American journal of physiology. Regulatory, integrative and comparative physiology最新文献

Accurate and reproducible tools to evaluate skeletal muscle contractility help to advance the field of physiology by defining skeletal muscle function in the context of skeletal muscle development, disease, aging, and injury recovery. The biomechanical assessment of muscle strength can be accomplished by measuring in vivo muscle torque, specifically, the muscle force generated at a moment arm around a joint. This approach to assess skeletal muscle contractility in preclinical animal studies primarily measures muscle torque in anesthetized animals using noninvasive electrophysiological stimulation. This method is advantageous because skeletal muscle contractions are evoked in a controlled, quantifiable manner that is independent of subject motivation, allowing for maximal functional data and reproducible research outcomes. The purpose of this Cores of Reproducibility in Physiology (CORP) review is to discuss the underlying physiology of the in vivo method, to highlight common outcomes and their physiological importance, and to provide considerations for technical reproducibility and data interpretation. The hope is this CORP will provide skeletal muscle researchers with the foundational and practical knowledge to better incorporate the in vivo technique in their future studies.

Dynamic cerebral autoregulation (dCA) demonstrates directional sensitivity (DS_CA), depending on increases or reductions in mean arterial blood pressure (MAP). DS_CA dependence on the efficiency of dCA has not been reported. A retrospective study of 172 healthy subjects (88 female, age 19-82 yr), with 5-min recordings of MAP, cerebral blood velocity (middle cerebral artery, MCAv), end-tidal CO₂, and electrocardiogram, led to estimates of the MCAv step response to changes in MAP. The strength of DS_CA was expressed by the difference between the MCAv step responses for the positive derivative component of MAP and the corresponding negative derivative component. The efficiency of dCA was expressed by the original autoregulation index (ARI_orig), ranging from 0 to 9, calculated from the original MAP. For the entire population, DS_CA strength was not associated with ARI_orig or any other parameters. However, when taking biological sex and age into account, markers of DS_CA strength showed significant linear regressions with ARI_orig, with negative slopes for younger females (P = 0.0037-0.011, late phase of the step responses), no influence in older females (P > 0.69), and positive slopes for both younger and older males (early phase of the step responses, P = 0.003-0.041). This contrasting pattern of the influences of sex and age is in agreement with the known effects of gonadal hormones on the myogenic response and endothelial function of the cerebral circulation. Clinical studies of the diagnostic and/or prognostic value of DS_CA parameters need to take into account the influences of sex, age, and the ARI_orig.NEW & NOTEWORTHY Dynamic cerebral autoregulation (dCA) is more efficient for increases in mean arterial blood pressure (MAP) compared with reductions in MAP. We found that directional sensitivity of dCA is dependent on its efficiency, with differences depending on sex and age. In older women, strength of directional sensitivity (DS_CA) is not affected by dCA efficiency, but in younger women, DS_CA decreases with dCA efficiency, whereas in both younger and older men, DS_CA strength increases with dCA efficiency.

The differential diagnosis within polyuria-polydipsia syndrome, especially in the pediatric population, remains challenging. Despite its limited accuracy, the water deprivation test (WDT) is the reference test in pediatrics. We retrospectively analyzed WDT performed in 65 pediatric patients (mean age 8.2 yr; 0-17.9). We evaluated the accuracy and safety of the WDT, investigated possible baseline variables that could predict outcomes, and reevaluated interruption and interpretation criteria. Among the 83 WTDs performed, 47 (56.6%) were conclusive (accuracy = 53%). The simplified 2-h WDT was inconclusive in 47.6% of the sample. A baseline urinary osmolality (uOsm) greater than 279 mosmol/kgH₂O excluded arginine vasopressin deficiency (AVP-D) and/or AVP resistance (AVP-R) in all patients (sensitivity = 100%; specificity = 74%; P < 0.01). A uOsm greater than 533 mOsm/kgH₂O at the time of WTD discontinuation also excluded the diagnosis of AVP disorders in all subjects (sensitivity = 100%; specificity = 100%; P < 0.01). Therefore, a baseline uOsm > 279 mOsm/kgH₂O and a peak uOsm > 533 mOsm/kgH₂O excluded AVP disorders. These new cutoffs can improve WDT accuracy and should be validated in prospective studies. No serious adverse effects (SAEs) were observed. The lower limit of 3% weight loss was the criterion for early WDT interruption in nine conclusive tests. The demonstrated safety encourages us to use weight losses greater than 5% as stopping intervals and also tolerate a more extended test duration when necessary. In conclusion, WDT in children and adolescents is safe and still necessary until better diagnostic tools are proven helpful in pediatric patients with polyuria-polydipsia syndrome.NEW & NOTEWORTHY This large pediatric cohort study confirms the safety of the water deprivation test but reveals its limited diagnostic accuracy. Updated diagnostic criteria can improve performance and reduce unnecessary testing. A baseline urinary osmolality (uOsm) > 279 mOsm/kgH₂O excluded arginine vasopressin (AVP) disorders with 100% sensitivity and 74% specificity and an interrupt uOsm > 533 mOsm/kgH₂O excluded them with 100% sensitivity and specificity. A weight loss >5% was a safe threshold. Prospective, multicenter studies are needed to generalize these findings.

Current therapeutics for hypoxic/ischemic brain damage can benefit from insights resulting from the study of hypoxia/anoxia-resistant organisms. Hypoxia resistance, however, is not a common feature in mammalian models. Being naturally exposed to hypoxic/anoxic conditions, the sea hare Aplysia californica could become a very useful model for the study of hypoxia resistance. Here, we experimentally exposed two cohorts of A. californica, resulting from crosses of adults with different environmental exposure histories, to daily 6 h pulses of hypoxic water conditions (<1.8 mgO₂/mL) for six consecutive days. The transcriptional response to hypoxia was evaluated in the abdominal and pleural/pedal ganglia through the exposure, during rapid reoxygenation, and after >12 h of recovery. Resistance to hypoxia was observed in the offspring of wild animals, with no significant changes in growth and reflex performance, compared with unexposed controls of the same cohort. Impairments were observed however in the offspring of lab-reared individuals. Transcriptional response to hypoxia was larger in the abdominal ganglia compared with the pleural/pedal for both cohorts, and significant differences between cohorts were observed for both ganglia. Overall, wild-cross animals displayed a significant reduction in the expression of metabolic genes, and an increased expression of genes involved in stress-response and immune system functions compared with the lab-cross cohort, both under control conditions and during hypoxia exposures. The resistant group displayed similar gene-level regulation as that described to be involved in hypoxia/ischemia preconditioning (HPC/IPC) in mammalian models, including the frontloading of HIF1-a orthologs and other neuroprotective genes like VEGF and HSP70.NEW & NOTEWORTHY Our results indicate that regular exposure to challenging natural conditions activates mechanisms involved in hypoxia resistance in Aplysia californica. This experience is passed to the next generation, fading in the absence of exposure for at least two generations. Gene expression and physiological responses varied significantly between resistant and sensitive sea hares under normoxic and hypoxic conditions, displaying clear evidence of preconditioning in core hypoxia response pathways like HIF.

Penguins are among the most specialized thermoregulators on the planet; however, the same adaptations that maximize heat retention underwater likely hinder heat dissipation on land, possibly creating dangerous thermoregulatory challenges when encountering warming terrestrial habitats. Penguins are subject to strictly terrestrial phases, such as molting, when metabolic heat production, insulation, and energetic constraints are heightened. We assessed thermoregulation in molting captive king penguins (Aptenodytes patagonicus) using simultaneous measurements of core and surface temperatures to test two hypotheses. Under the thermal challenge hypothesis, an initial rise in heat dissipation effort (i.e., increased peripheral vasomotion) followed by a rise in core temperature would indicate failure to prevent hyperthermia. Under the warm-up hypothesis, an initial rise of core temperature concomitant or followed by an increase in peripheral vasomotion would indicate regulated hyperthermia, possibly to accelerate feather development. Core and surface temperatures increased drastically but concomitantly during molt, providing tentative support to the warm-up hypothesis. Molting penguins did not pant, suggesting that peripheral heat dissipation was sufficient to regulate molting-induced hyperthermia. Core and subcutaneous temperatures in wild individuals resembled patterns measured in captivity, despite lower heat load and additional options for behavioral thermoregulation. These results indicate that hyperthermia is prevalent in molting king penguins, and documenting the timing of temperature changes provides novel insights for the molting physiology of penguins. Because molting-induced hyperthermia may contribute to heat load, we caution that molting may increase the susceptibility of wild penguins to heat stress, especially as regions near the poles warm at a disproportionately rapid rate.NEW & NOTEWORTHY Penguins may experience heat stress while molting, which causes increased metabolic heat generation and insulation. We assessed thermoregulation in molting captive king penguins (Aptenodytes patagonicus) using simultaneous measurements of core and surface temperatures. By measuring temperature throughout the entirety of the molt, we found that hyperthermia and increased peripheral heat dissipation are prevalent in molting king penguins. We caution that molting-induced hyperthermia may contribute to the susceptibility of penguins to heat stress in the wild.

As climate change intensifies, marine organisms face multiple environmental stressors that challenge their survival and adaptability. Oxidative stress occurs when environmental conditions deviate far from an organism's optimal range, and responses vary due to diverse molecular and physiological pathways. Stress responses can differ by sex and be influenced by multiple stressors, yet the underlying mechanisms remain poorly understood. This study examined sex differences in stress response in copepods Calanus finmarchicus, one of the most ecologically important animals in the marine ecosystem. Adult males and females were exposed to paraquat, an oxidative stress inducer, to assess survival, metabolic rate, and expression of antioxidant genes and chaperones. In addition, females were subjected to combined heat and paraquat stress to explore interactive effects on stress tolerance. Males exhibited greater upregulation of antioxidant enzymes but had lower survival than females in response to paraquat exposure. Despite similar metabolic rates between sexes, females were larger and had greater lipid sac volume than males, which may contribute to their higher resilience and survival under paraquat exposure. In females, combined paraquat and heat stress had a synergistic detrimental effect on survival but only heat stress impacted metabolic rate. In addition, heat stress modulated female's gene expression, antagonizing glutathione-S-transferase III and enhancing superoxide dismutase expression. A potential threshold for superoxide dismutase and catalase fold change was identified in paraquat-exposed females. Understanding the variability in stress responses is crucial for predicting species resilience to climate change and environmental disturbances, ultimately informing conservation and ecosystem management strategies.NEW & NOTEWORTHY This individual-based study reveals sex-specific differences in stress responses of the copepod Calanus finmarchicus to oxidative stress, with males showing higher sensitivity but no significant different metabolic strategies compared with females. It also identifies the antagonistic and synergistic effects of heat and paraquat-induced oxidative stress on antioxidant gene expression, and a potential maximum threshold for superoxide dismutase and catalase fold change in females.

Ulcerative colitis (UC) is a serious inflammatory bowel disease with a significantly increasing incidence globally. Current treatment options often exhibit unstable efficacy and notable side effects, making the exploration of alternative therapies particularly important. Peucedanum praeruptorum Dunn, a traditional Chinese medicine, contains various bioactive compounds, among which praeruptorin A (PA) has garnered attention for its anti-inflammatory potential. This study aimed to investigate the anti-UC effects of PA in a dextran sulfate sodium (DSS)-induced colitis mouse model and in Caco-2 cells and its underlying mechanisms. Preliminary results indicate that PA alleviates symptoms of DSS-induced ulcerative colitis, significantly reduces the expression of inflammatory factors, decreases colonic apoptosis, and repairs damaged intestinal barrier function in mice. PA also had protective effects on DSS-induced barrier dysfunction and inflammation in Caco-2 cells. Further research demonstrated that PA inhibits the phosphorylation of the STAT-1 and STAT-3 proteins, whereas AG490, an inhibitor of STAT-1 and STAT-3, effectively mimics the intestinal protective effects of PA. In addition, network pharmacology and molecular docking analyses were conducted to further elucidate the molecular targets and mechanisms of PA. These analyses revealed key pathways and potential interactions, supporting the hypothesis that PA exerts its protective effects through the modulation of inflammatory and apoptotic pathways. In summary, these findings support the protective role of PA in ulcerative colitis in vivo and in vitro and suggest its potential as an intervention for the prevention and treatment of this condition.NEW & NOTEWORTHY This study revealed that praeruptorin A (PA) alleviates symptoms of ulcerative colitis in a DSS-induced mouse model, reduces inflammatory factors levels, and promotes intestinal barrier repair in both DSS-induced colitis model mice and Caco-2 cells. The effects of PA are linked to STAT-1 and STAT-3 inhibition, highlighting its potential as a therapeutic intervention.

Insulin resistance has been associated with acute mountain sickness (AMS) risk, but the influence of active ascent is unclear. Thirty-two unacclimatized soldiers (23 ± 4 yr; 80 ± 14 kg) were tested at baseline residence (BLR), hiked ∼5 km (n = 16) or were driven (n = 16) to 4,300 m, and stayed for 4 days (∼66 h). Venous blood was taken each morning at BLR and during high altitude (HA) exposure days 2-4 (HA2-4) and the evening on day 1 at HA (HA1). Metabolites and hormones were measured, and insulin resistance (HOMA-IR) was calculated. AMS cerebral factor score (AMS-C) was measured daily and peak scores were calculated. Active ascenders had higher energy expenditure (1,265 ± 351 vs. 408 ± 208 kcal) and lower oxygen saturation ([Formula: see text]) (75 ± 3 vs. 82 ± 3%) during ascent. Norepinephrine and lactate were higher (P < 0.007) in active ascenders on HA1. All other data were combined due to lack of group differences. Glucose, insulin, and HOMA-IR were elevated (P < 0.05) on HA2 (105.9 ± 12.3 mg/dL; 12.1 ± 6.8 µIU/mL; 3.2 ± 2.1 au) and HA3 (101.8 ± 11.2 mg/dL; 10.2 ± 5.5 µIU/mL; 2.2 ± 1.4 au) vs. baseline and returned to normal on HA4. Epinephrine (P < 0.001) and cortisol (P = 0.004) were elevated on HA1 and HA2 vs. baseline, respectively. GLP-1 was higher on HA1 vs. HA2 and HA3 (P < 0.021). Glucose (r_rm = 0.42; P = 0.001), insulin (r_rm = 0.29; P = 0.001), HOMA-IR (r_rm = 0.27; P = 0.002), epinephrine (r_rm = 0.34; P < 0.001), and norepinephrine (r_rm = 0.20; P = 0.027) were significantly correlated with AMS-C. Transient perturbations to glucose metabolism during 4 days of HA exposure influences AMS severity without further impact from active ascent.NEW & NOTEWORTHY We demonstrate insulin resistance during 4 days of exposure at 4,300 m is positively correlated with acute mountain sickness (AMS) severity. This builds on previous data showing insulin sensitivity and carbohydrate metabolism at sea-level predict AMS. The blood glucose excursions appear at least partly mediated by cortisol and nocturnal hypoxemia.

Aging is associated with cerebrovascular impairment, increasing the risk for neurovascular and degenerative diseases. Intermittent hypoxic conditioning (IHC) has been proposed as a valuable strategy to enhance vascular health. However, its effects in cerebrovascular territories remain unclear, particularly in older adults. Eighteen elderly individuals (62-79 yr, 11 males) were randomly assigned to either an IHC (n = 8) or a control group (CTL, n = 10). Both groups underwent 24 sessions (3 sessions/wk) of passive moderate exposure to either intermittent hypoxia (targeted oxygen saturation by pulse oximetry = 75%-80%) or sham hypoxia. Middle cerebral artery (MCA) reactivity to hypo- (hyperventilation task) and hypercapnia (carbon dioxide ramp administration) was assessed using transcranial Doppler ultrasound. Cerebrovascular reactivity to carbon dioxide (CVR_CO2) was evaluated in both absolute and relative changes in MCA blood velocities (MCAv), before (Pre), 3-4 days after (post 1), and 2 mo after (post 2) intervention cessation. As expected, MCAv decreased during hypocapnia (CTL = -15.7 ± 7.0 cm/s; IHC = -15.9 ± 6.0 cm/s) and increased during hypercapnia (CTL = 20.7 ± 8.4 cm/s; IHC = 18.2 ± 11.1 cm/s) at all time points in both groups. However, compared with CTL, IHC did not significantly improve any CVR_CO2 parameters (e.g., relative CVR_CO2 to hypercapnia, Pre: CTL = 4.3 ± 1.9, IHC = 3.1 ± 2.0; post 1: CTL = 4.1 ± 1.6, IHC = 3.4 ± 1.6; post 2: CTL = 4.7 ± 2.0, IHC = 3.5 ± 1.7 cm/s/mmHg; P = 0.739). The present work does not support the potential benefits of IHC on cerebrovascular function. However, future studies are required to confirm these preliminary results and may consider a more comprehensive appraisal of the cerebral hemodynamic control.NEW & NOTEWORTHY This study is the first to investigate the effects of IHC on CVR_CO2 over the short- and mid-term in elderly individuals. Contrary to our initial hypothesis, 8 wk of moderate IHC did not enhance CVR_CO2 at any time point.

Irisin contributes critically to modulating metabolism and tissue survival in muscles and adipocytes. Whether deficiency of irisin impacts the hemorrhagic injury and/or whether the effect of irisin deficiency on hemorrhagic injury primarily relies on irisin, which is currently unknown. We use an irisin knockout mouse to eliminate irisin and pharmacological approaches in a mouse hemorrhagic model to determine the function of irisin on hemorrhage and resuscitation (H/R). Hemorrhage was induced by achieving a mean arterial blood pressure of 35-45 mmHg for 60 min, followed by 2 h of resuscitation in mice. Experimental groups were divided as follows (n = 6-8 per group): sham groups I and II: wild-type (WT) mice and irisin-knockout (KO) mice were subjected to femoral catheterization without H/R; groups III and IV: WT mice and irisin-KO mice were subjected to H/R, respectively; groups V and VI: irisin (50 μg/kg, iv) was infused into WT and irisin-KO H/R mice during resuscitation. Mean blood pressure, myocardial function, serum cytokine, inflammatory cell infiltration, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptosis, active caspase 3, components of oxidative phosphorylation, and mitochondrial ATPase activity in muscles were determined. Irisin deficiency exacerbated cardiac dysfunction in H/R in association with increases in interleukin 6, the infiltration of inflammatory cells, active caspase-3, and reduced oxidative phosphorylation and ATPase activities. The effects of irisin deletion on H/R were rescued by irisin. Deletion of irisin exacerbated injury of H/R, which was rescued by infusion of irisin, suggesting a key role of irisin in the regulation of hemorrhage/resuscitation.NEW & NOTEWORTHY Deletion of irisin resulted in a reduction in cardiac function and hemodynamics and exacerbated inflammation and tissue injury in response to hemorrhagic injury. Irisin rescued the hemorrhage-induced cardiac depression and attenuated the inflammatory response induced by irisin deficiency in hemorrhagic injury, suggesting that irisin contributes critically to the protective role in hemorrhage/resuscitation.