J. Appl. Physiol. [JOURNAL]
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200 papers
Spironolactone ameliorates the endothelial dysfunction induced by visceral adipose tissue in obese female mice exposed to early life stress.
Ahmed N, Turner MB, Leachman JR … +4 more , Seebold A, Cincinelli C, Dalmasso C, Loria AS
J Appl Physiol (1985) · 2026 Jun · PMID 42095486 · Publisher ↗
Previously, we have shown that female mice exposed to maternal separation and early weaning (MSEW), a mouse model of early life stress, display an exacerbated obesogenic response to a hypercaloric diet via a mechanism th...
Previously, we have shown that female mice exposed to maternal separation and early weaning (MSEW), a mouse model of early life stress, display an exacerbated obesogenic response to a hypercaloric diet via a mechanism that most likely involves the mineralocorticoid receptor (MR). This study investigated whether perivascular adipose tissue-derived factors influence vascular endothelial function in obese female MSEW mice using the MR antagonist spironolactone in vivo. C57BL/6J mice pups were subjected to MSEW or control rearing. At weaning, female mice were placed on a high-fat diet for 20 wk and treated with vehicle or spironolactone (100 mg/kg/day) for two additional weeks. Mice were then euthanized, thoracic aortas were isolated and cleaned to assess endothelial function in aortic rings preincubated with either DMEM, or explant media from either perivascular adipose tissue (PVAT) or mesenteric adipose tissue (MESAT) incubated in DMEM (2 h, 37°C). MSEW did not influence acetylcholine (ACh)-induced maximal relaxation in isolated rings of vehicle-treated mice preincubated with DMEM or PVAT explant media. However, preincubation with MESAT explant media impaired relaxation only in MSEW mice. Overall, spironolactone improved vascular relaxation in isolated rings preincubated with either type of adipose tissue explant; however, this effect was enhanced in rings from MSEW mice preincubated with their MESAT explant media. Taken together, these findings suggest that MESAT-derived endocrine and inflammatory mediators promote endothelial dysfunction in obese female mice exposed to MSEW, whereas spironolactone ameliorates this effect. Adverse childhood experiences (ACEs) are associated with increased cardiometabolic disease risk, where women display a greater visceral adipose tissue expansion. This study identifies potential visceral adipose tissue-specific factors that contribute to vascular dysfunction, provides mechanistic insight into sex-specific cardiometabolic vulnerability, and highlights MR signaling as a potential therapeutic target to reduce health disparities linked to childhood adversity.
High- and moderate-intensity exercise training differentially impact microvascular function in skeletal muscle of mice lacking adiponectin.
Medarev S, Zheng X, Evola V … +8 more , Parr M, Foster A, Rathakrishnan A, Park H, Maraj J, Ghosh P, Machin DR, Muller-Delp J
J Appl Physiol (1985) · 2026 Jun · PMID 42090335 · Publisher ↗
We tested the hypothesis that the absence of circulating adiponectin, associated with reduced aerobic exercise, contributes to impaired microvascular function and oxidative capacity in the skeletal muscle of adult mice....
We tested the hypothesis that the absence of circulating adiponectin, associated with reduced aerobic exercise, contributes to impaired microvascular function and oxidative capacity in the skeletal muscle of adult mice. Adiponectin knockout (AdipoKO) and wild-type (WT) mice were assigned to either a moderate- or high-intensity exercise (EX) training protocol or remained sedentary (SED) for an 8- to 10-wk period. At the end of this period, in vivo microvascular dynamics were measured, followed by ex vivo assessment of arteriolar vasoreactivity. Oxidative capacity and capillary density in skeletal muscle were evaluated using citrate synthase activity assays and immunohistochemical staining for lectin, respectively. Our results showed that moderate-intensity exercise training increased oxidative capacity in the soleus muscle of WT mice, whereas AdipoKO mice did not show similar improvements. Moderate-intensity exercise training also increased capillary-to-fiber ratio in WT mice; however, these exercise training-associated vascular adaptations were absent in AdipoKO mice. Moderate-intensity exercise training increased vasorelaxation to acetylcholine in arterioles from AdipoKO mice as compared with those from WT mice. In contrast, high-intensity exercise training augmented flow-mediated vasodilation in arterioles from WT mice, but not in arterioles from AdipoKO mice. These findings suggest that adiponectin is important for exercise training-induced improvements in skeletal muscle oxidative capacity and microvascular function. The lack of adiponectin disrupts these beneficial adaptations, suggesting that adiponectin plays an important role in mediating vascular health responses to aerobic exercise training in skeletal muscle. Endothelial and microvascular adaptations to exercise are limited in the absence of adiponectin. In wild-type mice, moderate exercise improved oxidative capacity, perfusion, and capillarity, whereas high-intensity exercise enhanced flow-mediated vasodilation. These adaptations were lost in adiponectin-deficient mice, underscoring adiponectin's essential role in linking aerobic training to cardiovascular health.
Reflex vasodilation and sweating in response to passive whole body heating are blunted in women with major depressive disorder.
Fisher KG, Leach OK, Greaney JL … +2 more , Alexander LM, Kenney WL
J Appl Physiol (1985) · 2026 Jun · PMID 42090275 · Full text
Major depressive disorder (MDD) is associated with alterations in the mechanistic regulation of body temperature, including altered circadian temperature profiles, reduced sweating, and blunted cutaneous vasodilation. Se...
Major depressive disorder (MDD) is associated with alterations in the mechanistic regulation of body temperature, including altered circadian temperature profiles, reduced sweating, and blunted cutaneous vasodilation. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may affect vascular function and sweating; however, heat stress thermoregulation in MDD and during SSRI or SNRI therapy has not been measured. The purpose of this study was to measure reflex cutaneous vasodilation and sweating responses during passive heating in women with MDD who were non- or chronically treated with either SSRI or SNRI monotherapy. Sixteen women (aged 18-36 yr) with unmedicated MDD, 16 women with SSRI-treated MDD, 16 women with SNRI-treated MDD, and 16 nondepressed women were passively heated using a water-perfused suit to increase core temperature (T) by 1.0°C. Forearm blood flow (FBF; venous occlusion plethysmography) was measured at every 0.1°C increase in T, normalized to mean arterial pressure (MAP), and expressed as forearm vascular conductance (FVC). Skin blood flow (SkBF; laser-Doppler flowmetry) and local sweat rate (LSR; ventilated sweat capsule) were continuously measured. FVC was lower in unmedicated MDD compared with nondepressed ( = 0.03) and SSRI-treated ( = 0.01). FVC in SNRI-treated was not different from nondepressed ( = 0.09) or MDD ( = 1.0) but lower than SSRI-treated women ( = 0.03). Greater increases in mean body temperature from baseline were required for the onset of LSR and SkBF in unmedicated MDD compared with all other groups (all < 0.05). Together, these findings suggest alterations in reflex thermoregulation in unmedicated women with MDD; these effects may be ameliorated by antidepressant pharmacotherapies. Reflex skin vasodilation is blunted in women with MDD who are not using antidepressant medications compared with women with MDD currently taking SSRIs and nondepressed women. In addition, unmedicated women with MDD have a delayed onset of thermoregulatory effector function. This suggests that there are alterations in the central control of thermoregulation in women with MDD not using pharmacotherapies; however, these detrimental effects may be partially ameliorated by common antidepressant medications, specifically SSRIs.
The other half of the sprinting coin: the neuromuscular profile of a 91-yr-old female world record sprinter.
Colosio M, Dobrzycki I, Teigen LE … +10 more , Carbonaro M, Ansaldo M, Gatti M, Brusco CM, Canepari M, Bottinelli R, Botter A, Porcelli S, Franchi MV, Sundberg CW
J Appl Physiol (1985) · 2026 Jun · PMID 42090218 · Full text
A 91-yr-old female set the W90 world record in the 200 m sprint in 2024. We characterized her neuromuscular function, fatigability, denervation markers, and single-fiber contractile properties, and, where possible, compa...
A 91-yr-old female set the W90 world record in the 200 m sprint in 2024. We characterized her neuromuscular function, fatigability, denervation markers, and single-fiber contractile properties, and, where possible, compared these outcomes with published reference data. Knee extensor muscle architecture, force, power, fatigability, and motor unit (MU) behavior were assessed in vivo, and a vastus lateralis biopsy was analyzed for single-fiber contractile properties and markers of denervation. Quadriceps cross-sectional area was 36.5 cm, with fascicle length, pennation angle, and muscle thickness of 6.7 cm, 11.6°, and 1.4 cm, respectively. Knee extensor maximal voluntary isometric contraction (MVIC) torque was 79 Nm, power was 28 W, and power declined by 43% during a 4-min fatiguing task. MU recruitment threshold was 12 ± 11% of MVIC. Single-fiber absolute and specific force were 0.88 ± 0.19 mN and 114 ± 10 kN/m for myosin heavy chain (MyHC) I and 0.74 ± 0.23 mN and 171 ± 23 kN/m for MyHC IIa fibers. Less than 1% of fibers were positive for the denervation marker neural cell adhesion molecule (NCAM), no fibers expressed embryonic MyHC, and ∼1% of MyHC II fibers expressed neonatal MyHC. In vivo muscle size, force, power, and fatigability were largely within the range for individuals one decade younger. MU behavior was comparable with individuals 20 yr younger. MyHC I fibers produced greater absolute force than reported in untrained young females and females in their eighth decade, whereas MyHC II fiber force was lower because of smaller fiber size. Denervation markers were less prevalent than typically reported at this age. Collectively, these findings illustrate the heterogeneous effects of aging on different features of neuromuscular function, even in an elite older female sprint athlete. We report in vivo neuromuscular function, single-fiber mechanics, and denervation markers in a 91-yr-old female who holds the W90 200 m world record. Despite reduced muscle size, force, and power, as well as pronounced fast-fiber atrophy, markers of denervation were similar to those in young females and single-fiber force in slow fibers was preserved. Together, these data highlight the differential effects of lifelong sprint training and aging on neural versus muscular components of the neuromuscular system.
One half of the sprinting coin: the oxygen transport cascade of a 91-yr-old female world-record sprinter.
Colosio M, Pilotto AM, Ansaldo M … +8 more , Dobrzycki I, Pellegrino MA, Bottinelli R, Re R, Botter A, Franchi MV, Sundberg CW, Porcelli S
J Appl Physiol (1985) · 2026 Jun · PMID 42090203 · Full text
A 91-yr-old female set the W90 world record in the 200-m sprint in 2024, surpassing her previous record by 1.13 s. This study characterized her cardiorespiratory fitness, skeletal muscle oxidative capacity, fiber-type di...
A 91-yr-old female set the W90 world record in the 200-m sprint in 2024, surpassing her previous record by 1.13 s. This study characterized her cardiorespiratory fitness, skeletal muscle oxidative capacity, fiber-type distribution, capillarization, and satellite cells and compared these outcomes, where possible, to published reference data. Cardiorespiratory responses were assessed during a ramp cycling test to exhaustion, and muscle oxidative capacity (mV̇o) was determined using near-infrared spectroscopy during repetitive arterial occlusions. Fiber-type distribution, cross-sectional area, capillarization, satellite cell content and localization, and mitochondrial respiratory capacity were analyzed in a vastus lateralis biopsy. Peak oxygen uptake (V̇o) was 23 mL·kg·min at 98 W, with a maximal heart rate of 141 beats·min and cardiac output of 13.6 L·min. The mV̇o recovery rate constant () was 1.83 min. Fiber composition was 57% fast MyHC II fibers (50% IIa, 5% IIa-IIx, and 2% IIx), 38% slow MyHC I fibers, and 5% hybrid I-IIa fibers. MyHC I fibers were larger, more vascularized, and had satellite cells located closer to capillaries [4,267 ± 2,181 μm; 1.67 individual capillary-to-fiber ratio (C/F), 5.58 capillaries × 1,000 μm capillary-to-fiber perimeter exchange index (CFPE), 1.8-µm satellite cell-to-capillary distance] than MyHC II fibers (2,752 ± 1,608 μm; 1.03 C/F, 4.00 capillaries × 1,000 μm CFPE and 10.4 µm, respectively). Mitochondrial O flux was 58 and 68 pmol·(s·mg) during coupled and uncoupled respiration, respectively. The athlete's cardiorespiratory and oxidative capacity resembled those of females in their 50s or younger. Collectively, her large, well-vascularized slow fibers, high proportion of fast fibers, and preserved muscle oxidative capacity likely contributed to her world record performance, illustrating the remarkable plasticity of skeletal muscle even in very advanced age. We report an in vivo and ex vivo characterization of cardiorespiratory fitness and muscle oxidative capacity in a 91-yr-old female who holds the W90 200-m world record. She exhibited a high muscle oxidative capacity and a muscle fiber profile with large, well-vascularized slow fibers and a relatively high proportion of fast fibers. These findings suggest that components of the oxygen transport and utilization system can be well-preserved into very advanced age in a lifelong sprinter.
Early women's health research on endurance exercise training and cardiovascular aging at the University of Colorado Boulder using the masters athlete model.
Seals DR, DeSouza CA, Tanaka H … +4 more , Moreau KL, Darvish S, Ambrose C, Davy KP
J Appl Physiol (1985) · 2026 Jun · PMID 42090127 · Publisher ↗
As male physiology was historically viewed as the "norm" and data on females were considered difficult to interpret, little information regarding the effects of regular exercise on women's health over the lifespan was av...
As male physiology was historically viewed as the "norm" and data on females were considered difficult to interpret, little information regarding the effects of regular exercise on women's health over the lifespan was available leading into the 1990s. In 1993, we initiated research at the University of Colorado Boulder to determine the effects of endurance exercise training on healthy cardiovascular aging in women. To do so, we used a "masters athlete model" in which midlife and older female distance runners were compared with their healthy, but nonexercising peers, as well as young adult women. The masters runners (∼50-70 yr, mostly postmenopausal) had a maximal oxygen consumption (V̇o) almost twice that of nonexercising postmenopausal women, in part due to a larger total blood volume. The masters runners showed stable body mass with age/menopause and exhibited much smaller age-related differences in total body fatness and abdominal adiposity than nonexercising women, related in part to preserved resting metabolic rate. The masters runners maintained a healthier overall systolic blood pressure profile and showed smaller differences in large elastic artery (aorta and carotid arteries) stiffness with age/menopause compared with nonexercising women. In contrast to nonexercising women, circulating coagulation and fibrinolytic activity was well-preserved with age/menopause in the masters runners. Masters runners also maintained greater heart rate variability, more favorable regulation of plasma glucose and insulin, and a superior plasma lipid-lipoprotein profile compared with nonexercising postmenopausal women. In contrast to males, female masters athletes did not demonstrate greater vascular endothelial function than their nonexercising peers. Collectively, this work represented the first systematic research conducted on the benefits of endurance exercise training on optimal cardiovascular function and health with age/menopause in women using the masters athlete model.
Pirfenidone attenuates hyperoxia-induced lung injury and pulmonary hypertension in a mouse model of bronchopulmonary dysplasia in newborn mice.
Zhang M, Zhang J, Bu X … +2 more , Ye W, Zhou J
J Appl Physiol (1985) · 2026 Jun · PMID 42089976 · Publisher ↗
Bronchopulmonary dysplasia (BPD) is a major complication of prematurity frequently accompanied by life-threatening pulmonary hypertension (PH). Pirfenidone (PFD), an antifibrotic drug approved for adults, exhibits multim...
Bronchopulmonary dysplasia (BPD) is a major complication of prematurity frequently accompanied by life-threatening pulmonary hypertension (PH). Pirfenidone (PFD), an antifibrotic drug approved for adults, exhibits multimodal properties, but its therapeutic efficacy and underlying mechanisms in neonatal BPD-associated PH (BPD-PH) remain to be elucidated. This study aimed to evaluate the therapeutic potential of PFD and its underlying mechanisms in a hyperoxia-induced mouse model of BPD. We found that PFD treatment enhanced alveolarization, reduced pulmonary fibrosis, attenuated pulmonary vascular remodeling, and right ventricular hypertrophy. These protective effects were accompanied by decreased expression of inflammatory cytokines, improved oxidative stress profiles, and concomitant suppression of Wnt5A signaling and transforming growth factor-β1/Smad pathway activation. Collectively, these findings identify PFD as a potential modulator of lung injury and vascular remodeling in experimental BPD. However, as these observations are derived from a preclinical model, further studies are required to define safety, dosing, and efficacy before clinical translation. This study demonstrates that PFD, an antifibrotic drug, alleviates alveolar simplification, pulmonary vascular remodeling, and right ventricular hypertrophy in a hyperoxia-induced neonatal mouse model of BPD. These protective effects were associated with suppression of Wnt5A-mediated noncanonical signaling and TGF-β/Smad activation, together with reduced inflammation and oxidative stress. These findings reveal a previously unrecognized mechanism underlying the protective effects of PFD and support its potential repurposing as a therapeutic strategy for BPD-PH.
Age moderates the association between handgrip strength and large artery stiffness in women.
Mascone SE, Lefferts WK, Ranadive SM … +1 more , Lefferts EC
J Appl Physiol (1985) · 2026 Jun · PMID 42089952 · Publisher ↗
Women's cardiovascular disease risk increases during midlife, in part, due to accelerated vascular dysfunction. Age-related vascular dysfunction includes increases in large artery stiffness, which may be mitigated by mai...
Women's cardiovascular disease risk increases during midlife, in part, due to accelerated vascular dysfunction. Age-related vascular dysfunction includes increases in large artery stiffness, which may be mitigated by maintaining muscular strength. However, the relationship between handgrip strength and large artery stiffness through the lifespan in women is unknown. The present purpose was to evaluate the relationship between handgrip strength and large artery stiffness in women. Maximal voluntary contraction relative to body weight (MVC/BW), carotid artery stiffness (β-stiffness), and aortic stiffness [carotid-femoral pulse wave velocity (cfPWV)] were measured in 216 women ( = 54 young 29 ± 9 yr, = 73 middle-aged 56 ± 6 yr, and = 89 older 72 ± 6 yr). Multivariate linear regression was used to evaluate the relationship between large artery stiffness and MVC/BW, age, and the MVC/BW by age interaction while adjusting for potential confounders. In the fully adjusted model, age [ = 0.23 (95% CI, 0.12, 0.35), < 0.001] and the age by MVC/BW interaction [ = -0.28 (-0.55, -0.02), = 0.04] were associated with β-stiffness. Similar results were observed with cfPWV [age: = 0.15 (0.09, 0.20), < 0.001; age × MVC/BW: = -0.15 (0.28, -0.02) = 0.02], which remained after further adjustment for mean arterial pressure. Simple slope analyses revealed inverse associations between MVC/BW and cfPWV ( = 0.02) and β-stiffness ( = 0.07) among older women, with weak to no associations observed among young or middle-aged women ( = 0.19-0.75). Age modifies the relationship between relative handgrip strength and large artery stiffness in women. The direction of the relationship between relative handgrip strength and large artery stiffness changes across the lifespan in women, with greater handgrip strength being associated with lower large artery stiffness after middle age. The present study investigated the association between relative handgrip strength and large artery stiffness in women across the lifespan. Greater relative handgrip strength was not associated with large artery stiffness in young or middle-aged women but was associated with lower large artery stiffness in older women. This age-moderating effect suggests the impact of muscular strength on large artery stiffness changes across the lifespan and becomes more important for vascular health in women following midlife.
Modeling cerebrovascular dynamics during transitions in exercise intensity.
Hedge ET, Hughson RL
J Appl Physiol (1985) · 2026 Jun · PMID 42065612 · Publisher ↗
Cerebral blood flow is a tightly controlled variable that is regulated by multiple integrative physiological mechanisms. Many of the factors that influence cerebral blood flow change during exercise in an intensity-depen...
Cerebral blood flow is a tightly controlled variable that is regulated by multiple integrative physiological mechanisms. Many of the factors that influence cerebral blood flow change during exercise in an intensity-dependent manner, leading to complex interactions, with the net effect of all factors dictating the blood flow response. Research to date has largely focused on investigating cerebrovascular responses to exercise during discrete steady-state stages, but recently, dynamic modeling of the cerebrovascular response to transitions in exercise intensity has gained interest as a novel way to study cerebrovascular health and function. Indeed, studying the dynamic adjustment of a variable in response to an external stimulus provides important information about the integrity and function of the controlling system. In the context of the cerebrovascular response to exercise, it is important to recognize that the primary stimulus inducing a change in cerebral blood flow is not simply an increase in external work being performed, but rather the integrative exercise response that includes changes in arterial blood pressure, cardiac output, arterial partial pressure of carbon dioxide, autonomic nervous system activity, and cerebral metabolism. However, disentangling the contribution of separate factors and mechanisms to the dynamic cerebrovascular response to exercise is complicated. Accordingly, in this review, we ) provide an overview of different modeling approaches that have been applied to investigate cerebrovascular kinetics during exercise transitions, ) discuss considerations when modeling cerebrovascular responses to exercise, and ) provide perspectives to help inform modeling approaches for future work.
Diffuse correlation spectroscopy opens new frontiers in respiratory physiology.
Koike J, Fujii N
J Appl Physiol (1985) · 2026 May · PMID 42060793 · Publisher ↗
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Reply to Koike and Fujii.
Ichinose M, Nakabayashi M, Ono Y
J Appl Physiol (1985) · 2026 May · PMID 42060792 · Publisher ↗
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Reduced skeletal muscle perfusion accompanies skeletal muscle atrophy after severe spinal cord injury.
Clayton ZS, Nguyen BL, Kok HJ … +11 more , Reynolds MC, Conover CF, Wnek RD, Buckley KH, Kura JR, Otzel DM, Luo YE, Barton ER, Beck DT, McCullough DJ, Yarrow JF
J Appl Physiol (1985) · 2026 May · PMID 42060380 · Full text
The goal of this study was to gain insight into an understudied physiological mechanism that may influence skeletal muscle atrophy following spinal cord injury (SCI). Specifically, we quantified skeletal muscle blood flo...
The goal of this study was to gain insight into an understudied physiological mechanism that may influence skeletal muscle atrophy following spinal cord injury (SCI). Specifically, we quantified skeletal muscle blood flow (BF) rates in paralyzed hindlimbs throughout the acute to subacute recovery period in a severe contusion SCI model. Secondary objectives were to characterize temporal changes in circulating and tissue-level markers of capillary density and vascular dysfunction, and vascular-related gene expression within hindlimb skeletal muscle. We hypothesized that SCI would reduce skeletal muscle BF and be accompanied by increases in circulating markers of vascular dysfunction, along with reductions in skeletal muscle capillary density and vascular-related gene expression. Four-month-old Sprague-Dawley male rats underwent T laminectomy (sham surgery) or severe contusion SCI. Hindlimb skeletal muscle mass, absolute BF rates, and mass-corrected BF rates were lower at 1, 2, and 4 wk in SCI versus sham, with the most distinct BF differences present in the soleus (∼50% lower, < 0.001). Bulk RNA sequencing revealed that genes related to coagulation, blood vessel maintenance, and endothelial cell health were lower in soleus muscle after SCI, with most differences occurring at 1-2 wk. Circulating platelet endothelial cell adhesion molecule-1, a marker of vascular dysfunction, was higher at 2-3 wk post-SCI ( < 0.05), whereas no differences in soleus capillary density were detected. Our results reveal reduced limb perfusion and signs of vascular dysfunction in paralyzed hindlimb skeletal muscle during the acute post-SCI period in a rodent severe SCI model. Future studies examining mechanisms of vascular dysfunction after SCI or testing interventions to improve vascular function should consider this timeframe. First study to assess temporal blood flow/perfusion rates in paralyzed plantar flexor muscles throughout the acute to subacute period after SCI and to determine the relation with skeletal muscle capillarization. Results demonstrate that reduced skeletal muscle perfusion that develops in the paralyzed plantar flexor muscles throughout the acute to subacute post-SCI recovery period may be driven by reduced limb perfusion and damage to endothelial cells within skeletal muscle vasculature, independent of skeletal muscle capillarization.
Sex differences in the power-duration relationship for dynamic knee extension are largely explained by muscle size.
Ghitter RS, Isidori AL, Whittier DE … +1 more , MacInnis MJ
J Appl Physiol (1985) · 2026 May · PMID 42059830 · Publisher ↗
Although males generally outperform females in absolute exercise tasks, it is unclear whether these differences persist for small muscle mass exercise when accounting for muscle size and anatomical factors. The purpose o...
Although males generally outperform females in absolute exercise tasks, it is unclear whether these differences persist for small muscle mass exercise when accounting for muscle size and anatomical factors. The purpose of this study was to compare the power-duration relationship for dynamic knee extension exercise between healthy males ( = 12) and females ( = 12) matched for maximal aerobic fitness relative to fat-free mass (V̇o: 59.5 ± 7.9 vs. 59.2 ± 6.0 mL·kgFFM·min; = 0.921). Participants completed four constant work rate tests to measure critical power (CP) and the curvature constant ('). Using magnetic resonance imaging (MRI), quadriceps volume was assessed to estimate and control for muscle mass, and the patellar tendon moment arm (PTMA) was measured to estimate quadriceps force. Males demonstrated a significantly greater CP ( = 0.003), CP torque ( < 0.001), CP quadriceps force ( = 0.003), and ' ( = 0.031) compared with females. No sex difference in CP measures remained after controlling for quadriceps mass ( > 0.05). An interaction between sex and quadriceps mass regarding ' ( = 0.036) revealed a positive association in males ( = 0.001) but not in females ( = 0.926). After adjusting for quadriceps mass, whole body and single-leg aerobic fitness were related to CP ( < 0.05). Maximal quadriceps force was related to ' ( = 0.044), but strength did not appear to influence CP independently of quadriceps mass ( > 0.05). Overall, sex differences in absolute CP were largely explained by muscle size as opposed to an innate difference between male and female muscle, and variability in CP was not independently related to strength or PTMA. In males and females matched for aerobic fitness [maximal oxygen uptake normalized to fat-free mass (FFM)], dynamic knee extension critical power (CP) was greater in males, but after adjusting for differences in quadriceps muscle size, CP was similar between sexes. These findings indicate that sex differences in small muscle mass performance result from differences in muscle size, not innate differences in muscle endurance capacity.
The near-infrared diffuse correlation spectroscopy muscle perfusion index in human calf muscle: accounting for changes in hemoconcentration.
Bartlett MF, Davis KA, Englund EK … +2 more , Liu H, Nelson MD
J Appl Physiol (1985) · 2026 May · PMID 42059820 · Publisher ↗
During physiological provocations, relative changes in muscle blood flow and O extraction can be estimated using near-infrared diffuse correlation spectroscopy (NIRS-DCS). However, the NIRS-DCS blood flow index (BFI) may...
During physiological provocations, relative changes in muscle blood flow and O extraction can be estimated using near-infrared diffuse correlation spectroscopy (NIRS-DCS). However, the NIRS-DCS blood flow index (BFI) may underestimate perfusion changes unless changes in hemoconcentration are accounted for. Accordingly, we compared NIRS-DCS calculations of muscle perfusion and O extraction against MRI-derived arterial spin labeling (ASL) and MR susceptometry-based venous oximetry (SvO), respectively. Thirteen healthy young adults (5 F) completed an ischemic-reperfusion test and plantarflexion exercise inside the bore of a 3 T MRI scanner. NIRS-DCS BFI was either ) unadjusted (BFI), or converted into a muscle perfusion index (MPI) by ) scaling BFI linearly for changes in hemoconcentration (MPI), or ) scaling BFI for changes in hemoconcentration squared (MPI). Compared with ASL MRI, peak DCS perfusion was significantly lower during postischemic reperfusion when using BFI but not when using MPI or MPI. Similarly, end-exercise perfusion from BFI was significantly lower than ASL following plantarflexion exercise, whereas no difference was observed when comparing MPI and MPI to ASL. NIRS estimations of SvO were lower than MRI after 8 mins of ischemia, but similar following moderate-intensity plantarflexion exercise. However, following high-intensity exercise, NIRS estimations of SvO were similar to MRI only after accounting for changes in hemoconcentration. Collectively, these results highlight the importance of accounting for changes in hemoconcentration when using NIRS-DCS to estimate changes in muscle perfusion during physiological provocations such as ischemic reperfusion and exercise. We compared changes in skeletal muscle blood flow estimated by NIRS-DCS against arterial spin-labeling MRI during ischemic reperfusion and exercise. NIRS-DCS blood flow index underestimated relative changes in muscle perfusion across all procedures unless the calculations were adjusted for changes in hemoconcentration and total heme content, which resulted in a muscle perfusion index (MPI) that was almost superimposed on ASL-MRI. These results demonstrate that NIRS-DCS MPI noninvasively quantifies changes in muscle perfusion in humans.
High-precision aortic banding with O-rings: a versatile model for studying heart failure mechanisms in rats.
Hauge-Iversen IM, Melleby AO, Nordén ES … +5 more , Hasic A, Ugland H, Zhang L, Sjaastad I, Espe EKS
J Appl Physiol (1985) · 2026 Jun · PMID 42053991 · Publisher ↗
Animal models play a critical role in cardiovascular research, and reliable and reproducible phenotypes are essential. Aortic banding is a well-established technique for inducing pressure overload/heart failure in rats;...
Animal models play a critical role in cardiovascular research, and reliable and reproducible phenotypes are essential. Aortic banding is a well-established technique for inducing pressure overload/heart failure in rats; however, conventional methods often lead to variability in outcomes. This study aims to use rubber O-rings to achieve reliable pressure overload in rats and to investigate how varying ring sizes result in distinct cardiac phenotypes 6 wk postsurgery. Male Sprague-Dawley rats (∼100 g, ∼4 wk old) underwent surgical aortic banding using nitrile O-rings of three different sizes (1.5, 1.3, and 1.07 mm) plus a sham-operated group. The rats were then monitored for 6 wk, after which cardiac function and structure were evaluated using echocardiography and magnetic resonance imaging ( = 70 rats). Expression of molecular markers of cardiac remodeling was also quantified. We found that all banded rats developed significant left ventricular hypertrophy, with ∼42%-58% higher ventricular weights than controls. The 1.07 mm group showed a decline in stroke volume and ejection fraction, indicative of reduced systolic function, while also exhibiting signs of diastolic dysfunction. Congestion indices were also severely impacted in the 1.07 mm group, and tissue fibrosis gene expression was higher in the 1.5 mm and 1.07 mm groups. The O-ring method successfully creates distinct cardiac phenotypes that reflect various degrees of heart failure, from hypertrophy to congestion with reduced ejection fraction. The associated increase in cardiac fibrosis gene expression and impaired diastolic function with tighter constriction underscores the utility of this model for studying heart failure mechanisms. This study shows that the high-precision O-ring aortic banding method in rats reliably produces graded and reproducible cardiac phenotypes, ranging from compensated hypertrophy to congestive heart failure with reduced ejection fraction. By linking fixed degrees of pressure overload to distinct systolic, diastolic, and fibrotic adaptations quantified by echocardiography, MRI, and molecular analyses, the model provides a robust and translational platform for mechanistic studies of pressure overload-induced heart failure.
Intercellular contact is sufficient to drive fibroblast-to-myofibroblast transitions.
Chandar V, Goykadosh BM, Parameswaran H
J Appl Physiol (1985) · 2026 Jun · PMID 42053470 · Publisher ↗
Fibroblast cells play a key role in maintaining the extracellular matrix. During wound healing, fibroblasts differentiate into highly contractile myofibroblasts, which secrete extracellular matrix proteins, such as colla...
Fibroblast cells play a key role in maintaining the extracellular matrix. During wound healing, fibroblasts differentiate into highly contractile myofibroblasts, which secrete extracellular matrix proteins, such as collagen, to facilitate tissue repair. Under normal conditions, myofibroblasts undergo programmed cell death after healing to prevent excessive scar formation. However, in diseases such as fibrosis, myofibroblasts remain active even after the wound is closed, resulting in excessive collagen buildup and a stiff, fibrotic matrix. The reasons for the persistence of myofibroblasts in fibrosis are not well understood. Here, we show the existence of a mechanism where direct physical contact between a fibroblast and a myofibroblast is sufficient for fibroblasts to transition into myofibroblasts. We demonstrate that the fibroblast-myofibroblast transition can occur even in the absence of known biochemical cues, such as growth factor activation or mechanical cues from a stiff, fibrotic matrix. Furthermore, we demonstrate that contact-based fibroblast-myofibroblast activation can be inhibited by the Gαq/11/14 inhibitor FR900359, which prevents the formation of myofibroblasts. These findings provide new insights into the persistence of the myofibroblast phenotype and highlight potential approaches to regulate the fibroblast-to-myofibroblast transition. This study uncovers a novel mechanism of fibroblast-to-myofibroblast transition (FMT) driven by cell-cell contact. Myofibroblast-fibroblast contact elevates cytoskeletal tension in the fibroblast, which in turn drives transition via activation of the GqGPCR signaling pathway. This process occurs independently of exogenous biochemical cues or stiff matrices. Emphasizing the central role of cytoskeletal stress in FMT, these findings reveal a mechanoregulated pathway, opening potential new avenues to investigate myofibroblast persistence.
Guidelines for optimizing rigor and reproducibility in inclusion of premenopausal females in integrative physiology research.
Bradbury KE, McClung HL, Ranadive SM … +5 more , Oppenheimer AV, Goldenstein SJ, Stachenfeld NS, Charkoudian N, Giersch GEW
J Appl Physiol (1985) · 2026 Jun · PMID 42030271 · Publisher ↗
Increased inclusion of females in research has been recommended and discussed extensively in recent years. To enhance rigor, reproducibility, and generalizability of results, it is important to ensure that physiological...
Increased inclusion of females in research has been recommended and discussed extensively in recent years. To enhance rigor, reproducibility, and generalizability of results, it is important to ensure that physiological research, particularly studies of female physiology, is comparable. In this Guidelines review, we seek to highlight factors to consider and potentially control, depending on the specific research question and outcomes of interest, to enhance generalizability. We also provide recommendations for enhancing various study designs and for using specific terminology to enhance the ability for comparison across research studies. The goal of this Guidelines is to provide tools for research design, inclusion of premenopausal females, and relevant and appropriate controls, even when investigations are resource, study design (time, structure), or population constrained, by providing no-cost solutions.
Ventilatory inefficiency in obstructive lung disease reveals emergent [Formula: see text] equilibrium during exercise.
Haouzi P, Persaud P, McCully J
J Appl Physiol (1985) · 2026 Jun · PMID 42023426 · Publisher ↗
Ventilatory "inefficiency" during exercise in obstructive lung disease-such as that resulting from increased dead space or ventilation-perfusion mismatch-is commonly interpreted as a perturbation that requires an additio...
Ventilatory "inefficiency" during exercise in obstructive lung disease-such as that resulting from increased dead space or ventilation-perfusion mismatch-is commonly interpreted as a perturbation that requires an additional increase in minute ventilation and thus in V̇e/V̇co to preserve [Formula: see text] homeostasis. This observation raises a fundamental question: how could an increase in V̇e/V̇co during exercise be actively directed toward defending [Formula: see text] stability if no known neural signal, governing respiration, directly encodes ventilatory "inefficiency"? We retrospectively analyzed the lung-function and anthropometric data, as well as ventilatory and gas-exchange responses obtained at rest, lactate threshold (LaT), and peak exercise, of 443 patients with obstructive lung disease who underwent cardiopulmonary exercise testing and spanning a wide range of V̇e/V̇co. Relationships between [Formula: see text] and V̇e/V̇co, estimated V̇a/V̇co, and V̇d/V̇co were examined using power-law regression. Patients were then stratified by peak V̇e/V̇co, and group differences were assessed using Welch ANOVA, with effect sizes expressed as η and Cohen's . Across rest, LaT, and peak exercise, [Formula: see text] exhibited a continuous ≈1/x relationship with V̇e/V̇co that closely paralleled [Formula: see text]-V̇a/V̇co. Stratification by V̇e/V̇co consistently identified very large effect sizes for [Formula: see text]. This [Formula: see text]-V̇e/V̇co "phenotype" was also present in the normocapnic range. Hypercapnia was observed only in patients with low V̇e/V̇co. Arterial Pco obtained just at the exercise cessation retained a similar pattern, remaining inversely related to peak V̇e/V̇co. The present study supports the view that [Formula: see text] is emergent, and not defended, in this cohort of patients with chronic obstructive pulmonary disease (COPD). Implications for control of breathing during exercise are discussed. Despite very different levels of obstructive lung disease and ventilatory insufficiency, [Formula: see text] and [Formula: see text] display an inverse relationship with V̇e/V̇co across exercise levels. Stratification by V̇e/V̇co demonstrates that interindividual differences in V̇e/V̇co were driven by changes in effective alveolar ventilation. These results support the view that [Formula: see text] stability is apparent during exercise. [Formula: see text] passively emerges from the interactions between a constrained respiratory plant at any ventilatory drive.
Differential genioglossus muscle responses to changes in breathing route in awake people with and without obstructive sleep apnea.
Burke PGR, Jugé L, Knapman FL … +8 more , Yeung J, Bull C, Brown EC, Martins R, Gandevia SC, Eckert DJ, Butler JE, Bilston LE
J Appl Physiol (1985) · 2026 Jun · PMID 42003053 · Publisher ↗
This study examined the effects of nasal and oral breathing routes on genioglossus electromyographic activity (EMG), inspiratory (nadir) epiglottic pressures, and the pressure-dependent reflex regulation of inspiratory g...
This study examined the effects of nasal and oral breathing routes on genioglossus electromyographic activity (EMG), inspiratory (nadir) epiglottic pressures, and the pressure-dependent reflex regulation of inspiratory genioglossus EMG in awake supine participants. We hypothesized that oral breathing reduces negative pharyngeal pressure swings during inspiration and, via a pressure-dependent reflex mechanism, reduces phasic inspiratory genioglossus EMG. Twenty participants with obstructive sleep apnea (OSA) and 8 people without OSA were recruited into this study. Measurements included multiunit genioglossus EMG via percutaneous bipolar electrodes, airflow via nasal pneumotach, epiglottic pressure, and end-tidal CO. Participants were studied while in supine position, breathing quietly via nose, then switched to oral breathing for ∼5 min/route, and then repeated the protocol. Oral breathing reduced inspiratory epiglottic negative pressures by ∼50% in all participants [OSA nasal: -4 ± 1.8 (SD) cmHO; oral: -1.8 ± 0.8 cmHO; non-OSA nasal: -2.4 ± 1.6 cmHO; oral: -1.1 ± 0.8 cmHO]. In people without OSA and a third of people with OSA, oral breathing was associated with reduced phasic inspiratory genioglossus EMG and correlated with reduced inspiratory negative epiglottic pressure swings. Unexpectedly, in the remaining two-thirds of people with OSA, phasic inspiratory EMG was maintained and/or increased with oral breathing, despite reduced inspiratory negative pharyngeal pressure swings. Remarkably, the increased inspiratory genioglossus EMG during oral breathing in these participants with OSA was inversely correlated with epiglottic pressure. The divergent responses in most people with OSA may represent a reflex adaptation to oral breathing, perhaps due, at least in part, to increased and persistent nocturnal oral breathing. Breathing is supposed to occur through the nose. The switch to oral breathing occurs during exercise, with nasal congestion, or during sleep. This study reports that oral breathing is associated with different patterns of genioglossus muscle activity in individuals with and without obstructive sleep apnea (OSA). A subset of participants with OSA showed with oral breathing, despite reduced airway resistance, which was unexpected, and may represent a neural adaptation to increased oral breathing in OSA.
Left ventricular systolic function during isometric handgrip exercise and postexercise circulatory occlusion in healthy male and female adults.
Boyes NG, Nelson MD, Haykowsky MJ … +6 more , Elaschuk C, Luchkanych AMS, Khan MR, Karjala G, Olver TD, Tomczak CR
J Appl Physiol (1985) · 2026 May · PMID 41996171 · Publisher ↗
Postexercise circulatory occlusion (PECO) stimulates metabolically sensitive afferents, activating the muscle metaboreflex and eliciting a greater blood pressure response in males than females, possibly owing to greater...
Postexercise circulatory occlusion (PECO) stimulates metabolically sensitive afferents, activating the muscle metaboreflex and eliciting a greater blood pressure response in males than females, possibly owing to greater absolute exercise workloads that contribute to disproportionate increases in stroke volume (SV). We tested the hypotheses that isometric handgrip exercise (EX) and PECO would increase SV greater in males than females, and accounting for strength would negate differences. Ten males and 10 females underwent cardiac MRI during rest, EX, and PECO. SV, end-systolic (ESV) and end-diastolic volume (EDV), all indexed to body surface area, and wall stress, systolic blood pressure (SBP), and total peripheral resistance (TPR) were measured. EX and PECO lowered stroke volume index (SVi) in males (both < 0.001) but not females (both = 0.998). The reduction in SVi during EX and PECO in males remained with analysis of covariance (covariate handgrip strength; = 0.020). EX increased end-systolic volume index (ESVi) in both sexes ( ≤ 0.018), whereas ESVi increased during PECO in males ( < 0.001) but not females ( ≥ 0.092). EX and PECO increased end-diastolic volume index, SBP, TPR, and wall stress (all ≤ 0.015) in both sexes. The SVi response to PECO was negatively related to ESVi responses in males ( = -0.822, = 0.004) but not females ( = 0.216). PECO lowers SVi in males but not females independent of handgrip strength, despite comparable pressor responses. These novel findings support differential afterload sensitivity on SV between sexes in response to the exercise pressor and muscle metaboreflex. Remarkably, SV is not augmented as part of the pressor response elicited by isometric handgrip exercise or muscle metaboreflex activation in either sex. Moderate-intensity isometric handgrip exercise and postexercise circulatory occlusion decrease stroke volume in males but not females, even after accounting for handgrip strength. Sex differences in the stroke volume response to isometric handgrip exercise and the muscle metaboreflex appear driven by greater male sensitivity to ventricular afterload. In an isolated handgrip exercise-circulatory occlusion model, stroke volume does not increase as a component of the pressor response elicited by exercise or the muscle metaboreflex in either sex.
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