J. Appl. Physiol. [JOURNAL]
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200 papers
Thoroughbred horses susceptible to Recurrent Exertional Rhabdomyolysis have elevated skeletal muscle mitochondrial capacities.
Wesolowski LT, Artman JL, Semanchik PL … +5 more , Carson CP, Fenger CK, Pagan JD, Valberg SJ, White-Springer SH
J Appl Physiol (1985) · 2026 Jul · PMID 42397046 · Publisher ↗
Recurrent Exertional Rhabdomyolysis (RER) is a skeletal muscle disease that can intermittently impede careers of equine athletes. Manifesting as episodes of muscular stiffness and degeneration, RER causes lost training a...
Recurrent Exertional Rhabdomyolysis (RER) is a skeletal muscle disease that can intermittently impede careers of equine athletes. Manifesting as episodes of muscular stiffness and degeneration, RER causes lost training and competition days. RER is associated with abnormal intracellular calcium (Ca) regulation. Calcium released from the sarcoplasmic reticulum to initiate contraction may also be transported into mitochondria, which impacts energy production. RER-susceptible horses exhibit down-regulated mitochondrial proteins but upregulated mitochondrial genes. Thus, mitochondrial function may be impacted by Ca irregularities in RER horses. Fourteen race-fit female Thoroughbred horses were used to test the hypothesis that horses which had previously experienced at least 2 ER episodes (n = 8; mean ± SD 3.1 ± 1.1 yr) would have impaired skeletal muscle mitochondrial capacities compared to control racehorses (n = 6; 3.5 ± 1.4 yr). Gluteus medius samples were analyzed for oxidative phosphorylation () and electron transfer () capacities via high-resolution respirometry. Contrary to our hypothesis, integrative (per mg) NADH-linked (), maximal (), maximal () and succinate-linked () tended to be greater ( ≤ 0.1) while intrinsic (relative to citrate synthase activity) and tended to be greater ( ≤ 0.1) and and were greater ( ≤ 0.03) in RER-susceptible compared to control horses. Horses susceptible to RER appeared to have greater skeletal muscle mitochondrial capacities, which might be consequent to aberrant intramuscular Ca handling . The clinical significance of this finding remains unclear but further investigation could lead to mitochondrially-targeted treatment and management strategies.
Change in Neutrophil-to-Lymphocyte Ratio after acute and chronic exercise: A Systematic Review and Meta-Analysis.
Khanzadeh S, Mohammadzadeh S, Fayedeh F … +1 more , Shields RK
J Appl Physiol (1985) · 2026 Jul · PMID 42390909 · Publisher ↗
Chronic inflammation contributes to many common diseases, and exercise is a widely accessible tool to modulate it. This meta-analysis evaluates the neutrophil-to-lymphocyte ratio (NLR), a simple inflammatory marker, to b...
Chronic inflammation contributes to many common diseases, and exercise is a widely accessible tool to modulate it. This meta-analysis evaluates the neutrophil-to-lymphocyte ratio (NLR), a simple inflammatory marker, to better understand and optimize the anti-inflammatory effects of exercise. The present meta-analysis aims to systematically evaluate existing evidence on NLR changes induced by acute and chronic exercise. This study was registered in PROSPERO (CRD420251042422). Studies were selected based on PICO criteria: Population (P) - human participants regardless of age or health; Intervention (I) - acute or chronic exercise; Comparison (C) - NLR levels before exercise; Outcome (O) - Within- subject change in NLR measured before and after exercise. We searched PubMed, EMBASE, Scopus, Web of Science, and the Cochrane Library extensively. Pooled results were expressed as mean difference (MD) with 95% confidence intervals (CI) using STATA version 19.0. Twenty-six studies with a total of 1203 participants were included. NLR levels showed no significant change immediately after acute exercise (MD = 0.03; 95% CI: -0.24 to 0.30; p = 0.82; k = 12, I² = 93.6%) but increased significantly one-to-three hours post-exercise (MD = 1.23; 95% CI: 0.46 to 1.99; p = 0.002; k = 5, I² = 93.3%). Chronic exercise was associated with a significant overall decrease in NLR (MD = -0.30; 95% CI: -0.56 to -0.04; p = 0.02; k = 15, I² = 98.4%). Studies with older participants reported greater reductions in NLR following chronic exercise. Sensitivity analysis confirmed that no single study had a disproportionate influence on the pooled estimates, and publication bias tests did not suggest bias. Acute exercise induces a transient increase in NLR between one-to-three-hours post-exercise, while chronic exercise leads to sustained reductions, reinforcing the value of exercise as a non- pharmacologic strategy to reduce systemic inflammation, as reflected by this inflammatory marker.
Ankylosing spondylitis and muscle sympathetic nerve activity: a case study.
Murvich AM, Curtis C, Bigalke JA … +1 more , Carter JR
J Appl Physiol (1985) · 2026 Jul · PMID 42390825 · Publisher ↗
Inflammatory diseases are associated with elevated cardiovascular (CV) risk, and heightened muscle sympathetic nerve activity (MSNA) is a potential contributor. This case study characterized MSNA in two patients with ank...
Inflammatory diseases are associated with elevated cardiovascular (CV) risk, and heightened muscle sympathetic nerve activity (MSNA) is a potential contributor. This case study characterized MSNA in two patients with ankylosing spondylitis (AS) and evaluated the effect of TNF-α blockade therapy. Two males diagnosed with AS (Case 1: 34 years, 26kg/m; Case 2: 22 years, 31kg/m) participated. In Case 1, 10-minutes of continuous beat-to-beat blood pressure, heart rate (HR), and MSNA were recorded on two occasions 3-months apart. Case 2 similarly underwent 10-minutes of autonomic monitoring before and after 6-months of routine-care TNF-α blockade. In Case 1, systolic (SBP: 120 vs. 121 mmHg) and diastolic (DBP: 64 vs. 70 mmHg) blood pressure, HR (58 vs. 59 beats/min), and MSNA (32 vs. 37 bursts/min) were similar across the two visits, suggesting reliable MSNA in our AS patient. Case 2 also demonstrated higher-than-expected resting MSNA (45 bursts/min) when considering age and BMI, and further demonstrated marked reductions in SBP (146 vs. 124 mmHg), DBP (84 vs. 70 mmHg), HR (76 vs. 69 beats/min), and MSNA (45 vs. 26 bursts/min) following 6-mo of TNF-α blockade. The present case study indicates that heightened sympathetic activity is a potential physiological mechanism contributing to increased CV disease in populations with AS. Furthermore, suppression of inflammation or symptom amelioration may help attenuate the increased sympathetic activity and potentially lower cardiovascular risk over time within this unique rheumatic population. While caution is necessary given the case study approach, future work examining neural cardiovascular control in AS patients appears warranted.
Intracranial vasomotor and blood flow responses to light intensity aerobic exercise in young adults: a 4D flow MRI study.
Moir ME, Howery AJ, Spahic A … +10 more , Corkery AT, Baumhardt PF, Coovadia Y, Loggie NA, Gaynor-Metzinger SHA, Eisenmenger LB, Eldridge MW, Johnson KM, Wieben O, Barnes JN
J Appl Physiol (1985) · 2026 Jun · PMID 42370989 · Publisher ↗
Aerobic exercise elicits an increase in cerebral blood flow. This finding is evidenced by augmented internal carotid artery (ICA) and vertebral artery (VA) blood flow measured extracranially and supported by an increase...
Aerobic exercise elicits an increase in cerebral blood flow. This finding is evidenced by augmented internal carotid artery (ICA) and vertebral artery (VA) blood flow measured extracranially and supported by an increase in intracranial blood velocity (e.g., middle cerebral artery [MCA]). To date, no studies have quantified intracranial blood flow or vessel cross-sectional area (CSA) during exercise given challenges in combining aerobic exercise with magnetic resonance imaging (MRI) approaches. The present study leveraged an MRI-compatible exercise device and novel 4D flow MRI sequences that are less sensitive to motion artifacts to evaluate vasomotor and blood flow responses during aerobic exercise, and to explore the influence of biological sex. Thirty-four young adults (18 females, 31±5 years of age) completed supine exercise at 30% V̇O in the MRI bore and CSA and blood flow were quantified in multiple intracranial arteries. Light intensity exercise elicited an increase in blood flow within the large intracranial arteries including the left ICA (∆18±17mL/min, <0.001), right ICA (∆23±18mL/min, <0.001), and basilar artery (∆15±14mL/min, <0.001). Overall, global cerebral blood flow increased 58 ± 40 mL/min (<0.001). Further, light intensity exercise elicited vasodilation in the large intracranial arteries including the left ICA (∆0.8±1.2mm, =0.001), right ICA (∆0.9±1.1mm, <0.001), and basilar artery (∆0.5±0.7mm, <0.001). Biological sex influenced blood flow responses in the left ACA (=0.048) but did not impact CSA responses (all >0.08). This study provides novel insights to intracranial blood flow and vasomotor responses during aerobic exercise in young adults and the influence of biological sex.
Comparative assessments of the COSMED adaptive mixing chamber vs. breath-by-breath methods for oxygen uptake measurements in recreationally active adults.
Borrani F, Conedera L, Finel L … +4 more , Daucourt C, Malatesta D, Baggish AL, Neyroud D
J Appl Physiol (1985) · 2026 Jun · PMID 42370953 · Publisher ↗
Respiratory gas exchange during cardiopulmonary exercise testing (CPET) is commonly measured using either a mixing chamber (MC) or a breath-by-breath (BxB) technique. MC measurements reduce the impact of erratic ventilat...
Respiratory gas exchange during cardiopulmonary exercise testing (CPET) is commonly measured using either a mixing chamber (MC) or a breath-by-breath (BxB) technique. MC measurements reduce the impact of erratic ventilatory patterns thereby improving the accuracy of oxygen uptake (V̇O) values, but often lack adequate temporal resolution for ventilatory thresholds (VTs) determination. Accordingly, BxB is preferred when both V̇O and VTs determination are sought simultaneously. Recently, an adaptive MC (aMC) with high temporal resolution was developed. The aims of this study were to examine the concordance of aMC- and BxB-derived gas exchange data, and to determine if the aMC provides adequate temporal resolution for the assessment of VTs. Fourteen healthy, recreationally active individuals (7 females, 7 males; 23.6 ± 1.4 years; 171.8 ± 9.0 cm; 67.9 ± 11.1 kg) performed a maximal CPET on a treadmill with gas exchanges being measured simultaneously using BxB and aMC techniques. Compared to BxB measurement, V̇O values at peak effort were 5.0 ± 7.8% lower using the aMC (p = 0.0419). Similar bias was observed for V̇O values obtained at submaximal workloads. Noteworthy, the aMC provided adequate temporal resolution to identify VTs among all participants in whom they could be measured with confidence using BxB (n=13/14). The aMC provides consistent and reproducibly lower V̇O values compared to BxB acquisition and provides adequate temporal resolution to determine VTs during incremental effort CPET. This newly developed technology appears to integrate the well-established strengths of both conventional MC and BxB gas exchange measurement techniques.
Can we assess exercise metabolism from skin? Metabolomic profiles in skin dialysate collected during exercise.
Yajima K, Maimaituxun G, Murakami T … +4 more , Mitsuhashi S, Watanabe K, Nishiyasu T, Fujii N
J Appl Physiol (1985) · 2026 Jun · PMID 42363903 · Publisher ↗
Monitoring exercise intensity is essential for optimizing the health benefits of physical activity. Indirect calorimetry is the gold-standard method for assessing metabolic stress during exercise, though, its reliance on...
Monitoring exercise intensity is essential for optimizing the health benefits of physical activity. Indirect calorimetry is the gold-standard method for assessing metabolic stress during exercise, though, its reliance on extensive equipment for sampling and analyzing exhaled gases restricts its widespread application. Skin interstitial fluid may represent an ideal biofluid for the continuous monitoring of whole-body metabolism and exercise intensity. However, specific metabolites in skin interstitial fluid that are more closely associated with metabolic variables measured by indirect calorimetry remain unknown. We examined which metabolites in skin interstitial fluid most closely reflect metabolic responses assessed by indirect calorimetry during a continuous graded exercise protocol. Twelve young participants (5 females) exercised at low, moderate, and high-intensity phases (25%, 50%, and 75% VO₂peak), each lasting 20 min. Skin dialysate, which reflects the composition of skin interstitial fluid, were collected via intradermal microdialysis during each exercise, and metabolites in the dialysate were measured and analyzed. Medium- and long-chain acylcarnitines in skin dialysate increased during moderate-intensity exercise in line with elevations in whole-body fat oxidation. During high-intensity phase, lactic acid in skin dialysate was elevated along with increases in whole-body carbohydrate oxidation. Many metabolites including those mentioned above in skin dialysate were correlated with whole-body metabolic responses. Our preliminary data suggest that metabolite concentrations in skin interstitial fluid may be associated with variables measured by indirect calorimetry. These findings may inform the future development of wearable devices that could potentially be used for continuous and noninvasive monitoring of exercise intensity.
Characterization of intracranial pressure variations in ventricular and subarachnoid spaces of the rat brain.
Hernandez-Isidro C, Passaglia CL
J Appl Physiol (1985) · 2026 Jun · PMID 42363891 · Publisher ↗
Intracranial pressure (ICP) is a dynamic physiological signal shaped by cerebrospinal fluid flow, vascular pulsations, and brain tissue compliance, yet most knowledge of CSF (cerebrospinal fluid) hydrodynamics comes from...
Intracranial pressure (ICP) is a dynamic physiological signal shaped by cerebrospinal fluid flow, vascular pulsations, and brain tissue compliance, yet most knowledge of CSF (cerebrospinal fluid) hydrodynamics comes from pathological states in humans. To better understand physiological ICP variability, dual recordings were obtained in 15 healthy anesthetized Brown-Norway rats using pressure sensors connected to cannulas in the lateral ventricle (vICP) and subarachnoid space (sICP). Spectral analysis quantified cardiac and respiratory oscillations, while slower waves were detected by thresholding, characterized with principal component analysis, and modeled to estimate amplitude and duration. In 5 animals, intracranial hypertension was induced via ventricular fluid infusion. Mean pressures differed slightly, but not significantly, between compartments (vICP 6.05 ± 0.90 mmHg vs. sICP 5.90 ± 0.90 mmHg, p = 0.06). Both sites showed rapid cardiac and respiratory fluctuations without measurable delay. Slower B-like waves were also present but peaked earlier in vICP than sICP (1.2 ± 0.7 s). These waves had a larger amplitude and shorter duration in vICP (0.51 ± 0.22 mmHg; 7.5 ± 2.1 s) than in sICP (0.29 ± 0.09 mmHg; 10.7 ± 3.4 s). During ICP elevation, B-like waves increased in amplitude in both compartments and shortened in duration in vICP, while their occurrence rate remained unchanged. These findings demonstrate compartment-specific ICP dynamics in rats and indicate that B-like waves originate in the ventricles before propagating outward, supporting a localized neurogenic mechanism and establishing the rat as a useful model for studying the physiological basis and function of B-waves in CSF homeostasis.
Biomedical Research in an Age of Anxiety: Four Papers for Worried Minds.
Joyner MJ
J Appl Physiol (1985) · 2026 Jun · PMID 42359839 · Publisher ↗
In this essay I review and summarize four older "thought" papers about how science is communicated and practiced. These papers were written by the Nobel Prize winner Peter Medawar, the eminent physiologist Julious Comroe...
In this essay I review and summarize four older "thought" papers about how science is communicated and practiced. These papers were written by the Nobel Prize winner Peter Medawar, the eminent physiologist Julious Comroe, Eugene Robin a renowned clinical investigator, and David Horrobin an innovative scientist and early player in biotechnology. These papers all question how we frame what we do and tell stories about what we find. Several caution against excessive objectivity, hype, groupthink, and what we now call fear of missing out. They argue for imagination, creativity and critical thinking. While there are many threats to biomedical research beyond the control of individual scientists, I believe these papers offer insight about things we can do from the inside out to improve the practice and culture of science. I am also hopeful that insights from these papers, if broadly acted on, could help improve public confidence in and support for biomedical research.
Training status augments mechanisms of rapid‑onset vasodilation in healthy young adults.
Stanford MD, Akbari Fakhrabadi A, Buelow AA … +8 more , Matney JE, Mixon C, Akubude AJ, Nwafor I, Yabluchanskiy A, Larson RD, Larson DJ, Kellawan JM
J Appl Physiol (1985) · 2026 Jun · PMID 42359819 · Publisher ↗
Rapid onset vasodilation (ROV) is the immediate, transient increase in muscle blood flow following contraction and is mediated by chemical, mechanical, and, potentially, neural mechanisms. Although exercise training has...
Rapid onset vasodilation (ROV) is the immediate, transient increase in muscle blood flow following contraction and is mediated by chemical, mechanical, and, potentially, neural mechanisms. Although exercise training has been shown to preserve ROV in older adults, it remains unclear whether training promotes adaptation in specific contributing mechanisms. This study tested the hypothesis that a history of forearm training increases ROV. Sixteen healthy young males (8 trained, 8 sedentary) completed two trials of 1s voluntary forearm contractions (5, 10, 15kg; 20% and 100% of maximal voluntary contraction), electrically-stimulated involuntary contractions (5 and 10mA), and mechanical forearm compression (50, 200, 300mmHg) (randomly ordered). Forearm blood flow (ultrasound) and mean arterial pressure (finger photoplethysmography) were measured beat-to-beat and used to calculate Forearm vascular conductance (FVC). Data from the two trials of each contraction/compression were averaged together to form a singular response. Forearm and hand lean mass, as measured via dual-energy X-ray absorptiometry (DXA), did not differ between groups. Trained participants displayed greater absolute ROV responses to voluntary and involuntary contractions (p ≤ 0.05 for all), as well as to higher-intensity mechanical compressions (p ≤ 0.05 for 300mmHg ΔFVC, 200mmHg and 300mmHg ΔFVC). Additionally, ROV responses increased disproportionately with absolute voluntary contraction intensity in trained participants (Training Status x Intensity interaction ΔFVC: p = 0.02, η = 0.29). These findings extend upon previous research which has demonstrated training-related preservation of ROV and indicate that exercise training enhances rapid vascular responsiveness across multiple stimulus modalities, providing new insight into training-induced adaptations in vascular regulation.
A Physics-Informed Deep Learning Framework for Estimating Muscle Activation Patterns Following Achilles Tendon Repair.
Chen D, Sun D, Li Y … +11 more , Zhao R, Li F, Zhou Z, Wang D, Song Y, Cen X, Yuan Y, Kovács B, Goda TJ, Fang J, Gu Y
J Appl Physiol (1985) · 2026 Jun · PMID 42359776 · Publisher ↗
Accurate soleus (SOL) activation assessment is essential for Achilles tendon rupture (ATR) recovery, yet direct measurement remains a clinical challenge. This study proposes a physics-informed Transformer Neuromusculoske...
Accurate soleus (SOL) activation assessment is essential for Achilles tendon rupture (ATR) recovery, yet direct measurement remains a clinical challenge. This study proposes a physics-informed Transformer Neuromusculoskeletal Model (NMM) to estimate muscle activations during various locomotor tasks. We evaluated the framework using data from 40 participants, including 20 healthy controls and 20 postoperative ATR patients. By integrating forward dynamic constraints, the NMM estimates SOL activation using joint kinematics and a minimal subset of superficial electromyography (tibialis anterior, gastrocnemius medialis, and gastrocnemius lateralis). Performance was validated against conventional benchmarks, including static optimization (SO) and synergistic extrapolation (SYNX), and subsequently applied to evaluate muscle co-activation patterns in ATR patients. Results indicated that NMM preserved superior spectral integrity and yielded more plausible signal energy than SO and SYNX ( < 0.05). In ATR patients, the model identified a phase-dependent shift in SOL recruitment: reduced activation during early-to-mid stance and compensatory elevation during terminal stance (87.50-100%, < 0.01). Co-activation analysis corroborated this, showing reduced early-stance but heightened late-stance levels ( < 0.05). Furthermore, the correlation between the co-activation index and peak torque revealed a transition from efficiency-driven to stability-prioritizing strategies in ATR patients. We conclude that the NMM framework effectively characterizes specific muscle co-activation patterns during ATR recovery. By significantly reducing sensor requirements while maintaining diagnostic depth for deep muscle recruitment, it provides a practical and streamlined tool for routine clinical gait monitoring.
Resistance Exercise Training Status Augments Microvascular Responses to Acute Resistance Exercise in Middle-Aged Women.
Mascone SE, Blake EF, Weiner CM … +5 more , Landers-Ramos RQ, Prior SJ, Kuzmiak-Glancy S, Lefferts WK, Ranadive SM
J Appl Physiol (1985) · 2026 Jun · PMID 42359721 · Publisher ↗
Women experience increased hypertension risk in midlife, which may impact cerebrovascular hemodynamics. Resistance exercise training has emerged as a key means to target hypertension risk. Older women experience benefici...
Women experience increased hypertension risk in midlife, which may impact cerebrovascular hemodynamics. Resistance exercise training has emerged as a key means to target hypertension risk. Older women experience beneficial vascular effects of resistance exercise training from repeated exposures to acute resistance exercise (RE). To investigate acute RE and vascular health in women, we evaluated the impact of acute RE on macrovascular, microvascular, and cerebrovascular function in untrained and resistance-trained middle-aged women. The following measurements were performed before and after acute RE in 23 untrained (51±6yr) and 19 resistance-trained (48±6yr; 10.6±11.1yr resistance training experience) middle-aged women: macrovascular function (brachial artery flow-mediated dilation [FMD]), microvascular function [reactive hyperemic area under the curve (RHAUC) during FMD], and middle cerebral artery blood velocity (MCAv) and cerebrovascular reactivity (CVR). Acute RE included 3 sets of 8-12 repetitions at 60-80% of 1 repetition maximum (1RM) for 8 resistance exercises. While there was no effect of acute RE or training status on FMD, both groups exhibited decreased normalized FMD, MCAv, and MCA conductance after acute RE (RE effect: p=0.003, p=0.01, p=0.002). Resistance-trained middle-aged women exhibited exaggerated RHAUC increases after acute RE as compared to untrained middle-aged women (interaction: p=0.005). Further, there may be a differential CVR response (interaction: p=0.046) between untrained and resistance-trained middle-aged women that warrants further investigation. The findings suggest acute RE reduces macrovascular function and MCAv while increasing microvascular function in middle-aged women, indicating differential effects of acute RE along the vascular tree. Further, resistance exercise training status appears to augment microvascular responses to acute RE in middle-aged women compared to untrained counterparts.
Judicious elevation of ambient carbon dioxide during hypobaric hypoxia to improve oxygenation in airline passengers - a randomized feasibility study.
Post TE, De Gioannis R, Rooney D … +7 more , Wittkowski M, Lau P, Lecheler L, Jordan J, Zange J, Rittweger J, Aeschbach D
J Appl Physiol (1985) · 2026 Jun · PMID 42340161 · Publisher ↗
Despite pressurization of airliner cabins, some passengers experience in-flight hypobaric hypoxia with blood oxygen saturation dropping below 90%, potentially causing discomfort and increasing the risk of medical events....
Despite pressurization of airliner cabins, some passengers experience in-flight hypobaric hypoxia with blood oxygen saturation dropping below 90%, potentially causing discomfort and increasing the risk of medical events. Enrichment of the cabin air with CO may augment passengers' blood and tissue oxygenation by stimulating respiratory drive, thereby increasing health and safety during air travel. In a randomized double-blind crossover study we exposed 17 healthy adults (8 women; age range: 18-40 years) on separate days to two ambient CO levels (0.1 vs. 1.0% indoor sea level equivalents; 0.76 vs. 7.60 mmHg partial pressure) during 6 hours of hypobaric hypoxia (~565 mmHg total barometric pressure; corresponding to 2,438 m altitude) in an altitude chamber simulating long-haul flight conditions. We measured oxygen saturation of the blood (SpO), brain and muscle (tissue saturation index derived from near-infrared spectroscopy), respiration, and cognitive function (sustained attention, working memory, hand-eye coordination) hourly. Additionally, we conducted capillary blood gas analyses at baseline, 15 minutes and 6 hours after hypoxia onset. During hypobaric hypoxia ambient CO enrichment on average increased pCO from 36.3 to 38.3 mmHg, pO from 60.9 to 68.3 mmHg, and minute ventilation from 9.7 to 10.4 l/min, while reducing the time fraction of SpO < 90% from 18.8 to 2.5%. Tissue oxygenation increased in the brain from 62.8 to 63.9% whereas no change was found in muscle. High ambient CO had no effect on cognitive performance. Taken together, enrichment of cabin air with CO during hypobaric hypoxia may improve blood and brain oxygenation.
Single-Oligation of hemoglobin links aerobic and anaerobic metabolism.
Burchert HH, Stringer WW, Dash RK
J Appl Physiol (1985) · 2026 Jun · PMID 42339846 · Publisher ↗
Oxygen (O) binding and release by hemoglobin (Hb) are governed by cooperative interactions among its four subunits. During incremental workload exercise, femoral venous oxyhemoglobin (OHb) saturation exhibits a reproduci...
Oxygen (O) binding and release by hemoglobin (Hb) are governed by cooperative interactions among its four subunits. During incremental workload exercise, femoral venous oxyhemoglobin (OHb) saturation exhibits a reproducible, momentary increase at the gas exchange threshold-coinciding with the inflection point of the in vivo O non-equilibrium curve (ONC). This suggests a transient shift in Hb's binding dynamics. We hypothesized that at this threshold, Hb tetramers carrying ≤1 bound O become predominant. In this state, the last bound O promotes further cooperative binding, but its release confers no cooperative advantage for unloading, biasing toward O rebinding. Using the O equilibrium curve models of Dash . (2016) and Adair, we computed the distribution of Hb's O ligation states across 12 pooled mean femoral venous blood samples from incremental workload cardiopulmonary exercise testing of five healthy male participants. At the gas exchange threshold-where the ONC inflects and flattens-tetramers with ≤1 O indeed dominated. This ligation-state distribution is consistent with Perrella s (1999) cryogenic resolution of native human Hb, which shows that carbon monoxide-ligated Hb tetramers peak at ~15-20% saturation, matching femoral venous ranges at the gas exchange threshold. Our results suggest that, at sufficiently low O₂Hb saturation, Hb may favor O₂ rebinding over cooperative unloading. We propose that glycolytic proton production and other Bohr effectors may counter this predicted binding bias supporting continued O₂ unloading. If confirmed, this mechanism unifies long-standing controversies in O transport physiology, framing the Hb-Bohr system as a proportional-integral controller of tissue oxygenation.
Effects Of Neuromuscular Electrical Stimulation On Achilles Tendon Load.
Durigan JLQ, Smith AK, Felipe JT … +2 more , Cone SG, Silbernagel KG
J Appl Physiol (1985) · 2026 Jun · PMID 42339837 · Publisher ↗
Tendon loading assessed by shear wave tensiometry provides insight into tendon health and performance. Comparing loads during voluntary contractions and neuromuscular electrical stimulation (NMES) may inform rehabilitati...
Tendon loading assessed by shear wave tensiometry provides insight into tendon health and performance. Comparing loads during voluntary contractions and neuromuscular electrical stimulation (NMES) may inform rehabilitation strategies. This study compared Achilles tendon loading during voluntary plantarflexion (PF) and NMES-evoked contractions of the triceps surae in healthy individuals. Twenty participants (30.7 ± 7.8 years; 10 male, 10 female) performed ankle PF under four conditions using a dynamometer: maximal voluntary isometric contraction (MVIC), maximal tolerated NMES-evoked contraction (ESTIM), voluntary contraction at 20% MVIC torque (VOL20), and NMES-evoked contraction at 20% MVIC torque (ESTIM20). Achilles tendon loading was assessed using shear wave tensiometry. The MVIC generated the highest PF torque values (mean ± SD, 78.8 ± 17.2 N.m), followed by ESTIM (29.6 ± 9.7 N.m), VOL20 (18.1 ± 4.8 N.m), and ESTIM20 (16.7 ± 3.9 N.m), respectively. Normalized shear wave speeds at MVIC [(NMES-evoked shear wave speed or 20% MVIC shear wave speed * voluntary shear wave speed) * 100] were not significantly different between MVIC (100%) and ESTIM (82.1 ± 28.5%), nor between VOL20 (62.6 ± 24.6%) and ESTIM20 (68.9 ± 28.6%), despite differences in PF torque. In conclusion, Achilles tendon loading did not differ between MVIC and ESTIM despite a 62.3% lower torque in ESTIM. At 20% torque output, tendon loading was similar between VOL20 and ESTIM20 conditions. These findings challenge the assumption that increases in PF torque produce proportional increases in Achilles tendon load and may reflect contribution from synergistic muscles or compensatory activation at higher force levels.
Complex flow in the proximal internal carotid artery challenges Doppler flow assumptions.
Ling SHT, Zafiris E, Cohen JN … +1 more , Au JS
J Appl Physiol (1985) · 2026 Jun · PMID 42339817 · Publisher ↗
Conventional duplex ultrasound is commonly used to measure blood velocity in the internal carotid artery (ICA) for disease screening and cerebral or extracranial flow estimation. Pouseillian-based flow calculations assum...
Conventional duplex ultrasound is commonly used to measure blood velocity in the internal carotid artery (ICA) for disease screening and cerebral or extracranial flow estimation. Pouseillian-based flow calculations assume laminar flow, which is violated by turbulence and recirculation zones generated by the complex ICA geometry downstream of the carotid bifurcation. This study used vector flow imaging (VFI) to determine how far downstream of the carotid sinus complex flow persists and evaluate guidelines recommending flow measurement 2 cm distal to the bifurcation. Sixteen healthy adults (8 females, 24 ± 3 yrs) completed VFI scans at rest and during dynamic handgrip exercise (DHG) at 20% and 40% maximal voluntary contraction (MVC). Multidirectional flow length (MDFL) was assessed by visual analysis of where flow returned to a laminar pattern. At rest, MDFL was 2.45 ± 0.36 cm distal to the carotid sinus. MDFL did not change from baseline to 20% MVC (p = 0.23) but decreased from 20% to 40% MVC (2.24 ± 0.43 vs. 1.98 ± 0.47 cm; p < 0.01). During 20% MVC, flow complexity increased at all scanning locations, indicating decreased flow coherence with moderate DHG. Conventional Doppler-derived ICA blood flow remained unchanged across conditions, highlighting discrepancies between imaging modalities. These results underscore the need for caution when interpreting Doppler flow measurements in the ICA. We recommend landmarking blood flow locations as distal along the ICA as possible to minimize the effects of non-laminar flow patterns on ICA blood flow estimation.
Local ischemic preconditioning improves skeletal muscle blood flow and vasodilation during exercise in older adults.
Shelley JE, Seo D, Casey DP
J Appl Physiol (1985) · 2026 Jun · PMID 42339779 · Publisher ↗
Aging is associated with reduced blood flow responses in contracting skeletal muscle partially attributed to an impaired ability to offset sympathetic-mediated vasoconstriction. Ischemic preconditioning (IPC) attenuates...
Aging is associated with reduced blood flow responses in contracting skeletal muscle partially attributed to an impaired ability to offset sympathetic-mediated vasoconstriction. Ischemic preconditioning (IPC) attenuates sympathetic vasoconstrictor responsiveness in the forearm of young males. Therefore, we tested the hypothesis that IPC would improve vasoconstrictor responsiveness and exercise hyperemia in older adults. Eleven subjects (64±7 years) completed rhythmic handgrip exercise trials before and after one of three intervention periods: remote IPC (non-exercising arm), local IPC (exercising arm), or time control (TC). IPC interventions involved four cycles of 5 minutes upper arm occlusion followed by 5 minutes reperfusion, whereas TC involved no cuff occlusion. Lower body negative pressure (LBNP) was used to elicit sympathetic-mediated vasoconstriction during the handgrip trials. Forearm blood flow (FBF; ml/min) was measured via Doppler ultrasound, with forearm vascular conductance (FVC; ml·min·100 mmHg) calculated as the quotient of FBF and mean arterial pressure. % change in FVC in response to LBNP during handgrip exercise was used to assess vasoconstrictor responsiveness. Local IPC attenuated the reduction in FVC from pre to post (-15.4±4.1 to -9.3±5.4%, P<0.001), whereas no change was observed with remote IPC (-13.4±3.4 to -11.9±2.5%, P=0.11) and TC (-14.4±3.5 to -13.8±4.1%, P=0.52). Additionally, the changes (Δ) in FBF (154±61 to 182±59 ml/min, P<0.001) and FVC (151±59 to 174±60 ml·min·100 mmHg, P=0.002) from baseline to steady state exercise were increased following local IPC, but not remote IPC. Our data demonstrate that application of local IPC acutely improves exercise hyperemia and reduces sympathetic-mediated-vasoconstriction in skeletal muscle of older adults.
Shoe Heel-Toe Drop Affects Running Economy.
Renninger K, Beck ON
J Appl Physiol (1985) · 2026 Jun · PMID 42324241 · Publisher ↗
To run faster, distance runners need shoes that reduce their metabolic energy expenditure. Here, we studied how shoe heel-toe drop affects metabolic energy expenditure during running. To do so, we studied 20 runners as t...
To run faster, distance runners need shoes that reduce their metabolic energy expenditure. Here, we studied how shoe heel-toe drop affects metabolic energy expenditure during running. To do so, we studied 20 runners as they ran at 3.5 m/s in custom footwear that varied in heel-toe drop: 0, 10, 20, and 30 mm. Shoe model and mass were fixed. Overall, increasing shoe heel-toe drop increased net metabolic power during running (η²ₚ = 0.12, p=0.016); where changing from a 20 to 0 mm heel-toe drop reduced net metabolic power by 1.6%. Higher heel-toe drop decreased average vertical ground reaction force (η²ₚ = 0.10, p=0.011) and increased average ankle effective mechanical advantage (η²ₚ = 0.28, p<0.001). Higher heel-toe drop shoes increased average ankle plantarflexion angle (η²ₚ = 0.75, p<0.001), leading to shorter medial gastrocnemius fascicle operating lengths at touch-down, toe-off, and on average during ground contact (η²ₚ ≤ 0.14 p≤0.026). Additionally, higher heel-toe drop increased peak and average knee moments during running (η²ₚ ≤ 0.40, p<0.001). Therefore, longer triceps surae muscle fascicle operating lengths and reduced knee extensor moments contribute to more economical running in shoes with a lower heel-toe drop. Based on the metabolic and biomechanical findings, recreational and high-caliber distance runners who want to run faster should opt for shoes with a zero heel-toe drop.
Invasive exercise hemodynamics in obstructive and non-obstructive hypertrophic cardiomyopathy.
Baratto C, Caravita S, Perego GB … +13 more , Soranna D, Cipullo F, Rella V, Mariani D, Zambon A, Muraru D, Badano LP, Paleari S, Ferrazzi P, Olivotto I, Parati G, Cecchi F, Crotti L
J Appl Physiol (1985) · 2026 Jun · PMID 42313006 · Publisher ↗
Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease, that may lead to exertional dyspnea through dynamic left ventricular outflow tract obstruction (LVOTO), left ventricular (LV) diastolic dysfunction and/or lef...
Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease, that may lead to exertional dyspnea through dynamic left ventricular outflow tract obstruction (LVOTO), left ventricular (LV) diastolic dysfunction and/or left atrial myopathy. Deciphering the relative contribution of these alterations to exercise pathophysiology may be clinically relevant. We sought to characterize the hemodynamic adaptation to exercise of HCM patients, using supine left and right heart catheterization. Twenty-five HCM patients underwent rest and exercise cardiac catheterization. Patients were subdivided into non-obstructive HCM (no-HOCM) and obstructive HCM (HOCM), these latter defined by LVOTO > 30 mmHg at rest (overt HOCM, irrespective of exercise LVOTO), or ≥ 50 mmHg during or after exercise despite LVOTO <30 mmHg at rest (latent HOCM). Ten patients (40%) were classified as no-HOCM while 15 (60%) were classified as HOCM (8 with overt HOCM and 7 with latent or post-exercise HOCM). LV end-diastolic pressure, mean pulmonary artery wedge pressure (PAWP) and PAWP V waves (the latter a marker of left atrial stiffness), did not differ between HOCM and no-HOCM at rest. However, during exercise both PAWP and PAWP V waves increased to a larger extent in no-HOCM (23±3 vs 14±3 mmHg and +28±4 vs +14±3 mmHg, respectively, p<0.05). In overt HOCM, LVOTO reduced by 22±8 mmHg (p<0.01) during exercise. Our findings suggest that during exercise no-HOCM patients may display steeper increase in left atrial pressure than HOCM, suggesting more advanced left atrial myopathy / low left atrial compliance. LVOTO may paradoxically reduce during supine exercise in overt HOCM.
Beneficial vascular effects of oral phosphatidylserine supplementation in type 2 diabetes.
McMillan NJ, Augenreich MA, Ramirez-Perez FI … +14 more , Power G, Burr K, Lateef OM, Manikandan N, Foote CA, Imkaew N, Jurrissen TJ, Lazo-Fernandez Y, Betancourt-Cortes EE, Ferreira-Santos L, Beltran-Ornelas JH, Manrique-Acevedo C, Martinez-Lemus LA, Padilla J
J Appl Physiol (1985) · 2026 Jun · PMID 42312814 · Publisher ↗
Endothelial insulin resistance is a characteristic of type 2 diabetes (T2D) that contributes to reduced nitric oxide bioavailability, impaired vasodilation, and arterial stiffening. We recently provided evidence that end...
Endothelial insulin resistance is a characteristic of type 2 diabetes (T2D) that contributes to reduced nitric oxide bioavailability, impaired vasodilation, and arterial stiffening. We recently provided evidence that endothelial insulin resistance in T2D may be attributed to the shedding of insulin receptors by ADAM17. As prior work by others suggested that exogenous phosphatidylserine (PS) can competitively inhibit ADAM17, we hypothesized that oral PS supplementation would improve vascular function in diabetes. First, we corroborated the ability of PS to interact with and inhibit ADAM17 activity using approaches and experiments in isolated arteries. Next, we tested the vascular effects of PS in diabetic mice () and subsequently in individuals with T2D through a randomized, double-blind, placebo-controlled clinical trial. In a cell-free system, we found soluble PS binds to ADAM17 and blunts its activity, an effect also observed in cultured endothelial cells and isolated arteries, underscoring its inhibitory capacity. In diabetic mice, oral administration of PS (200mg/kg/day for 4wk) improved insulin-induced dilation in isolated resistance arteries and reduced and indices of arterial stiffness. In individuals with T2D, PS supplementation (900mg/day for 4wk, delivering ~280mg/day PS) enhanced leg blood flow responses to an oral glucose load and reduced load-dependent aortic pulse wave velocity. Lastly, we observed that PS reduced vascular oxidative stress. This work supports the potential of oral PS as a therapeutic strategy to improve vascular function in T2D, and suggests that the beneficial effects of PS may be driven by its vascular insulin-sensitizing and antioxidant actions.
Magnetic Resonance Markers of Supraspinatus Muscle Microvascular Function and Energetics Following a Rotator Cuff Tear.
Cooper KJ, Walter GA, Farmer KW … +3 more , Hotchkiss ZA, Forbes SC, Pozzi F
J Appl Physiol (1985) · 2026 Jun · PMID 42307471 · Publisher ↗
Rotator cuff tears (RCT) cause pain and disability in adults. Histological studies indicate that the degenerative process following a rotator cuff tear may disrupt the vascularity and energetics of the shoulder muscles....
Rotator cuff tears (RCT) cause pain and disability in adults. Histological studies indicate that the degenerative process following a rotator cuff tear may disrupt the vascularity and energetics of the shoulder muscles. Magnetic resonance imaging (MRI) post-contractile blood oxygen level-dependent (BOLD) response and 31phosphorus magnetic resonance spectroscopy (31P‑MRS) offer methods to non-invasively assess muscle microvascular function and energetic status in vivo. This study aimed to evaluate the post-contractile BOLD response and 31P-MRS as potential markers of microvascular function and energetic status of the supraspinatus muscle in individuals with chronic full‑thickness supraspinatus tendon tears and healthy individuals without a tear. Using a 3‑T MR Phillips system, all participants performed five 2‑s maximal isometric shoulder abductions to obtain a post-contractile BOLD response using a custom MR‑compatible dynamometer. Dixon fat/water imaging was used to quantify muscle fat fraction (FF). A surface 31P‑MRS coil acquired spectra concentrations of high energy phosphates and intracellular pH from the supraspinatus and surrounding muscles. Results revealed a lower peak BOLD response (P < 0.01) and longer time-to-peak (P = 0.02) in RCT, indicating impaired microvascular function. Analysis of 31P-MRS spectra showed elevated unlocalized Pi/PCr (P = 0.04) and PDE (P < 0.01) concentrations in RCT, consistent with muscle damage. No differences in muscle PCr (P = 0.30) or pH (P = 0.50) were observed. Overall, these findings support that the post-contractile BOLD response and 31P-MRS may be valuable markers to assess shoulder muscle health status and evaluate therapeutic interventions aimed at improving clinical outcomes following a rotator cuff tear.
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