Key pointsr Critical power represents an important threshold for neuromuscular fatigue development and may, therefore, dictate intensities for which exercise tolerance is determined by the magnitude of fatigue accrued.r Peripheral fatigue appears to be constant across O 2 delivery conditions for large muscle mass exercise, but this consistency is equivocal for smaller muscle mass exercise.r We sought to determine the influence of blood flow occlusion during handgrip exercise on neuromuscular fatigue development and to examine the relationship between neuromuscular fatigue development and W .r Blood flow occlusion influenced the development of both peripheral and central fatigue, thus providing further evidence that the magnitude of peripheral fatigue is not constant across O 2 delivery conditions for small muscle mass exercise.r W appears to be related to the magnitude of fatigue accrued during exercise, which may explain the reported consistency of intramuscular metabolic perturbations and work performed for severe-intensity exercise.Abstract The influence of the muscle metabolic milieu on peripheral and central fatigue is currently unclear. Moreover, the relationships between peripheral and central fatigue and the curvature constant (W ) have not been investigated. Six men (age: 25 ± 4 years, body mass: 82 ± 10 kg, height: 179 ± 4 cm) completed four constant power handgrip tests to exhaustion under conditions of control exercise (Con), blood flow occlusion exercise (Occ), Con with 5 min post-exercise blood flow occlusion (Con + Occ), and Occ with 5 min post-exercise blood flow occlusion (Occ + Occ). Neuromuscular fatigue measurements and W were obtained for each subject. Each trial resulted in significant peripheral and central fatigue. Significantly greater peripheral (79.7 ± 5.1% vs. 22.7 ± 6.0%) and central (42.6 ± 3.9% vs. 4.9 ± 2.0%) fatigue occurred for Occ than for Con. In addition, significantly greater peripheral (83.0 ± 4.2% vs. 69.0 ± 6.2%) and central (65.5 ± 14.6% vs. 18.6 ± 4.1%) fatigue occurred for Occ + Occ than for Con + Occ. W was significantly related to the magnitude of global (r = 0.91) and peripheral (r = 0.83) fatigue. The current findings demonstrate that blood flow occlusion exacerbated the development of both peripheral and central fatigue and that post-exercise blood flow occlusion prevented the recovery of both peripheral and central fatigue. Moreover, the current findings suggest that W may be determined by the magnitude of fatigue accrued during exercise.

BackgroundLung ischemia-reperfusion (IR) injury after transplantation as well as acute shortage of suitable donor lungs are two critical issues impacting lung transplant patients. This study investigates the anti-inflammatory and immunomodulatory role of human mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) to attenuate lung IR injury and improve of ex-vivo lung perfusion (EVLP)-mediated rehabilitation in donation after circulatory death (DCD) lungs.MethodsC57BL/6 wild-type (WT) mice underwent sham surgery or lung IR using an in vivo hilar-ligation model with or without MSCs or EVs. In vitro studies used primary iNKT cells and macrophages (MH-S cells) were exposed to hypoxia/reoxygenation with/without co-cultures with MSCs or EVs. Also, separate groups of WT mice underwent euthanasia and 1 h of warm ischemia and stored at 4 °C for 1 h followed by 1 h of normothermic EVLP using Steen solution or Steen solution containing MSCs or EVs.ResultsLungs from MSCs or EV-treated mice had significant attenuation of lung dysfunction and injury (decreased edema, neutrophil infiltration and myeloperoxidase levels) compared to IR alone. A significant decrease in proinflammatory cytokines (IL-17, TNF-α, CXCL1 and HMGB1) and upregulation of keratinocyte growth factor, prostaglandin E2 and IL-10 occurred in the BAL fluid from MSC or EV-treated mice after IR compared to IR alone. Furthermore, MSCs or EVs significantly downregulated iNKT cell-produced IL-17 and macrophage-produced HMGB1 and TNF-α after hypoxia/reoxygenation. Finally, EVLP of DCD lungs with Steen solution including MSCs or EVs provided significantly enhanced protection versus Steen solution alone. Co-cultures of MSCs or EVs with lung endothelial cells prevents neutrophil transendothelial migration after exposure to hypoxia/reoxygenation and TNF-α/HMGB1 cytomix.ConclusionsThese results suggest that MSC-derived EVs can attenuate lung inflammation and injury after IR as well as enhance EVLP-mediated reconditioning of donor lungs. The therapeutic benefits of EVs are in part mediated through anti-inflammatory promoting mechanisms via attenuation of immune cell activation as well as prevention of endothelial barrier integrity to prevent lung edema. Therefore, MSC-derived EVs offer a potential therapeutic strategy to treat post-transplant IR injury as well as rehabilitation of DCD lungs.

It is currently unknown whether sex differences exist in the cardiovascular consequences of the inspiratory muscle metaboreflex. We hypothesized that the activation of the inspiratory muscle metaboreflex will lead to less of an increase in mean arterial pressure (MAP) and limb vascular resistance (LVR) and less of a decrease in limb blood flow (Q̇L) in women compared with men. Twenty healthy men (n = 10, 23 ± 2 yr) and women (n = 10, 22 ± 3 yr) were recruited for this study. Subjects performed inspiratory resistive breathing tasks (IRBTs) at 2% or 65% of their maximal inspiratory mouth pressure (PIMAX). During the IRBTs, the breathing frequency was 20 breaths/min with a 50% duty cycle. At rest and during the IRBTs, MAP was measured via automated oscillometry, Q̇L was measured via Doppler ultrasound, and LVR was calculated. EMG was recorded on the leg to ensure no muscle contraction occurred. The 65% IRBT led to attenuated increases (P < 0.01) from baseline in women compared with men for MAP (W: 7.3 ± 2.0 mmHg; M: 11.1 ± 5.0 mmHg) and LVR (W: 17.7% ± 14.0%; M: 47.9 ± 21.0%), as well as less of a decrease (P < 0.01) in Q̇L (W: -7.5 ± 9.9%; M: -23.3 ± 10.2%). These sex differences in MAP, Q̇L, and LVR were still present in a subset of subjects matched for PIMAX The 2% IRBT resulted in no significant changes in MAP, Q̇L, or LVR across time or between men and women. These data indicate premenopausal women exhibit an attenuated inspiratory muscle metaboreflex compared with age-matched men.

In this review, we highlight the underlying mechanisms responsible for the sex differences in the exercise pressor reflex, and, importantly, the impact of sex hormones and menopausal status. The exercise pressor reflex is attenuated in pre-menopausal women compared to age-matched men. Specifically, activation of the metaboreflex (a component of the exercise pressor reflex) results in attenuated increases in blood pressure and sympathetic vasomotor outflow compared to agematched men. In addition, pre-menopausal women exhibit less transduction of sympathetic outflow to the peripheral vasculature than men. In stark contrast, post-menopausal women exhibit an augmented exercise pressor reflex arising from exaggerated metaboreflex-induced autonomic and cardiovascular reflexes. We propose that metaboreflex-induced autonomic and cardiovascular changes associated with menopause majorly contribute to the elevated blood pressure response during dynamic exercise in post-menopausal women. In addition, we discuss the potential mechanisms by which sex hormones in pre-menopausal women may impact the exercise pressor reflex as well as metaboreflex.

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Heart failure patients with reduced ejection fraction (HFrEF) exhibit severe limitations in exercise capacity (VO 2 peak). r One of the primary peripheral mechanisms suggested to underlie exercise intolerance in HFrEF is excessive locomotor muscle group III/IV afferent feedback; however, this has never been investigated in human heart failure. r HFrEF patients and controls performed an incremental exercise test to volitional exhaustion to determineVO 2 peak with lumbar intrathecal fentanyl or placebo. During exercise, cardiac output, leg blood flow and radial artery and femoral venous blood gases were measured. r With fentanyl, compared with placebo, patients with HFrEF achieved a higher peak workload, VO 2 peak, cardiac output, stroke volume and leg blood flow. r These findings suggest that locomotor muscle group III/IV afferent feedback in HFrEF leads to increased systemic vascular resistance, which constrains stroke volume, cardiac output and O 2 delivery thereby impairingVO 2 peak and thus exercise capacity.

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With inspiratory muscle metaboreflex activation, we hypothesized that, compared with their younger counterparts, older men and women would exhibit greater ) increases in mean arterial pressure (MAP) and limb vascular resistance (LVR) and) decreases in limb blood flow (Q̇) but ) no sex differences would be present in older adults. Sixteen young adults [8 young men (YM) and 8 young women (YW), 18-24 yr] and 16 older adults [8 older men (OM) and 8 older women (OW), 60-73 yr] performed inspiratory resistive breathing tasks (IRBTs) at 2% and 65% of their maximal inspiratory pressure. During the IRBTs, breathing frequency was 20 breaths/min with a 50% duty cycle. At baseline and during the IRBTs, MAP was measured via automated oscillometry, Q̇ was determined via Doppler ultrasound, and LVR was calculated. The 65% IRBT led to significantly greater increases in MAP in OW (15.9 ± 8.1 mmHg) compared with YW (6.9 ± 1.4 mmHg) but not ( > 0.05) between OM (12.3 ± 5.7 mmHg) and YM (10.8 ± 5.7 mmHg). OW (-20.2 ± 7.2%) had greater ( < 0.05) decreases in Q̇ compared with YW (-9.4 ± 10.2%), but no significant differences were present between OM (-22.8 ± 9.7%) and YM (-22.7 ± 11.3%) during the 65% IRBT. The 65% IRBT led to greater ( < 0.05) increases in LVR in OW (48.2 ± 25.5%) compared with YW (19.7 ± 15.0%), but no differences ( > 0.05) existed among OM (54.4 ± 17.8%) and YM (47.1 ± 23.3%). No significant differences were present in MAP, Q̇, or LVR between OM and OW. These data suggest that OW exhibit a greater inspiratory muscle metaboreflex compared with YW, whereas no differences between OM and YM existed. Finally, sex differences in the inspiratory muscle metaboreflex are not present in older adults. Premenopausal women exhibit an attenuated inspiratory muscle metaboreflex compared with young men; however, it is unknown whether these sex differences are present in older adults. Older women exhibited a greater inspiratory muscle metaboreflex compared with premenopausal women, whereas no differences were present between older and younger men.