Frontiers in Physiology

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ISSN / EISSN : 1664-042X / 1664-042X
Current Publisher: Frontiers Media SA (10.3389)
Total articles ≅ 10,200
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Bing Zhang, Xiaojun Tian, Guangqi Li, Han Zhao, Xuan Wang, Yanwei Yin, Junmin Yu,
Published: 12 May 2021
Frontiers in Physiology, Volume 12; doi:10.3389/fphys.2021.615974

Methane (CH4) exerted protective effects against lung ischemia-reperfusion (I/R) injury, but the mechanism remains unclear, especially the role of pulmonary surfactant. Therefore, this study aimed to explore the effects of CH4 inhalation on pulmonary surfactant in rat lung I/R injury and to elucidate the mechanism. Rats were randomly divided into three groups (n = 6): the sham, I/R control, and I/R CH4 groups. In the sham group, only thoracotomy was performed on the rats. In the I/R control and I/R CH4 groups, the rats underwent left hilum occlusion for 90 min, followed by reperfusion for 180 min and ventilation with O2 or 2.5% CH4, respectively. Compared with those of the sham group, the levels of large surfactant aggregates (LAs) in pulmonary surfactant, lung compliance, oxygenation decreased, the small surfactant aggregates (SAs), inflammatory response, oxidative stress injury, and cell apoptosis increased in the control group (P < 0.05). Compared to the control treatment, CH4 increased LA (0.42 ± 0.06 vs. 0.31 ± 0.09 mg/kg), oxygenation (201 ± 11 vs. 151 ± 14 mmHg), and lung compliance (16.8 ± 1.0 vs. 11.5 ± 1.3 ml/kg), as well as total antioxidant capacity and Nrf2 protein expression and decreased the inflammatory response and number of apoptotic cells (P < 0.05). In conclusion, CH4 inhalation decreased oxidative stress injury, inflammatory response, and cell apoptosis, and improved lung function through Nrf2-mediated pulmonary surfactant regulation in rat lung I/R injury.
, Jean-Christophe Lagacé, Martin Brochu, Isabelle J. Dionne
Published: 12 May 2021
Frontiers in Physiology, Volume 12; doi:10.3389/fphys.2021.656909

Skeletal muscle (SM) tissue has been repetitively shown to play a major role in whole-body glucose homeostasis and overall metabolic health. Hence, SM hypertrophy through resistance training (RT) has been suggested to be favorable to glucose homeostasis in different populations, from young healthy to type 2 diabetic (T2D) individuals. While RT has been shown to contribute to improved metabolic health, including insulin sensitivity surrogates, in multiple studies, a universal understanding of a mechanistic explanation is currently lacking. Furthermore, exercised-improved glucose homeostasis and quantitative changes of SM mass have been hypothesized to be concurrent but not necessarily causally associated. With a straightforward focus on exercise interventions, this narrative review aims to highlight the current level of evidence of the impact of SM hypertrophy on glucose homeostasis, as well various mechanisms that are likely to explain those effects. These mechanistic insights could provide a strengthened rationale for future research assessing alternative RT strategies to the current classical modalities, such as low-load, high repetition RT or high-volume circuit-style RT, in metabolically impaired populations.
, Gregory J. Grosicki
Published: 12 May 2021
Frontiers in Physiology, Volume 12; doi:10.3389/fphys.2021.660818

The cellular events underpinning exercise adaptation have long been studied since Holloszy's novel findings in rodents over 50 years ago (Holloszy, 1967). Contemporary advances in laboratory techniques have allowed researchers to further explore physiological adaptations to physical activity, and much attention has been given to elucidating the distinct biochemical responses to exercise of varying intensities. More specifically, comparison of high intensity interval training (HIIT) or sprint interval training (SIT), to moderate intensity continuous training (MICT) has been an area of great interest among exercise physiologists. Spearheading these investigations, Burgomaster and colleagues provided evidence for robust and comparable metabolic adaptations when 6-weeks of low-volume SIT was pitted against conventional MICT, despite markedly reduced total training volume in the SIT group (66% less time, 90% less energy expenditure) (Burgomaster et al., 2008). Follow-up studies supporting these findings have provided continued enthusiasm for HIIT/SIT as a time-efficient strategy to improve cardiometabolic health (Gillen and Gibala, 2014; Gillen et al., 2016; Wolfe et al., 2020). HIIT has since become one of the most popular fitness trends as reported by the American College of Sports Medicine (ACSM) (#5 in 2021 survey) (Thompson, 2021). While we acknowledge these findings and are advocates for HIIT, we feel as though it is also important to appreciate the discrepant nature of HIIT and MICT, which may foster unique physiological adaptations with relevant health implications. Few, if any of these adaptations are mutually exclusive, but their magnitude may vary in a manner that should be considered to when determining exercise prescription. Cardiorespiratory fitness (i.e., VO2max) is an independent predictor of cardiovascular and all-cause mortality (Myers et al., 2002) and sets the upper limit for aerobic metabolism (Joyner, 1991; Joyner and Coyle, 2008), justifying its use as an endpoint for studies comparing HIIT vs. MICT. By in large, most (Burgomaster et al., 2008), but not all (Gillen et al., 2016; Gerosa-Neto et al., 2019), studies show greater improvements in VO2max with HIIT vs. MICT (Milanović et al., 2015) (Helgerud et al., 2007). For example, in an 8-week training study Helgerud and colleagues observed significantly greater improvements in VO2max (~4-5ml/kg/min), cardiac output (~3L/min), and stroke volume (~15ml/beat) with HIIT [~95% max heart rate (MHR)] vs. MICT (70% MHR) (Helgerud et al., 2007). Similar findings were seen in obese men and women where the 4 × 4-min group had greater VO2max gains (10%) compared to 10 × 1-min (3.3%) or 45-min of MICT (3.1%) (Bækkerud et al., 2016), but differs from the results of Morales-Palomo using equivalent exercise dosages in those with metabolic syndrome (MetS), where all groups improved equally (~12%) (Morales-Palomo et al., 2019). However, given the documented role of central factors in limiting maximal oxygen consumption (Saltin, 1985), it seems reasonable that efforts limited by VO2max would preferentially promote central cardiovascular adaptations. An important consideration is the potential for diminishing returns (Tjønna et al., 2013) and cardiac complications (O'keefe et al., 2012) with excess volumes of high intensity endurance training. In untrained but otherwise healthy subjects, Tjonna and colleagues demonstrated that a single 4-min high intensity treadmill bout 3x/week elicited equivalent improvement in VO2max (~10%) as the same workload repeated four times per session (Tjønna et al., 2013). Further, it should be noted that extreme high intensity training volumes undertaken in a small subset of endurance athletes may be deleterious to heart health (O'keefe et al., 2012). Nonetheless, the inverse dose-response relationship between exercise volume and mortality (Arem et al., 2015) suggests volume plays a critical role in mediating the health benefits associated with physical activity, but unfortunately the specific dose of exercise was unavailable in this retrospective cohort. Ultimately, whether the benefits of MICT can be achieved through low volume HIIT is unclear, and worthy of greater scrutiny. Prolonged efforts of low-moderate intensity training (40–70% HRR; 1yr) are needed to validate the safety and efficacy of long-term HIIT, as it is currently unclear how physiological adaptations to HIIT vs. MICT would manifest over more than the typical 8–12 weeks employed in conventional training studies. Extrapolating these data to suggest HIIT as the superior exercise mode, or as a [retracted] 2019 meta-analysis coined it: a “magic bullet” (Viana et al., 2019), is premature and unjustified given the current literature. Figure 1. Comparing physiological adaptations between MICT and HIIT/SIT. Two arrows denotes greater magnitude of adaptation. A one-size-fits-all approach is rarely the case in physiology. Further, a training distribution of >20% higher intensity training at the expense of MICT may cause autonomic disruption and diminishing performance returns (Stoggl and Sperlich, 2015). While this work examined elite endurance athletes who are not representative of the general population, a regimen consisting of only HIIT/SIT could promote overtraining pathology and stagnate the training process along with persistent complex I bypass which could prove to be undesirable resulting in a curtailment of performance/health adaptations. Thus, appreciable amounts MICT appears to be a necessary component of training, supported by the proposed volume-dependence of mitochondrial adaptation to exercise (Bishop et al., 2019b). If improved health is the desired outcome, adopting a pyramidal training intensity distribution similar that of elite athletes (Stoggl and Sperlich, 2015) with varying intensities may likely the preferred approach to promote sustainability and to reap all the...
Israel Pérez-Torres, Verónica Guarner-Lans, Elizabeth Soria-Castro, Linaloe Manzano-Pech, Adrián Palacios-Chavarría, Rafael Ricardo Valdez-Vázquez, Jose Guillermo Domínguez-Cherit, Hector Herrera-Bello, Humberto Castillejos-Suastegui, Lidia Moreno-Castañeda, et al.
Published: 11 May 2021
Frontiers in Physiology, Volume 12; doi:10.3389/fphys.2021.667024

The kidnapping of the lipid metabolism of the host’s cells by severe acute respiratory syndrome (SARS-CoV-2) allows the virus to transform the cells into optimal machines for its assembly and replication. Here we evaluated changes in the fatty acid (FA) profile and the participation of the activity of the desaturases, in plasma of patients with severe pneumonia by SARS-CoV-2. We found that SARS-CoV-2 alters the FA metabolism in the cells of the host. Changes are characterized by variations in the desaturases that lead to a decrease in total fatty acid (TFA), phospholipids (PL) and non-esterified fatty acids (NEFAs). These alterations include a decrease in palmitic and stearic acids (p ≤ 0.009) which could be used for the formation of the viral membranes and for the reparation of the host’s own membrane. There is also an increase in oleic acid (OA; p = 0.001) which could modulate the inflammatory process, the cytokine release, apoptosis, necrosis, oxidative stress (OS). An increase in linoleic acid (LA) in TFA (p = 0.03) and a decreased in PL (p = 0.001) was also present. They result from damage of the internal mitochondrial membrane. The arachidonic acid (AA) percentage was elevated (p = 0.02) in the TFA and this can be participated in the inflammatory process. EPA was decreased (p = 0.001) and this may decrease of pro-resolving mediators with increase in the inflammatory process. The total of NEFAs (p = 0.03), PL (p = 0.001), cholesterol, HDL and LDL were decreased, and triglycerides were increased in plasma of the COVID-19 patients. Therefore, SARS-CoV-2 alters the FA metabolism, the changes are characterized by alterations in the desaturases that lead to variations in the TFA, PL, and NEFAs profiles. These changes may favor the replication of the virus but, at the same time, they are part of the defense system provided by the host cell metabolism in its eagerness to repair damage caused by the virus to cell membranes.
Seth M. Davis, Jared T. Zuke, Mariah R. Berchulski,
Published: 11 May 2021
Frontiers in Physiology, Volume 12; doi:10.3389/fphys.2021.660792

Neonatal pain such as that experienced by infants in the neonatal intensive care unit is known to produce later-life dysfunction including heightened pain sensitivity and anxiety, although the mechanisms remain unclear. Both chronic pain and stress in adult organisms are known to influence the corticotropin-releasing factor (CRF) system in the Central Nucleus of the Amygdala, making this system a likely candidate for changes following neonatal trauma. To examine this, neonatal rats were subjected to daily pain, non-painful handling or left undisturbed for the first week of life. Beginning on postnatal day, 24 male and female rats were subjected to a 4-day fear conditioning and sensory testing protocol. Some subjects received intra-amygdalar administration of either Vehicle, the CRF receptor 1 (CRF1) receptor antagonist Antalarmin, or the CRF receptor 2 (CRF2) receptor antagonist Astressin 2B prior to fear conditioning and somatosensory testing, while others had tissue collected following fear conditioning and CRF expression in the CeA and BLA was assessed using fluorescent in situ hybridization. CRF1 antagonism attenuated fear-induced hypersensitivity in neonatal pain and handled rats, while CRF2 antagonism produced a general antinociception. In addition, neonatal pain and handling produced a lateralized sex-dependent decrease in CRF expression, with males showing a diminished number of CRF-expressing cells in the right CeA and females showing a similar reduction in the number of CRF-expressing cells in the left BLA compared to undisturbed controls. These data show that the amygdalar CRF system is a likely target for alleviating dysfunction produced by early life trauma and that this system continues to play a major role in the lasting effects of such trauma into the juvenile stage of development.
Soroosh Sanatkhani, Sotirios Nedios, Prahlad G. Menon, Andreas Bollmann, Gerhard Hindricks,
Published: 11 May 2021
Frontiers in Physiology, Volume 12; doi:10.3389/fphys.2021.633135

Atrial fibrillation (AF) is the most common arrhythmia that leads to thrombus formation, mostly in the left atrial appendage (LAA). The current standard of stratifying stroke risk, based on the CHA2DS2-VASc score, does not consider LAA morphology, and the clinically accepted LAA morphology-based classification is highly subjective. The aim of this study was to determine whether LAA blood-borne particle residence time distribution and the proposed quantitative index of LAA 3D geometry can add independent information to the CHA2DS2-VASc score. Data were collected from 16 AF subjects. Subject-specific measurements included left atrial (LA) and LAA 3D geometry obtained by cardiac computed tomography, cardiac output, and heart rate. We quantified 3D LAA appearance in terms of a novel LAA appearance complexity index (LAA-ACI). We employed computational fluid dynamics analysis and a systems-based approach to quantify residence time distribution and associated calculated variable (LAA mean residence time, t m) in each subject. The LAA-ACI captured the subject-specific LAA 3D geometry in terms of a single number. LAA t m varied significantly within a given LAA morphology as defined by the current subjective method and it was not simply a reflection of LAA geometry/appearance. In addition, LAA-ACI and LAA t m varied significantly for a given CHA2DS2-VASc score, indicating that these two indices of stasis are not simply a reflection of the subjects' clinical status. We conclude that LAA-ACI and LAA t m add independent information to the CHA2DS2-VASc score about stasis risk and thereby can potentially enhance its ability to stratify stroke risk in AF patients.
Lianguo Wang, Rachel C. Myles, I-Ju Lee, Donald M. Bers,
Published: 11 May 2021
Frontiers in Physiology, Volume 12; doi:10.3389/fphys.2021.656516

Sarcoplasmic reticulum (SR) Ca2+ cycling is tightly regulated by ryanodine receptor (RyR) Ca2+ release and sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) Ca2+ uptake during each excitation–contraction coupling cycle. We previously showed that RyR refractoriness plays a key role in the onset of SR Ca2+ alternans in the intact rabbit heart, which contributes to arrhythmogenic action potential duration (APD) alternans. Recent studies have also implicated impaired SERCA function, a key feature of heart failure, in cardiac alternans and arrhythmias. However, the relationship between reduced SERCA function and SR Ca2+ alternans is not well understood. Simultaneous optical mapping of transmembrane potential (Vm) and SR Ca2+ was performed in isolated rabbit hearts (n = 10) using the voltage-sensitive dye RH237 and the low-affinity Ca2+ indicator Fluo-5N-AM. Alternans was induced by rapid ventricular pacing. SERCA was inhibited with cyclopiazonic acid (CPA; 1–10 μM). SERCA inhibition (1, 5, and 10 μM of CPA) resulted in dose-dependent slowing of SR Ca2+ reuptake, with the time constant (tau) increasing from 70.8 ± 3.5 ms at baseline to 85.5 ± 6.6, 129.9 ± 20.7, and 271.3 ± 37.6 ms, respectively (p < 0.05 vs. baseline for all doses). At fast pacing frequencies, CPA significantly increased the magnitude of SR Ca2+ and APD alternans, most strongly at 10 μM (pacing cycle length = 220 ms: SR Ca2+ alternans magnitude: 57.1 ± 4.7 vs. 13.4 ± 8.9 AU; APD alternans magnitude 3.8 ± 1.9 vs. 0.2 ± 0.19 AU; p < 0.05 10 μM of CPA vs. baseline for both). SERCA inhibition also promoted the emergence of spatially discordant alternans. Notably, at all CPA doses, alternation of SR Ca2+ release occurred prior to alternation of diastolic SR Ca2+ load as pacing frequency increased. Simultaneous optical mapping of SR Ca2+ and Vm in the intact rabbit heart revealed that SERCA inhibition exacerbates pacing-induced SR Ca2+ and APD alternans magnitude, particularly at fast pacing frequencies. Importantly, SR Ca2+ release alternans always occurred before the onset of SR Ca2+ load alternans. These findings suggest that even in settings of diminished SERCA function, relative refractoriness of RyR Ca2+ release governs the onset of intracellular Ca2+ alternans.
Antonio Barajas-Martínez, Elizabeth Ibarra-Coronado, Ruben Fossion, Juan Claudio Toledo-Roy, Vania Martínez-Garcés, Juan Antonio López-Rivera, Geraldine Tello-Santoyo, Rusland D. Lavin, José Luis Gómez, Christopher R. Stephens, et al.
Published: 11 May 2021
Frontiers in Physiology, Volume 12; doi:10.3389/fphys.2021.678507

Within human physiology, systemic interactions couple physiological variables to maintain homeostasis. These interactions change according to health status and are modified by factors such as age and sex. For several physiological processes, sex-based distinctions in normal physiology are present and defined in isolation. However, new methodologies are indispensable to analyze system-wide properties and interactions with the objective of exploring differences between sexes. Here we propose a new method to construct complex inferential networks from a normalization using the clinical criteria for health of physiological variables, and the correlations between anthropometric and blood tests biomarkers of 198 healthy young participants (117 women, 81 men, from 18 to 27 years old). Physiological networks of men have less correlations, displayed higher modularity, higher small-world index, but were more vulnerable to directed attacks, whereas networks of women were more resilient. The networks of both men and women displayed sex-specific connections that are consistent with the literature. Additionally, we carried out a time-series study on heart rate variability (HRV) using Physionet’s Fantasia database. Autocorrelation of HRV, variance, and Poincare’s plots, as a measure of variability, are statistically significant higher in young men and statistically significant different from young women. These differences are attenuated in older men and women, that have similar HRV distributions. The network approach revealed differences in the association of variables related to glucose homeostasis, nitrogen balance, kidney function, and fat depots. The clusters of physiological variables and their roles within the network remained similar regardless of sex. Both methodologies show a higher number of associations between variables in the physiological system of women, implying redundant mechanisms of control and simultaneously showing that these systems display less variability in time than those of men, constituting a more resilient system.
Chrysoula Kourtidou-Papadeli, Christos A. Frantzidis, Sotiria Gilou, Christina E. Plomariti, Christiane M. Nday, Dimitrios Karnaras, Lefteris Bakas, Panagiotis D. Bamidis, Joan Vernikos
Published: 11 May 2021
Frontiers in Physiology, Volume 12; doi:10.3389/fphys.2021.644661

Purpose Increasing the level of gravity passively on a centrifuge, should be equal to or even more beneficial not only to astronauts living in a microgravity environment but also to patients confined to bed. Gravity therapy (GT) may have beneficial effects on numerous conditions, such as immobility due to neuromuscular disorders, balance disorders, stroke, sports injuries. However, the appropriate configuration for administering the Gz load remains to be determined. Methods To address these issues, we studied graded G-loads from 0.5 to 2.0g in 24 young healthy, male and female participants, trained on a short arm human centrifuge (SAHC) combined with mild activity exercise within 40–59% MHR, provided by an onboard bicycle ergometer. Hemodynamic parameters, as cardiac output (CO), stroke volume (SV), mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were analyzed, as well as blood gas analysis. A one-way repeated measures ANOVA and pairwise comparisons were conducted with a level of significance p < 0.05. Results Significant changes in heart rate variability (HRV) and its spectral components (Class, Fmax, and VHF) were found in all g loads when compared to standing (p < 0.001), except in 1.7 and 2.0g. There were significant changes in CO, cardiac index (CI), and cardiac power (CP) (p < 0.001), and in MAP (p = 0.003) at different artificial gravity (AG) levels. Dose-response curves were determined based on statistically significant changes in cardiovascular parameters, as well as in identifying the optimal G level for training, as well as the optimal G level for training. There were statistically significant gender differences in Cardiac Output/CO (p = 0.002) and Cardiac Power/CP (p = 0.016) during the AG training as compared to standing. More specifically, these cardiovascular parameters were significantly higher for male than female participants. Also, there was a statistically significant (p = 0.022) gender by experimental condition interaction, since the high-frequency parameter of the heart rate variability was attenuated during AG training as compared to standing but only for the female participants (p = 0.004). Conclusion The comprehensive cardiovascular evaluation of the response to a range of graded AG loads, as compared to standing, in male and female subjects provides the dose-response framework that enables us to explore and validate the usefulness of the centrifuge as a medical device. It further allows its use in precisely selecting personalized gravity therapy (GT) as needed for treatment or rehabilitation of individuals confined to bed.
Zairong Wei, Shenyou Shu, Mingjun Zhang, Sitian Xie, Shijie Tang, Kaiyu Nie,
Published: 10 May 2021
Frontiers in Physiology, Volume 12; doi:10.3389/fphys.2021.637924

Schwann cell-like cells (SCLCs) derived from human amniotic mesenchymal stem cells (hAMSCs) have been shown to promote peripheral nerve regeneration, but the underlying molecular mechanism was still poorly understood. In order to investigate the heterogeneity and potential molecular mechanism of SCLCs in the treatment of peripheral nerve regeneration at a single cell level, single-cell RNA sequencing was applied to profile single cell populations of hAMSCs and SCLCs. We profiled 6,008 and 5,140 single cells from hAMSCs and SCLCs, respectively. Based on bioinformatics analysis, pathways associated with proliferation, ECM organization, and tissue repair were enriched within both populations. Cell cycle analysis indicated that single cells within these two populations remained mostly in the G0/G1 phase. The transformation of single cells from hAMSCs to SCLCs was characterized by pseudotime analysis. Furthermore, we identified a subpopulation of SCLCs that highly expressed genes associated with Schwann cell proliferation, migration, and survival, such as JUN, JUND, and NRG1., Genes such as PTGS2, PITX1, VEGFA, and FGF2 that promote nerve regeneration were also highly expressed in single cells within this subpopulation, and terms associated with inflammatory and tissue repair were enriched in this subpopulation by pathway enrichment analysis. Our results indicate that a subpopulation of SCLCs with nerve regeneration signatures may be the key populations that promote nerve regeneration.
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