Frontiers in Physiology
ISSN / EISSN : 1664-042X / 1664-042X
Published by: Frontiers Media SA (10.3389)
Total articles ≅ 11,378
Latest articles in this journal
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.726253
Hypoxia adversely affects the pulmonary circulation of mammals, including vasoconstriction leading to elevated pulmonary arterial pressures. The clinical importance of changes in the structure and function of the large, elastic pulmonary arteries is gaining increased attention, particularly regarding impact in multiple chronic cardiopulmonary conditions. We establish a multi-disciplinary workflow to understand better transcriptional, microstructural, and functional changes of the pulmonary artery in response to sustained hypoxia and how these changes inter-relate. We exposed adult male C57BL/6J mice to normoxic or hypoxic (FiO2 10%) conditions. Excised pulmonary arteries were profiled transcriptionally using single cell RNA sequencing, imaged with multiphoton microscopy to determine microstructural features under in vivo relevant multiaxial loading, and phenotyped biomechanically to quantify associated changes in material stiffness and vasoactive capacity. Pulmonary arteries of hypoxic mice exhibited an increased material stiffness that was likely due to collagen remodeling rather than excessive deposition (fibrosis), a change in smooth muscle cell phenotype reflected by decreased contractility and altered orientation aligning these cells in the same direction as the remodeled collagen fibers, endothelial proliferation likely representing endothelial-to-mesenchymal transitioning, and a network of cell-type specific transcriptomic changes that drove these changes. These many changes resulted in a system-level increase in pulmonary arterial pulse wave velocity, which may drive a positive feedback loop exacerbating all changes. These findings demonstrate the power of a multi-scale genetic-functional assay. They also highlight the need for systems-level analyses to determine which of the many changes are clinically significant and may be potential therapeutic targets.
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.726345
Maintenance of telomere length is essential to delay replicative cellular senescence. It is controversial on whether growth differentiation factor 11 (GDF11) can reverse cellular senescence, and this work aims to establish the causality between GDF11 and the telomere maintenance unequivocally. Using CRISPR/Cas9 technique and a long-term in vitro culture model of cellular senescence, we show here that in vitro genetic deletion of GDF11 causes shortening of telomere length, downregulation of telomeric reverse transcriptase (TERT) and telomeric RNA component (TERC), the key enzyme and the RNA component for extension of the telomere, and reduction of telomerase activity. In contrast, both recombinant and overexpressed GDF11 restore the transcription of TERT in GDF11KO cells to the wild-type level. Furthermore, loss of GDF11-induced telomere shortening is likely caused by enhancing the nuclear entry of SMAD2 which inhibits the transcription of TERT and TERC. Our results provide the first proof-of-cause-and-effect evidence that endogenous GDF11 plays a causal role for proliferative cells to maintain telomere length, paving the way for potential rejuvenation of the proliferative cells, tissues, and organs.
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.721242
The gastric mucosa is disturbed when breastfeeding is interrupted, and such early weaning (EW) condition permanently affects the differentiation of zymogenic cells. The aim of the study was to evaluate the immediate and long-term effects of EW on gastric cell proliferation, considering the molecular markers for cell cycle, inflammation, and metaplasia. Overall, we investigated the lifelong adaptation of gastric growth. Wistar rats were divided into suckling-control (S) and EW groups, and gastric samples were collected at 18, 30, and 60 days for morphology, RNA, and protein isolation. Inflammation and metaplasia were not identified, but we observed that EW promptly increased Ki-67-proliferative index (PI) and mucosa thickness (18 days). From 18 to 30 days, PI increased in S rats, whereas it was stable in EW animals, and such developmental change in S made its PI higher than in EW. At 60 days, the PI decreased in S, making the indices similar between groups. Spatially, during development, proliferative cells spread along the gland, whereas, in adults, they concentrate at the isthmus-neck area. EW pushed dividing cells to this compartment (18 days), increased PI at the gland base (60 days), but it did not interfere in expression of cell cycle molecules. At 18 days, EW reduced Tgfβ2, Tgfβ3, and Tgfbr2 and TβRII and p27 levels, which might regulate the proliferative increase at this age. We demonstrated that gastric cell proliferation is immediately upregulated by EW, corroborating previous results, but for the first time, we showed that such increased PI is stable during growth and aging. We suggest that suckling and early weaning might use TGFβs and p27 to trigger different proliferative profiles during life course.
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.757000
Editorial on the Research Topic Entrainment of Biological Rhythms Circadian rhythms are ubiquitous and are observed in nearly all organisms that have been studied which inhabit our planet. These include animals, plants, fungi as well as some bacteria. These endogenous clocks will tick along nicely with an approximately 24 h period in constant conditions because they are generated by the so-called “transcriptional-translation-feedback-loops” (TTFLs) that were first described in Drosophila. The pioneers of this fly research, Jeff Hall, Michael Rosbash, and Mike Young were awarded the 2017 Nobel Prize in Medicine or Physiology reflecting the importance of their contribution to understanding a fundamental feature of life, namely, rhythmicity. These TTFLs appear to be bolted on and interconnected to a more primitive metabolic oscillator, which, under certain conditions, can be observed in the absence of the TTFL in a number of model species (Edgar et al., 2012). While these oscillators are endogenous, their major role is presumed to be in anticipating the regular fluctuations in the environment that are associated with the Earth spinning on its axis every 24 h and preparing the organism for its daily chores. For animals this might mean foraging, finding a mate, outwitting predators and avoiding extreme daily heat or cold. In addition there are other geophysical cycles to which organisms are sensitive, for example the seasonal changes caused by the Earth's tilt around its axis as it circles the Sun. There is also the gravitational pull of the Moon on the oceans which generates 12.4 h cycles in the ebb and flow of the tides to which shoreline algae, animals and plants have responded by evolving circatidal cycles of behaviour and physiology. Other lunar-related cycles include semi-lunar (~15 days) and lunar cycles (29.5 days) which have important implications for the reproductive cycles of many organisms. All of these cycles, circadian and non-circadian entrain to environmental “Zeitgebers” (time-givers) the most important of which is the light cycle, but temperature cycles, social stimuli, seasonal photoperiodic changes, vibration or water pressure changes can be equally effective in “entraining” a biological clock to its optimal phase. It is entrainment that determines the time of day or chronotype, yet this property of circadian clocks is less well understood than free running rhythm. This special edition of Frontiers is dedicated to “entrainment” in all its various forms. There are two extensive Drosophila reviews, one by George and Stanewsky, who focus on temperature entrainment of the fly clock and how the peripheral sense organs send temperature information to the brain and the other by Mazzotta et al. who review the neurogenetic basis for the effects of light on sleep in the fly. Light and temperature entrainment is developed further by Kaniewska et al. in the linden bug (Pyrrhocoris apterus), a relatively new model for seasonal biology in which environmental inputs to the circadian clock have yet to be explored. In flies, the original M and E hierarchical oscillator neurogenetic model has dedicated M (morning) clock neurons that are important for the morning burst of locomotor activity at dawn and the E (evening) neurons determine the late afternoon activity before lights off. By expressing the canonical clock protein PER in only M or E neurons, Menegazzi et al. show that under changing photoperiods the flies had difficulty in regulating their M or E activity at the appropriate times. This adds to the growing body of evidence that the M and E clock neurons are required to act as interacting network to generate normal locomotor activity, particularly under the more natural photoperiodic conditions found in temperate regions. The clock network is further studied by Van De Maas de Azevedo et al. who show that glutamate signalling from dorsal neurons in the clock network is required to generate the normal response to constant light, which is arrhythmicity. This also has implications because under natural conditions Drosophila species in the extreme northern hemisphere are not (nor need to be) strongly rhythmic under very long daylengths (Bertolini et al., 2019). This theme of extreme environmental conditions such as constant light or long or short photoperiods that are prevalent in polar regions is the focus of the contribution by Appenroth et al. who study the High Arctic Svalbard ptarmigan (Lagopus muta hyperborea) and by Carmona et al. who study the effects of photoperiodic chronodisruption on pregnant female rats and the lingering effects this has on gene expression in their male progeny. In the former study, by investigating core body temperature and locomotor activity cycles, the authors reveal that the ptarmigan shows very weak rhythms, if at all, in both phenotypes under both constant light (LL) and constant darkness (DD) but are rhythmic under both long and short photoperiods under light-dark (LD) cycles. As shown in studies of reindeer, polar animals need not stay rhythmic under arrhythmic environmental conditions (Lu et al., 2010). In Carmona's et al. paper, pregnant female rats exposed to repeated abrupt reversals of the LD cycle gave birth to males, who at 90 days of age showed not only altered liver clock gene expression compared to animals who had gestated in an unchanging LD cycle, but also in genes that are risk factors for cardiovascular disease. There are clear medical implications for chronodisruption during pregnancy. In zebrafish, unlike mammals, it has been long established that peripheral tissues have light sensitive clocks (Whitmore et al., 2000). Zebrafish encode a bewildering array of opsin genes (>30), and Steindal and Whitmore reveal that one third of these are expressed in cell lines from early larvae and about half of these are clock-controlled. Canonical clock genes such as Per1 can also be induced and...
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.758972
Editorial on the Research Topic The Integrative Physiology of Metabolic Downstates Homeostasis relies upon the exquisite integration of diverse physiological functions, such as neuromuscular and cardiorespiratory functions and energy and thermal balance, in the face of external and internal challenges. The latter include physical exercise, which represents a short-term “metabolic upstate” of increased energy expenditure. To the other end of the spectrum, diverse physiological behaviors including sleep, daily torpor, and hibernation represent “metabolic downstates” of decreased energy expenditure. The study of physical exercise has been key for our current understanding of integrative physiology, for instance highlighting the role of feedforward control by central commands in complementing negative feedback regulation of physiological variables. In contrast, the integrative physiology of “metabolic downstates” remains insufficiently understood. This Research Topic aimed to contribute to bridge this knowledge gap by bringing together cutting-edge updates on the integrative physiology of “metabolic downstates.” Remarkably, the Research Topic attracted important contributions on the molecular, cellular, and metabolic aspects of the integrative physiology of hibernation. Focusing on molecular mechanisms, Fu et al. reported exciting new evidence on dynamic RNA regulation in the brain of 13-lined ground squirrels (Ictidomys tridecemlineatus) in physiologically distinct phases of hibernation, providing evidence for regulated transcription and RNA turnover during hibernation. Wang et al. uncovered hitherto unrecognized dynamics of calcium ions and calcium-handling proteins in the skeletal muscles of hibernating Daurian ground squirrels (Spermophilus dauricus), in the face of significantly decreased metabolic activity. Relevant to the cellular aspects of the integrative physiology of metabolic downstates, Huber et al. reported novel evidence of a temperature-compensated reduction of neutrophil oxidative burst capacity in hibernating garden dormice (Eliomys quercinus), while Dias et al. reviewed the evidence comparing the molecular aspects of cellular quiescence of hematopoietic stem cells with hibernation at the cellular level, revealing several key shared factors. The general aspects of metabolic adaptation associated with hibernation were reviewed by Giroud et al., who emphasized the mechanisms enabling heterotherms to protect their key organs against potential threats, such as reactive oxygen species. The evidence on protein metabolism in hibernation was reviewed by Bertile et al., focusing on the mechanisms that spare muscle proteins in the face of the inactivity that accompanies hibernation. Lipid metabolism was addressed by Watts et al. who demonstrated that metabolic rate and body mass loss in hibernating garden dormice do not differ with the dietary levels of essential polyunsaturated fatty acids in the fall season preceding hibernation, highlighting a preserved regulation of peroxisome proliferator-activated receptor pathway. Lastly, system-level adaptations to short photoperiod exposure in terms of body mass, fur insulation, locomotor activity, and core body temperature were investigated by Haugg et al. in Djungarian hamsters (Phodopus sungorus), providing insights into preconditions and proximate stimuli of hibernation. On an apparently different note, Shirota et al. contributed a detailed report of discrepancies in the time course of sleep stage dynamics, electroencephalographic activity and heart rate variability over sleep cycles in the night of adaptation to the sleep laboratory in healthy young adults. Their study is of interest for the design and interpretation of human sleep studies and is appropriate to this Research Topic because sleep is also a “metabolic downstate” (Silvani et al., 2018). Taken together, the research and review papers in this Research Topic drafted a remarkable picture of the complexity of the integrative physiology of hibernation, which is the metabolic downstate that was addressed by most contributions. This complexity stems not only from the multiplicity of the levels of physiological integration, but also from the temporal dynamics of hibernation, which is typically interrupted by short inter-bout arousals, and by differences among hibernator species. This complexity also brings about the potential to uncover basic mechanisms that may be conserved in evolution and harnessed to improve healthcare. For instance, understanding the mechanisms that preserve protein mass during hibernation could conceivably help limit muscle protein loss in conditions of inactivity or weight loss therapy. Knowledge of the mechanisms that limit circulating innate immune cell activity in hibernation could have clinical relevance in the context of therapeutic hypothermia and reperfusion injury. In perspective, it is tempting to speculate that greater knowledge of the integrative physiology of hibernation may allow its artificial reproduction in human subjects, with potential implications for healthcare as well as for long-range space exploration (Cerri et al., 2021). By subtraction, the topics that were less covered in this article collection indicate important areas for future research. One such topic concerns whether and to what extent findings in multi-day hibernating species may be replicated during shallower daily torpor bouts in the house mouse (Mus musculus). This replication would allow researchers to leverage the power of genetic manipulations and analyses in Mus musculus, although, as shown by Fu et al. in this article collection, tools for genetic analysis in hibernating mammals are catching up. The other underrepresented topic is integrative sleep physiology, particularly as related to decreases in metabolic rate during sleep. The technical difficulty of measuring multiple physiological variables...
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.743153
Background: Ventilator-induced lung injury (VILI) via respiratory mechanics is deeply interwoven with hemodynamic, kidney and fluid/electrolyte changes. We aimed to assess the role of positive fluid balance in the framework of ventilation-induced lung injury. Methods: Post-hoc analysis of seventy-eight pigs invasively ventilated for 48 h with mechanical power ranging from 18 to 137 J/min and divided into two groups: high vs. low pleural pressure (10.0 ± 2.8 vs. 4.4 ± 1.5 cmH2O; p < 0.01). Respiratory mechanics, hemodynamics, fluid, sodium and osmotic balances, were assessed at 0, 6, 12, 24, 48 h. Sodium distribution between intracellular, extracellular and non-osmotic sodium storage compartments was estimated assuming osmotic equilibrium. Lung weight, wet-to-dry ratios of lung, kidney, liver, bowel and muscle were measured at the end of the experiment. Results: High pleural pressure group had significant higher cardiac output (2.96 ± 0.92 vs. 3.41 ± 1.68 L/min; p < 0.01), use of norepinephrine/epinephrine (1.76 ± 3.31 vs. 5.79 ± 9.69 mcg/kg; p < 0.01) and total fluid infusions (3.06 ± 2.32 vs. 4.04 ± 3.04 L; p < 0.01). This hemodynamic status was associated with significantly increased sodium and fluid retention (at 48 h, respectively, 601.3 ± 334.7 vs. 1073.2 ± 525.9 mmol, p < 0.01; and 2.99 ± 2.54 vs. 6.66 ± 3.87 L, p < 0.01). Ten percent of the infused sodium was stored in an osmotically inactive compartment. Increasing fluid and sodium retention was positively associated with lung-weight (R 2 = 0.43, p < 0.01; R 2 = 0.48, p < 0.01) and with wet-to-dry ratio of the lungs (R 2 = 0.14, p < 0.01; R 2 = 0.18, p < 0.01) and kidneys (R 2 = 0.11, p = 0.02; R 2 = 0.12, p = 0.01). Conclusion: Increased mechanical power and pleural pressures dictated an increase in hemodynamic support resulting in proportionally increased sodium and fluid retention and pulmonary edema.
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.735573
The porosity of liver sinusoidal endothelial cells (LSEC) ensures bidirectional passive transport of lipoproteins, drugs and solutes between the liver capillaries and the liver parenchyma. This porosity is realized via fenestrations – transcellular pores with diameters in the range of 50–300 nm – typically grouped together in sieve plates. Aging and several liver disorders severely reduce LSEC porosity, decreasing their filtration properties. Over the years, a variety of drugs, stimulants, and toxins have been investigated in the context of altered diameter or frequency of fenestrations. In fact, any change in the porosity, connected with the change in number and/or size of fenestrations is reflected in the overall liver-vascular system crosstalk. Recently, several commonly used medicines have been proposed to have a beneficial effect on LSEC re-fenestration in aging. These findings may be important for the aging populations of the world. In this review we collate the literature on medicines, recreational drugs, hormones and laboratory tools (including toxins) where the effect LSEC morphology was quantitatively analyzed. Moreover, different experimental models of liver pathology are discussed in the context of fenestrations. The second part of this review covers the cellular mechanisms of action to enable physicians and researchers to predict the effect of newly developed drugs on LSEC porosity. To achieve this, we discuss four existing hypotheses of regulation of fenestrations. Finally, we provide a summary of the cellular mechanisms which are demonstrated to tune the porosity of LSEC.
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.709804
Individuals sojourning at high altitude (≥2,500m) often develop acute mountain sickness (AMS). However, substantial unexplained inter-individual variability in AMS severity exists. Untargeted metabolomics assays are increasingly used to identify novel biomarkers of susceptibility to illness, and to elucidate biological pathways linking environmental exposures to health outcomes. This study used untargeted nuclear magnetic resonance (NMR)-based metabolomics to identify urine metabolites associated with AMS severity during high altitude sojourn. Following a 21-day stay at sea level (SL; 55m), 17 healthy males were transported to high altitude (HA; 4,300m) for a 22-day sojourn. AMS symptoms measured twice daily during the first 5days at HA were used to dichotomize participants according to AMS severity: moderate/severe AMS (AMS; n=11) or no/mild AMS (NoAMS; n=6). Urine samples collected on SL day 12 and HA days 1 and 18 were analyzed using proton NMR tools and the data were subjected to multivariate analyses. The SL urinary metabolite profiles were significantly different (p≤0.05) between AMS vs. NoAMS individuals prior to high altitude exposure. Differentially expressed metabolites included elevated levels of creatine and acetylcarnitine, and decreased levels of hypoxanthine and taurine in the AMS vs. NoAMS group. In addition, the levels of two amino acid derivatives (4-hydroxyphenylpyruvate and N-methylhistidine) and two unidentified metabolites (doublet peaks at 3.33ppm and a singlet at 8.20ppm) were significantly different between groups at SL. By HA day 18, the differences in urinary metabolites between AMS and NoAMS participants had largely resolved. Pathway analysis of these differentially expressed metabolites indicated that they directly or indirectly play a role in energy metabolism. These observations suggest that alterations in energy metabolism before high altitude exposure may contribute to AMS susceptibility at altitude. If validated in larger cohorts, these markers could inform development of a non-invasive assay to screen individuals for AMS susceptibility prior to high altitude sojourn.
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.726414
Purpose: To develop a method for individual parameter estimation of four hydraulic-analogy bioenergetic models and to assess the validity and reliability of these models’ prediction of aerobic and anaerobic metabolic utilization during sprint roller-skiing. Methods: Eleven elite cross-country skiers performed two treadmill roller-skiing time trials on a course consisting of three flat sections interspersed by two uphill sections. Aerobic and anaerobic metabolic rate contributions, external power output, and gross efficiency were determined. Two versions each (fixed or free maximal aerobic metabolic rate) of a two-tank hydraulic-analogy bioenergetic model (2TM-fixed and 2TM-free) and a more complex three-tank model (3TM-fixed and 3TM-free) were programmed into MATLAB. The aerobic metabolic rate (MR ae ) and the accumulated anaerobic energy expenditure (E an,acc ) from the first time trial (STT1) together with a gray-box model in MATLAB, were used to estimate the bioenergetic model parameters. Validity was assessed by simulation of each bioenergetic model using the estimated parameters from STT1 and the total metabolic rate (MR tot ) in the second time trial (STT2). Results: The validity and reliability of the parameter estimation method based on STT1 revealed valid and reliable overall results for all the four models vs. measurement data with the 2TM-free model being the most valid. Mean differences in model-vs.-measured MR ae ranged between -0.005 and 0.016 kW with typical errors between 0.002 and 0.009 kW. Mean differences in E an,acc at STT termination ranged between −4.3 and 0.5 kJ and typical errors were between 0.6 and 2.1 kJ. The root mean square error (RMSE) for 2TM-free on the instantaneous STT1 data was 0.05 kW for MR ae and 0.61 kJ for E an,acc , which was lower than the other three models (all P < 0.05). Compared to the results in STT1, the validity and reliability of each individually adapted bioenergetic model was worse during STT2 with models underpredicting MR ae and overpredicting E an,acc vs. measurement data (all P < 0.05). Moreover, the 2TM-free had the lowest RMSEs during STT2. Conclusion: The 2TM-free provided the highest validity and reliability in MR ae and E an,acc for both the parameter estimation in STT1 and the model validity and reliability evaluation in the succeeding STT2.
Frontiers in Physiology, Volume 12; https://doi.org/10.3389/fphys.2021.705153
Background: Induction of anesthesia with propofol is associated with a disturbance in hemodynamics, in part due to its effects on parasympathetic and sympathetic tone. The impact of propofol on autonomic function is unclear. In this study, we investigated in detail the changes in the cardiac autonomic nervous system (ANS) and peripheral sympathetic outflow that occur during the induction of anesthesia. Methods: Electrocardiography and pulse photoplethysmography (PPG) signals were recorded and analyzed from 30 s before to 120 s after propofol induction. The spectrogram was derived by continuous wavelet transform with the power of instantaneous high-frequency (HFi) and low-frequency (LFi) bands extracted at 1-s intervals. The wavelet-based parameters were then divided into the following segments: (1) baseline (30 s before administration of propofol), (2) early phase (first minute after administration of propofol), and (3) late phase (second minute after administration of propofol) and compared with the same time intervals of the Fourier-based spectrum [high-frequency (HF) and low-frequency (LF) bands]. Time-dependent effects were explored using fractional polynomials and repeated-measures analysis of variance. Results: Administration of propofol resulted in reductions in HFi and LFi and increases in the LFi/HFi ratio and PPG amplitude, which had a significant non-linear relationship. Significant between-group differences were found in the HFi, LFi, and LFi/HFi ratio and Fourier-based HF and LF after dividing the segments into baseline and early/late phases. On post hoc analysis, changes in HFi, LFi, and the LFi/HFi ratio were significant starting from the early phase. The corresponding effect size (partial eta squared) was > 0.3, achieving power over 90%; however, significant decreases in HF and LF were observed only in the late phase. The PPG amplitude was increased significantly in both the early and late phases. Conclusion: Propofol induction results in significant immediate changes in ANS activity that include temporally relative elevation of cardiac sympathovagal balance and reduced sympathetic activity. Clinical Trial Registration: The study was approved by the Institutional Review Board of Taipei Veterans General Hospital (No. 2017-07-009CC) and is registered at ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03613961).