J. Appl. Physiol. [JOURNAL]
Sun
200 papers
Case study: dose-dependent internal jugular vein response to lower body negative pressure in microgravity quantified by the flow directionality index.
Pentinat-Llurba H, Whittle RS, Robin A … +15 more , Reinarz C, Laygo DB, Rao R, Herrmann M, Harrison N, Harrison C, Vera-Trallero I, Puente B, García-Alonso S, Lanéelle D, Harrison ML, Allen J, Seidler RD, Flores O, Diaz-Artiles A
J Appl Physiol (1985) · 2026 May · PMID 41886283 · Publisher ↗
Microgravity produces a headward fluid shift that alters venous hemodynamics and has been associated with stagnant or retrograde flow in the internal jugular vein (IJV), raising concern for thrombosis risk during spacefl...
Microgravity produces a headward fluid shift that alters venous hemodynamics and has been associated with stagnant or retrograde flow in the internal jugular vein (IJV), raising concern for thrombosis risk during spaceflight. Lower body negative pressure (LBNP) has emerged as a promising countermeasure to partially restore hydrostatic gradients, yet its physiological effects in true microgravity remain poorly characterized. In this case study, we applied graded LBNP (0, -20, and -30 mmHg) during parabolic flight in a single female participant and obtained matching supine baseline measurements on the ground. Bilateral IJV cross-sectional area and flow were quantified using ultrasound, and IJV pressure was measured using compression sonography. To enhance characterization of venous flow, we developed the continuous flow directionality index (FDI), integrating time spent in antegrade, retrograde, and stagnant flow. Compared with 1 baseline, microgravity was associated with a larger IJV cross-sectional area and lower IJV pressure. Increasing LBNP reduced both variables across gravity conditions. In microgravity, IJV flow at LBNP of 0 mmHg included periods of stagnation, whereas -20 and -30 mmHg progressively improved venous return, reflected by higher FDI values. FDI provided greater granularity than traditional qualitative grading, revealing differences in flow quality otherwise difficult to detect. These findings demonstrate the feasibility and physiological relevance of graded LBNP during true microgravity to mitigate cephalad fluid shift-related alterations in jugular venous hemodynamics and introduce a sensitive quantitative approach for evaluating venous flow. This work establishes a foundation for future multisubject studies aimed at optimizing countermeasures for long-duration spaceflight. Microgravity alters jugular venous flow, which in turn may increase thrombosis risk. In this graded lower body negative pressure experiment performed in true microgravity conditions during parabolic flight, we show that increasing negative pressure improves venous drainage in a dose-dependent manner. A new flow directionality index reveals subtle changes in flow not captured by existing grading systems, supporting lower body negative pressure as a practical countermeasure to mitigate stagnant internal jugular vein blood flow during future space missions.
Patient-specific lung simulation incorporating regional elastance and recruitment to guide mechanical ventilation in acute respiratory distress syndrome.
Dunphy R, Quicken S, Kimmenade JV … +9 more , Mangold J, Shekarnabi M, Estopier Castillo V, Orkisz M, De Bie Dekker A, Paulussen I, Richard JC, Huberts W, Bayat S
J Appl Physiol (1985) · 2026 May · PMID 41874332 · Publisher ↗
Mechanical ventilation (MV) plays a vital role in intensive care, ensuring sufficient gas exchange in patients with acute respiratory distress syndrome (ARDS). However, ventilator-induced lung injury (VILI) remains a fre...
Mechanical ventilation (MV) plays a vital role in intensive care, ensuring sufficient gas exchange in patients with acute respiratory distress syndrome (ARDS). However, ventilator-induced lung injury (VILI) remains a frequent complication associated with MV, arising due to local lung tissue hyperinflation (HI) and cyclic alveolar recruitment/derecruitment (R/D). Determining optimal ventilator settings is a clinical challenge, since the full spectrum of local lung mechanics in a heterogenous lung cannot be assessed with overall mechanical measurements nor with routine imaging modalities. Computational modeling offers a promising approach for personalizing mechanical ventilation settings, by predicting the local lung mechanical behavior. We propose an in silico model of the respiratory system of a mechanically ventilated patients with ARDS, which integrates local patient-specific lung characteristics. These include both structural (airway tree and lung morphology) and functional (regional lung elastance and R/D dynamics) information, inferred from computed tomography (CT) data obtained at two different respiratory pressure instances. Our proof-of-principle simulations indicate that the model plausibly estimates the global respiratory pressure-volume curve, as well as regional lung biomechanical behavior, under positive pressure ventilation. Furthermore, we show that this model can be used to simulate the effect of changes in ventilator settings such as positive end-expiratory pressure (PEEP) or to simulate an impaired lung with worsening biomechanics. This model thereby provides a mechanistic foundation to eventually support clinicians in delivering more precise, patient-specific therapies, by offering a supplementary tool for optimizing ventilator settings. This study presents a computational model for simulating ventilatory response in mechanically ventilated patients with acute respiratory distress syndrome and introduces a novel method to estimate patient-specific lung mechanical properties from a dual-volume computed tomography (CT) protocol. The key purpose of the in silico model proposed in this paper is to provide clinicians with a complementary modality that supports decision-making surrounding mechanical ventilation.
Differential biological responses to dyspnea-inducing experimental respiratory challenges in healthy humans.
Rolland-Debord C, Niérat MC, Bianquis C … +10 more , Becker C, Launay JM, Vodovar N, Benoliel JJ, Lavault S, Razakamanantsoa L, Rivals I, Salem JE, Similowski T, Morélot-Panzini C
J Appl Physiol (1985) · 2026 May · PMID 41874223 · Publisher ↗
Dyspnea is the symptom that conveys the upsetting or distressing awareness of respiratory sensations. It is part of an ensemble of respiratory, neurovegetative, and behavioral manifestations resulting from the brain's re...
Dyspnea is the symptom that conveys the upsetting or distressing awareness of respiratory sensations. It is part of an ensemble of respiratory, neurovegetative, and behavioral manifestations resulting from the brain's reaction to abnormal respiratory-related afferents. This attests to a systemic phenomenon and suggests the existence of measurable biological changes. Different types of experimental respiratory challenges evoke different perceptual, physiological, and psychological responses, suggesting distinct mechanisms and the possibility of varied systemic biological responses. We investigated this hypothesis in 34 healthy volunteers (17 women) exposed to inspiratory threshold loading (ITL) and carbon dioxide stimulation with restricted ventilation (CO2-rv), in a randomized cross-over design. Blood and saliva samples were collected at baseline (0), at the end of a 5-min dyspnea challenge (1), and at 30 and 60 min postchallenge (2 and 3). They were analyzed for neuromodulators and inflammatory biomarkers. Substance P levels rose at all time points during both challenges, but were significantly higher after CO2-rv than after ITL. β-Endorphin levels rose similarly after both challenges, with a correlation to affective dyspnea ratings during ITL only ( = 0.527, = 0.0023). Brain-derived neurotrophic factor (BDNF) decreased after both stimuli, with lower values following ITL. There were no significant changes in salivary α-amylase, FGF-2, TNF-α, IL-1β, IL-8, or indoleamine/tryptophan 2,3-dioxygenase (IDO/TDO) activity, and salivary cortisol decreased. These results provide a biological substrate for the differences between responses to respiratory challenges. They open new avenues toward biology-guided research into respiratory-related brain suffering. Dyspnea can be induced through different types of respiratory challenges, including inspiratory loading and carbon dioxide stimulation with restricted ventilation. These paradigms elicit different physiological, perceptual, and psychological responses, suggesting distinct modes of engagement of respiratory-related brain suffering. This study shows that the associated biological responses also differ: Substance P levels were higher during the CO challenge, whereas β-endorphin changes were more closely linked to effortful breathing. These results open new avenues toward biology-guided research into respiratory-related brain suffering.
Acute nicotine withdrawal blunts the hypoxic ventilatory response in young adult female rats.
Fale M, Flanigan EG, Agnello A … +1 more , Wollman LB
J Appl Physiol (1985) · 2026 May · PMID 41874189 · Publisher ↗
Nicotine withdrawal after chronic exposure causes dysregulation of neural circuits, producing a variety of adverse signs and symptoms that are largely mediated through changes to nicotinic acetylcholine receptors (nAChRs...
Nicotine withdrawal after chronic exposure causes dysregulation of neural circuits, producing a variety of adverse signs and symptoms that are largely mediated through changes to nicotinic acetylcholine receptors (nAChRs). nAChRs are expressed throughout neural circuits mediating the hypoxic ventilatory response (HVR); however, whether nicotine withdrawal impacts this critical chemoreflex is unknown. We tested the hypothesis that nicotine withdrawal blunts the HVR in rats. We exposed 6-wk-old male and female Sprague-Dawley rats to chronic nicotine through their drinking water (0.2 g/L nicotine in 1% saccharin). Before experiments, half of the nicotine-exposed rats were switched to saccharin water alone to produce a nicotine withdrawal group. Rats in the control group drank saccharin water alone. We used plethysmography to test the early- and late-phase ventilatory response to a 5-min episode of 10% oxygen in all rats, corresponding to 6, 24, and 48 h of withdrawal in the withdrawal group. In both male and female rats, serum cotinine was significantly reduced by 6 h of nicotine withdrawal. In males, the HVR was not different between treatment groups. However, in females, although the HVR was the same in control rats and rats who continued nicotine exposure, both the early- and late-phase HVR were significantly blunted in animals in nicotine withdrawal. Nicotine withdrawal, although uncomfortable, is not considered dangerous. However, these results indicate that a blunted HVR is a previously unidentified consequence of nicotine withdrawal, which may help to explain the link between nicotine withdrawal and worse clinical outcomes in hospitalized patients. Nicotine is the highly addictive component of tobacco, and nicotine withdrawal is often observed in hospitalized smokers and is associated with poor clinical outcomes. Here, we show that a blunted HVR is a previously unidentified, and sex-specific consequence of nicotine withdrawal, suggesting that female patients in nicotine withdrawal may experience relatively more severe oxygen desaturation for a given hypoxic episode, which could lead to end-organ damage or failure, especially in the brain and heart.
Sweat output on the dorsal aspect of the forearm and foot.
Mack GW, Young AM, Bahr K … +2 more , Renfro A, Robinson A
J Appl Physiol (1985) · 2026 Apr · PMID 41873896 · Publisher ↗
We have used intradermal electrical stimulation to elicit a direct local sweating response in a reliable and dose-dependent manner. We applied this model to describe the dose-response characteristics of the forearm and f...
We have used intradermal electrical stimulation to elicit a direct local sweating response in a reliable and dose-dependent manner. We applied this model to describe the dose-response characteristics of the forearm and foot. We hypothesized that the sweat volume-response curve would be similar for the foot and forearm. The local sweat rate (LSR) was determined with a small sweat capsule (0.53 cm) flushed with dry air (100 mL/min). A constant 5-mA electrical stimulus was applied to the intradermal space at 10 different frequencies (0.2, 1, 2, 4, 8, 10, 12, 16, 32, and 64 Hz) to generate the stimulus-response curves. Subjects rested at an ambient temperature of 28°C. The data (means ± 1 SD; = 15; 8 females and 7 males) revealed that the stimulus-response curves were significantly different ( < 0.001) with the foot sweating being slightly higher than the forearm at low-stimulus frequencies. When sweat output was normalized as a percentage of the maximal area under the curve the analysis revealed a 21% increase in sweat output [AUC (%max)] for the foot between stimulus frequencies 0.2, 1, 2, and 4 Hz. The overall response curve for the foot was shifted upward ( = 0.011) at the lowest four stimulus frequencies, and the EC was lower for the foot (7.29 ± 2.79 Hz) than the forearm (8.8 ± 2.39 Hz; = 0.002). The significantly higher baseline indicates that the foot was slightly more sensitive to mild intradermal electrical stimulation than the forearm. We noted a greater sensitivity of the foot during direct activation of the sudomotor nerves compared to the forearm. This observation contrasts with earlier findings indicating similar sweating responses from the dorsal aspect of the foot and forearm.
The effect of sex on ventricular filling pressure during graded exercise in healthy young adults.
Leahy MG, Howden EJ, Lawley JS … +4 more , Cornwell WK, MacNamara JP, Levine BD, Sarma S
J Appl Physiol (1985) · 2026 Apr · PMID 41850275 · Publisher ↗
There are several sex differences in cardiovascular morphology. Specifically, females have smaller cardiac chambers compared with males. Whether a smaller left ventricular (LV) size contributes to higher filling pressure...
There are several sex differences in cardiovascular morphology. Specifically, females have smaller cardiac chambers compared with males. Whether a smaller left ventricular (LV) size contributes to higher filling pressures during dynamic exercise is unknown. We tested the hypothesis that smaller LV volumes and smaller stroke volume (SV) reserve in young females would be associated with greater LV filling pressures. Fourteen young males ( = 7; 34 ± 3 yr; peak oxygen uptake: 48.1 ± 4.5 mL/kg/min) and females ( = 7; 31 ± 3 yr; 39.6 ± 4.1 mL/kg/min) completed a maximal exercise test and an invasive exercise test with right heart catheterization. Hemodynamic response, including pulmonary capillary wedge pressure (PCWP), cardiac output, and SV (direct Fick), was measured during upright rest and cycle exercise at a standard absolute heart rate of 100 beats/min, as well as 70% and 90% heart rate (HR) maximum (HR). Females had a greater PCWP during exercise ( = 0.038), specifically when heart rate was matched at 100 beats/min (males: 7 ± 3, females: 10 ± 2 mmHg, = 0.040) and at 90% HR (males: 8 ± 3, females: 14 ± 3 mmHg, = 0.006). Females also had a smaller SV reserve (46 ± 19%) than males (70 ± 20%, = 0.076). There was an inverse relationship between the change in SV with exercise and PCWP ( = 0.22, = 0.003). The PCWP-cardiac output slope was significantly greater in females (0.9 ± 0.3 mmHg/L/min) than males (0.3 ± 0.2 mmHg/L/min, = 0.004). Females have higher PCWP for a given cardiac output and lower SV during exercise than males. These findings suggest smaller, absolute LV volumes are less distensible, which may contribute to apparent sex differences in adaptations to chronic endurance training and performance. Young healthy females have greater filling pressures during dynamic exercise relative to males. The augmented filling pressure in females points to a less distensible ventricle associated with smaller cardiac dimensions.
Respiratory muscle dysfunction in mechanical ventilation: a systematic review and meta-analysis of biological mechanisms.
González-Seguel F, Gustafson O, Robinson CM … +8 more , Villablanca C, Olave C, Muñoz-Muñoz F, Caceres-Parra C, Parry SM, Wen Y, Dupont-Versteegden EE, Mayer KP
J Appl Physiol (1985) · 2026 Apr · PMID 41843932 · Full text
Revealing biological mechanisms leading to respiratory muscle dysfunction is essential to improve clinical outcomes in patients with critical illness. The purpose was to identify biological mechanisms associated with res...
Revealing biological mechanisms leading to respiratory muscle dysfunction is essential to improve clinical outcomes in patients with critical illness. The purpose was to identify biological mechanisms associated with respiratory muscle dysfunction in patients with critical illness during mechanical ventilation or sepsis. Six databases were electronically searched from inception to January 2025, examining studies with muscle biopsies. Screening, data collection, and risk-of-bias were conducted in duplicate by two independent assessors. Meta-analysis was performed to determine differences in muscle biological parameters of patients with critical illness requiring mechanical ventilation compared with controls. From 22,036 titles screened, eight studies ( = 187 patients and = 161 controls) published between 2000 and 2024 met eligibility criteria. Muscle biopsies were taken between and in the intensive care unit from the diaphragm ( = 110; 3 studies), rectus abdominis ( = 68; 5 studies), external intercostal ( = 10; 1 study), and latissimus dorsi ( = 3; 1 study). Diaphragmatic fiber cross-sectional area was 30% smaller (mean difference [95% confidence interval] = -629 [-876, -382] μm), with lower proportion of type II fibers (-1.94 [-3.40, -0.49]%) compared with controls. Diaphragmatic fiber force of patients was more than two standard deviations lower (standardized mean difference = -2.49 [-3.84, -1.14]), and ubiquitinated protein levels were higher (2.09 [-0.14, 4.32]) than controls. Extramyocellular, mitochondrial, and gene expression parameters were assessed in some studies, but low sample size and high heterogeneity prevented meta-analyses. In conclusion, muscle biopsies from ventilated patients revealed atrophy, contractile weakness, and proteolysis markers. Standardized methodologies assessing respiratory muscles are needed to clarify biological mechanisms leading to muscle dysfunction and to guide respiratory muscle interventions.
Reply to Bassett and Armstrong.
McKenna ZJ, Crandall CG
J Appl Physiol (1985) · 2026 Mar · PMID 41843430 · Publisher ↗
Abstract loading — click title to view on PubMed.
Impact of skin wetting on body cooling.
Bassett DR, Armstrong LE
J Appl Physiol (1985) · 2026 Mar · PMID 41843429 · Publisher ↗
Abstract loading — click title to view on PubMed.
Equivalent cumulative energy yields unequal lung injury: effects of tidal volume and ventilation duration in experimental lung injury.
Magalhães RF, Vilardo ALDS, Conceição PHLD … +11 more , Dos Santos ACM, Oliveira CM, Antunes MA, Silva JD, Crooke PS, Cruz FF, Samary CDS, Martins CM, Silva PL, Marini JJ, Rocco PRM
J Appl Physiol (1985) · 2026 Apr · PMID 41843426 · Publisher ↗
Mechanical ventilation contributes to lung injury in acute respiratory distress syndrome, yet whether cumulative mechanical energy, the time-integrated delivery of ventilatory power, adequately reflects the risk of venti...
Mechanical ventilation contributes to lung injury in acute respiratory distress syndrome, yet whether cumulative mechanical energy, the time-integrated delivery of ventilatory power, adequately reflects the risk of ventilator-induced lung injury (VILI) remains uncertain. Because lung tissue exhibits nonlinear stress-strain behavior, the rate and amplitude of energy delivered may be as relevant as its magnitude. We tested whether different combinations of tidal volume (VT) and ventilation duration, matched for cumulative energy, produce distinct patterns of VILI following endotoxin-induced lung damage in male Wistar rats. Animals received intratracheal lipopolysaccharide (LPS) and, after 24 h, were mechanically ventilated (PEEP = 3 cmHO; inspired oxygen fraction = 0.40) using one of three strategies: VT = 6 mL/kg for 150 min (LVT-HMV), VT = 9 mL/kg for 100 min (MVT-MMV), or VT = 12 mL/kg for 75 min (HVT-LMV). Apparatus dead space was adjusted to maintain normocapnia. An LPS-exposed, nonventilated group served as a molecular and histological reference. Despite equivalent cumulative energy exposure, HVT-LMV resulted in higher plateau and driving pressures, greater alveolar overdistension, collapse, and pulmonary edema, and increased expression of interleukin-6 and vascular cell adhesion molecule-1. MVT-MMV produced intermediate structural injury with selective upregulation of mechanosensitive extracellular matrix markers, whereas LVT-HMV was associated with the least injury. Driving and plateau pressures correlated with indices of overdistension and extracellular matrix signaling but showed weaker associations with endothelial activation. These findings indicate that VILI depends not only on total energy delivery but also on its temporal distribution, and that cumulative energy alone is insufficient to predict lung injury risk. This study reveals that the timing of energy delivery, not just its magnitude, determines ventilator-induced lung injury in endotoxin-induced lung damage. Using a rat model, high tidal volumes delivered over short periods caused disproportionate overdistension, edema, and inflammation compared with lower tidal volumes over longer periods, despite equivalent cumulative energy. These findings challenge the conventional focus on total ventilatory energy and highlight the need for strategies that account for temporal distribution to optimize lung protection.
Evidence of histamine release in response to both aerobic and resistance exercise: histamine metabolites as biomarkers.
Gibson BM, Abbotts KSS, Cursetjee HF … +3 more , Wiedenfeld Needham K, Minson CT, Halliwill JR
J Appl Physiol (1985) · 2026 Apr · PMID 41837462 · Full text
Histamine released within skeletal muscle facilitates sustained postexercise vasodilation and contributes to the development of training adaptations. Quantifying the histamine response is challenging because histamine is...
Histamine released within skeletal muscle facilitates sustained postexercise vasodilation and contributes to the development of training adaptations. Quantifying the histamine response is challenging because histamine is rapidly broken down and metabolized. Thus, we explored the use of histamine's metabolites, 1-methylhistamine and 1-methylimidazole acetic acid, as biomarkers of the histamine response to exercise. We hypothesized that plasma concentrations and urinary production of these metabolites would increase following aerobic and resistance exercise. Twelve (1 female, 11 male) participants (V̇o: 51.9 ± 6.9 mL·kg·min; back squat 1-repetition maximum, 1-RM: 1.59 ± 0.26 kg·body wt) completed two separate exercise sessions: aerobic (30 min of cycling at 70% V̇o) and resistance (6 sets of 10 repetitions of back squats at 10-RM). Femoral artery blood flow was measured, and blood samples were obtained before, immediately after, and throughout 2 h of postexercise recovery. Urine was collected 24 h before exercise, from the start of exercise until 2 h after exercise, and for 24 h after exercise. Plasma concentrations of 1-methylhistamine and 1-methylimidazole acetic acid increased following both exercise sessions ( < 0.05). Likewise, urine production rates of 1-methylhistamine and 1-methylimidazole acetic acid increased following both exercise sessions ( < 0.05). Furthermore, receiver operating characteristic analysis for 1-methylimidazole acetic acid found strong evidence that urine production rates correctly discriminate between conditions (likelihood ratio 12, < 0.01; area under the curve 0.80, < 0.01). Thus, urine production rates of 1-methylhistamine and 1-methylimidazole acetic acid demonstrate utility as a biomarker of the histamine response to exercise. Histamine released from muscle increases blood flow and facilitates adaptation to exercise training. However, tracking the histamine response to exercise has been challenging because of its short half-life. We show that production of both 1-methylhistamine and 1-methylimidazole acetic acid, metabolites of histamine, increases with exercise. This provides a novel means to detect the histamine response to multiple forms of exercise, based on the appearance of histamine metabolites in the circulation or captured in urine.
Characterizing inspiratory duty cycle compensation to flow-limited breathing during drug-induced sleep endoscopy in obstructive sleep apnea.
Kane BL, Gouldman KP, Yu JL
J Appl Physiol (1985) · 2026 Apr · PMID 41817380 · Full text
Inspiratory duty cycle (IDC), the fraction of inspiratory time relative to total breath duration, serves as an adaptive response to flow-limited ventilation in obstructive sleep apnea (OSA). IDC compensation remains inco...
Inspiratory duty cycle (IDC), the fraction of inspiratory time relative to total breath duration, serves as an adaptive response to flow-limited ventilation in obstructive sleep apnea (OSA). IDC compensation remains incompletely characterized in the context of OSA pathophysiology. We studied the relationship of IDC and flow-limited breathing in OSA during drug-induced sleep endoscopy (DISE). Eighty-two adults with OSA underwent DISE with continuous positive airway pressure (CPAP) titration. Airflow (V), tidal volume (TV), and IDC were measured across varying levels of flow-limited breathing. Airway collapsibility was assessed by pharyngeal opening (P) and critical closing pressures (P). IDC compensation was quantified as the slope of IDC versus normalized TV (%PTV), representing the degree of IDC increase to declining ventilation. Patients were classified as high versus low IDC compensators based on this slope metric, and differences in P and P were compared between groups. As CPAP increased from flow-limited to non-flow-limited breathing, IDC decreased by 20%, whereas TV and ventilation more than doubled. IDC compensation varied among subjects with stronger compensators exhibiting higher airway collapsibility (P = 10.2 vs. 8.2 cmHO; = 0.01, P = 4.2 vs. 3.0 cmHO; = 0.03). IDC compensation reflects a physiological response that helps maintain ventilation under flow-limited conditions. Greater airway collapsibility was associated with stronger IDC compensation, reflecting the capacity of the respiratory system to tolerate increased mechanical load. DISE provides a unique experimental platform to quantify ventilatory timing responses, advancing our mechanistic understanding of respiratory compensation in OSA. This study describes inspiratory duty cycle (IDC) compensation as a measurable physiological mechanism that sustains ventilation during flow-limited breathing in obstructive sleep apnea. Using drug-induced sleep endoscopy with continuous positive airway pressure titration, we show IDC increased with worsening inspiratory flow limitation and that stronger IDC compensation is associated with greater airway collapsibility. These findings introduce IDC compensation as a novel marker of ventilatory adaptability and provide a framework for characterizing compensatory responses in OSA.
Advanced glycation end-products accumulate preferentially in type I muscle fibers of aging adults but are unchanged by training and polyphenol supplementation.
Flensted-Jensen M, Kleis-Olsen AS, Weinreich CM … +4 more , Schjerling P, Dela F, Couppé C, Svensson RB
J Appl Physiol (1985) · 2026 Apr · PMID 41801085 · Publisher ↗
Advanced glycation end-products (AGEs) accumulate with age and may contribute to skeletal muscle decline, yet their distribution within muscle compartments is unknown. Resistance training (RT) and high-intensity interval...
Advanced glycation end-products (AGEs) accumulate with age and may contribute to skeletal muscle decline, yet their distribution within muscle compartments is unknown. Resistance training (RT) and high-intensity interval training (HIIT) improve muscle function, but their effects on muscle AGEs remain unexplored. Polyphenols have antioxidant properties, which could limit AGE formation. This study investigated AGE accumulation in different muscle compartments and whether a 12-wk RT + HIIT intervention, with or without polyphenol supplementation, could modify AGE levels. Forty-one healthy middle-aged and older adults (55-70 yr) were randomized to receive a polyphenol-rich berry extract or placebo for 30 days, followed by 12 wk of supervised RT + HIIT. Vastus lateralis biopsies were collected before and after the intervention and analyzed for subtypes of AGEs using immunofluorescence. AGE immunoreactivity was quantified in type I and type II fibers and in the extracellular matrix (ECM). AGE immunoreactivity was higher in type I than in type II fibers ( < 0.0001) and most pronounced in the ECM ( < 0.05 vs. both fiber types). AGE signals did not differ between sexes and were unrelated to age or plasma IL-6. Neither training nor polyphenol supplementation altered AGE content in fibers or ECM. These findings provide the first evidence of fiber-type-associated localization of AGE immunoreactivity in humans. The absence of change following 12 wk of RT and HIIT, with or without polyphenol, suggests that AGE turnover in skeletal muscle is limited in short-term interventions, highlighting the need for longer strategies to reduce AGE accumulation. This study is the first to show that advanced glycation end-products (AGEs) may preferentially accumulate in type I muscle fibers and the extracellular matrix of middle-aged and older adults. Twelve weeks of resistance training combined with high-intensity interval training, with or without polyphenol supplementation, did not alter AGE levels. These findings suggest a fiber type-specific susceptibility to glycation and indicate that short-term lifestyle interventions are insufficient to reverse established AGE cross links in human skeletal muscle.
Retraction for Sun et al., volume 118, 2015, p. 224-237.
J Appl Physiol (1985) · 2026 Mar · PMID 41793769 · Publisher ↗
Abstract loading — click title to view on PubMed.
Sex differences in lower limb muscle atrophy during simulated microgravity exposure: implications for exploration spaceflight.
English KL, Ploutz-Snyder LL
J Appl Physiol (1985) · 2026 Mar · PMID 41785029 · Publisher ↗
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Load- and frequency-dependent impairments to isotonic power are greater than isometric torque following concentric-eccentric fatiguing contractions in humans.
Dudani RA, Zero AM, Rice CL
J Appl Physiol (1985) · 2026 Apr · PMID 41785012 · Publisher ↗
Prolonged low-frequency force depression (PLFFD) is the disproportionate loss of force in response to low frequencies (e.g., <20 Hz) of activation compared to high frequencies (e.g., >50 Hz) following fatiguing contracti...
Prolonged low-frequency force depression (PLFFD) is the disproportionate loss of force in response to low frequencies (e.g., <20 Hz) of activation compared to high frequencies (e.g., >50 Hz) following fatiguing contractions. While traditionally assessed using isometric contractions, the effect of PLFFD during dynamic contractions is much less explored. The purpose was to assess PLFFD at two loads (unloaded and 12.5% of maximal voluntary contraction) during dynamic isotonic and isometric contractions following a fatiguing task. Eighteen participants (23.3 ± 1.6 yr, 6 females) performed continuous, maximal isokinetic cycles of concentric and eccentric knee extension contractions until a 75% loss of concentric peak power. Percutaneous electrical stimulation of the quadriceps was used to assess PLFFD beginning at 30 min of recovery by comparing pre- and postfatigue 20:50-Hz ratios. The 20:50-Hz ratio for isometric torque declined 15.6% ( < 0.001), indicating PLFFD. The loaded dynamic isotonic 20:50-Hz power ratio was significantly more depressed than isometric torque (36.4%, < 0.001), but there was no difference in the relative decline between the unloaded and isometric conditions (22.9%, = 0.57). Furthermore, the 20:50-Hz isotonic velocity ratio was depressed with both loads (unloaded, 12.9% and loaded, 34.4% decrease, and both < 0.001), and this decline was greater than concentric torque in the loaded condition (34.4% and 7.4% decrease, respectively, < 0.001). Therefore, the larger decline in the power ratios was due to the combined deficits in both torque and velocity, indicating that during PLFFD the impairment of isotonic power is greater than isometric torque, which is further impaired at higher loads (i.e., 12.5%). The assessment of prolonged low-frequency force depression (PLFFD) following a dynamic fatiguing task of the knee extensors is underestimated when using traditional measures of isometric torque, compared to isotonic power, which is a more functionally relevant measurement of this state. Furthermore, when isotonic assessments were performed against a moderate load, the combined deficit in torque and angular velocity led to a greater decline in evoked power compared to isometric torque in response to low-frequency stimulation.
Shaping smooth muscle forces: the role of preconditioning in urinary smooth muscle.
Kiem S, Papenkort S, Borsdorf M … +2 more , Böl M, Siebert T
J Appl Physiol (1985) · 2026 Apr · PMID 41784165 · Publisher ↗
Smooth muscle (SM) exhibits rapid mechanical adaptation in response to various stimuli, posing challenges for reproducible experimental results and consistent material parameter determination in biomechanical modeling. P...
Smooth muscle (SM) exhibits rapid mechanical adaptation in response to various stimuli, posing challenges for reproducible experimental results and consistent material parameter determination in biomechanical modeling. Preconditioning involving repeated loading and unloading cycles is commonly used to stabilize mechanical responses before testing. However, their influence on tissue properties and data variability remains underexplored. This study compares the effects of three preconditioning routines-passive cycling (P), no preconditioning (P), and free contraction (P)-on the active and passive force responses of porcine urinary bladder (UB) SM tissue. Three tissue strips from 12 UBs were randomly assigned to one of the routines and underwent an identical protocol involving a passive stretch ramp and two isometric contractions (IC1, IC2) to evaluate active and passive force development. After P, the tissue generated the highest active (IC2: 44.7 ± 29.4 kPa) and passive tensions (IC2: 5.6 ± 4.3 kPa), though it also showed the highest variance in active tension. P resulted in the lowest variance in active tension, with a coefficient of variation (CV) of 45%, and P showed the lowest variance in passive tension, CV = 57%. These findings imply that the decision for a certain preconditioning protocol influences the observed mechanical properties. In this context, P appears promising for minimizing passive force variability and preventing creep-induced lengthening. This could offer a more reliable foundation for subsequent experiments analyzing mechanical parameters. This study underscores the importance of customized preconditioning strategies to enhance consistency and comparability in SM research and organ modeling. This study investigates how different preconditioning routines (passive cycling, no preconditioning, and free contraction) affect active and passive force generation in porcine urinary bladder smooth muscle. Using a subsequent standardized protocol, we show that the preconditioning choice influences both force magnitude and variability, with free contraction minimizing passive force variance and avoiding creep-induced lengthening. Our findings highlight the need for tailored preconditioning strategies to improve reproducibility in smooth muscle experiments and enhance biomechanical organ modeling.
Cardiac responses and adaptations to blood flow restriction exercise.
Cheung CP, Thompson KMA, Robertson AA … +3 more , Lynagh BM, Coates AM, Burr JF
J Appl Physiol (1985) · 2026 Apr · PMID 41779534 · Publisher ↗
Low-intensity endurance training with blood flow restriction (BFR) elicits greater improvements in maximal oxygen consumption (V̇o) compared with volume-matched training. However, determinants of V̇o, such as oxygen-carr...
Low-intensity endurance training with blood flow restriction (BFR) elicits greater improvements in maximal oxygen consumption (V̇o) compared with volume-matched training. However, determinants of V̇o, such as oxygen-carrying capacity and mitochondrial content, do not exhibit proportional improvement. Despite the hemodynamic alterations during BFR exercise that could stimulate remodeling, cardiac adaptations remain unexplored. We assessed cardiac function in athletes (11 M/5 F) at rest, during semirecumbent cycling with BFR, and at a matched work and heart rate (HR) using echocardiography. In an exploratory analysis, a subset of athletes (5 M/2 F) then completed 6 wk of low-intensity BFR walking three times per week, and echocardiograms were repeated. Compared with rest and unoccluded exercise, BFR increased arterial elastance (rest: 1.07 ± 0.32 mmHg/mL, BFR: 1.32 ± 0.33 mmHg/mL, work-match: 0.93 ± 0.25 mmHg/mL, HR-match: 0.97 ± 0.25 mmHg/mL; all < 0.01) and altered left ventricular (LV) filling, with a greater proportion of filling achieved through atrial contraction (rest: 45 ± 8%, BFR: 56 ± 8%, work-match: 49 ± 6%, HR-match: 46 ± 7%; all < 0.05) to maintain end-diastolic volume (rest: 163 ± 40 mL, BFR: 163 ± 40 mL vs. work-match: 167 ± 37 mL, HR-match: 168 ± 38 mL; = 0.5). Concurrently, stroke volume was reduced (rest: 99 ± 26 mL, BFR: 95 ± 23 mL, work-match: 109 ± 27 mL, HR-match: 110 ± 25 mL; < 0.05), and HR was elevated (rest: 54 ± 10 beats/min, BFR and HR-match: 87 ± 13 beats/min vs. work-match: 74 ± 11 beats/min; < 0.01) to maintain cardiac output (rest: 5.1 ± 1.2 L/min, BFR: 7.5 ± 1.0 L/min, work-match: 8.0 ± 1.2 L/min, HR-match: 9.1 ± 1.7 L/min; < 0.0001). BFR training did not affect LV mass index (Pre: 121 ± 18 g/m, Post: 123 ± 11 g/m; = 0.5), nor LV function at rest or during unoccluded exercise. However, posttraining, stroke volume during BFR exercise was increased (Pre: 101 ± 25 mL, Post: 113 ± 23 mL; = 0.03), suggesting adaptation of the cardiac response to this specific stress. This highlights how the heart supports oxygen delivery during BFR exercise and provides insight into how cardiac adaptations may contribute to BFR training-associated improvements in V̇o. Blood-flow restriction exercise uniquely challenges the heart through an increase in afterload, which necessitates altered diastolic filling patterns and increased heart rate to compensate for reduced stroke volume. Repeated exposure to low-intensity endurance-type blood-flow restriction exercise through training improves the hearts' ability to support stroke volume, specifically when performing blood-flow restriction exercise, but not low-intensity free-flow exercise.
Exogenous ketosis mitigates hypoxia-induced neural signaling alterations and cerebral oxygenation decline at rest in healthy males.
Vermaerke N, Vermeiren S, Tominec D … +6 more , Lauriks W, Robberechts R, Debevec T, Mantini D, Poffé C, Stalmans M
J Appl Physiol (1985) · 2026 Apr · PMID 41779434 · Publisher ↗
Intensive exercise and high-altitude exposure can disrupt neural activity and impair cognitive functioning. Previous research suggests that ketone ester (KE) ingestion may counteract cognitive impairments; however, its i...
Intensive exercise and high-altitude exposure can disrupt neural activity and impair cognitive functioning. Previous research suggests that ketone ester (KE) ingestion may counteract cognitive impairments; however, its impact on neural activity during exercise and hypoxia remains unclear. Therefore, we investigated the impact of KE on electroencephalography (EEG) patterns and cognition during hypoxia and exercise. Twelve healthy males completed three randomized crossover sessions: ) normoxia + placebo, ) hypoxia + placebo, and ) hypoxia + KE. Each session included normoxic endurance (ET) and high-intensity interval training (HIIT), followed by a 16-h period including sleep in either normoxia or hypoxia. The next day, participants performed a normoxic 30-min all-out time-trial (TT). EEG was recorded during rest and exercise, while cerebral tissue oxygenation index (cTOI) and cognitive performance were evaluated during rest. At rest, KE attenuated hypoxia-induced increases in alpha and beta power and cTOI declines. Nonetheless, cognitive performance remained unaffected. Brain activity rose throughout ET and normalized during recovery, while HIIT elicited a fluctuating neural response but normalized during recovery. Following TT, theta, alpha, and gamma power remained elevated during recovery. Altogether, these data, obtained in healthy males, show the potential of KE to stabilize resting-state EEG patterns in hypoxia. Moreover, they shed light on how EEG patterns vary with exercise intensity, with sustained postexercise increases in theta, alpha, and gamma power following high-intensity efforts. These findings suggest that KE can help to preserve neural stability under hypoxia and highlight EEG's potential for monitoring fatigue and tailoring training or recovery strategies. This study is the first to demonstrate the effects of ketone ester ingestion on hypoxia-induced neural alterations. Moreover, it uniquely combines measurements of cerebral oxygenation, cognitive performance, and electroencephalography (EEG) across low-, high-, and all-out exercise intensities, as well as during rest. Potentially highlighting EEG as a valuable tool for monitoring fatigue and optimizing training strategies.
Morning endurance training induces superior performance adaptations compared with afternoon training in mice.
Hesketh SJ, Douglas CM, Zhang X … +4 more , Wolff CA, Sexton CL, Nowicki ES, Esser KA
J Appl Physiol (1985) · 2026 Apr · PMID 41770536 · Full text
Endurance performance exhibits time-of-day variation in both humans and rodents, peaking in the late-active phase. However, whether the timing of endurance training influences performance adaptations remains unclear. To...
Endurance performance exhibits time-of-day variation in both humans and rodents, peaking in the late-active phase. However, whether the timing of endurance training influences performance adaptations remains unclear. To investigate, female mice were trained 5 days/wk for 6 wk at either ZT13 or ZT22, using treadmill running at 70% of each animal's maximal capacity. Endurance performance was assessed at baseline, , and . Secondary outcomes included blood glucose and lactate, cage activity, body composition, liver and skeletal muscle glycogen content, and mitochondrial and contractile protein expression. At baseline, late-active phase (ZT22)-tested mice exhibited significantly higher endurance capacity than early-active phase (ZT13)-tested mice ( < 0.05). Following 6 wk of training, ZT13-trained mice demonstrated a greater rate of improvement, with endurance increasing by 132% ( < 0.05), compared with 45% in afternoon ZT22-trained mice. By , performance improved but was similar between groups ( > 0.05), despite lower absolute training volumes in the ZT13 group. Both training groups reduced fat mass (ZT13: -31%, ZT22: -32%; < 0.05 vs. control), with no differences in lean mass, food intake or muscle, and liver glycogen content ( > 0.05). In skeletal muscle, ZT13-trained mice were associated with increased ( < 0.05) cytochrome oxidase subunit IV (COX IV) protein expression, citrate synthase activity, and shifts in myosin heavy chain (MyHC) isoform expression, without changes ( > 0.05) in mitochondrial content. ZT13 training elicited superior performance adaptations despite lower absolute workloads, indicating enhanced training efficiency. These findings identify exercise timing as a biologically relevant factor influencing endurance adaptation and variability in exercise responses. This study demonstrates that endurance training in the early-active phase induces greater performance adaptations than late-active phase training in mice, resulting in overcoming diurnal differences in exercise performance, despite lower absolute training volumes. These findings reveal exercise timing influences training efficiency, likely via circadian regulation of skeletal muscle metabolism. This work identifies time-of-day as a biologically relevant and underappreciated variable contributing to the heterogeneity of exercise responses, even in tightly controlled preclinical models.
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