anesthesia, the SSP was surgically isolated and maximum isometric force measured at 4-6 muscle lengths. Architectural analysis was performed, and maximum isometric stress was computed. Whole muscle length-tension curves were generated using architectural measurements to compare experimental physiology to theoretical predictions. Architectural measures are consistent with persistent radial and longitudinal atrophy over time in tenotomy that fail to recover after repair. Maximum isometric force was significantly decreased after 16 wks tenotomy and not significantly improved after repair. Peak isometric force reported here are greater than prior reports of rabbit SSP force after tenotomy. Peak stress was not significantly different between groups and consistent with prior literature of SSP stress. Muscle strain during contraction was significantly decreased after 8-wks of tenotomy and repair, indicating effects of tear and repair on muscle function. The experimental length-tension data was overlaid with predicted curves for each experimental group (generated from structural data), exposing the altered structure-function relationship for tenotomy and repair over time. Data presented here contribute to understanding the physiological implications of disease and repair in the rotator cuff
Swati A. Bhatawadekar, Anne E. Dixon, Ubong Peters, Nirav Daphtary, Kevin Hodgdon, David A. Kaminsky, Jason H.T. Bates
Journal of Applied Physiology; https://doi.org/10.1152/japplphysiol.00399.2021

Abstract:
Late-onset non-allergic (LONA) asthma in obesity is characterized by increased peripheral airway closure secondary to abnormally collapsible airways. We hypothesized that positive expiratory pressure (PEP) would mitigate the tendency to airway closure during bronchoconstriction, potentially serving as rescue therapy for LONA asthma of obesity. The PC20 dose of methacholine was determined in 18 obese participants with LONA asthma. At each of 4 subsequent visits, we used oscillometry to measure input respiratory impedance (Zrs) over 8 minutes; participants received their PC20 concentration of methacholine aerosol during the first 4.5 minutes. PEP combinations of either 0 or 10 cmH2O either during and/or after the methacholine delivery were applied, randomized between visits. Parameters characterizing respiratory system mechanics were extracted from the Zrs spectra. In 18 LONA asthma patients (14 females, BMI: 39.6±3.4 kg/m2), 10 cmH2O PEP during methacholine reduced elevations in the central airway resistance, peripheral airway resistance and elastance, and breathing frequency was also reduced. During the 3.5 min following methacholine delivery, PEP of 10 cmH2O reduced Ax and peripheral elastance compared to no PEP. PEP mitigates the onset of airway narrowing brought on by methacholine challenge, and airway closure once it is established. PEP thus might serve as a non-pharmacologic therapy to manage acute airway narrowing for obese LONA asthma.
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