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Pays tribute to George Leonard Collins, Jr. MD. Biographical and career details; His effort in finding and directing the Medical Liability Mutual Insurance Company and the Buffalo Sabres' professional hockey team.

Copyright of Southern Medical Journal is the property of Lippincott Williams & Wilkins and Its content may not be copied or emailed to multiple sites or posted to a listserv without the Copyright holder's express written permission. [Extracted from the article]

The purpose of this study was to examine the effects of 6 weeks of localized, muscle-focused (quadriceps femoris) passive heat therapy (PHT) on resistance artery function, exercise haemodynamics and exercise performance relative to knee extension (KE) exercise training (EX). We randomized 34 healthy adults (ages 18-36; n = 17 female, 17 male) to receive either PHT or sham heating sessions (120 min, 3 days/week), or EX (40 min, 3 days/week) over 6 weeks. Blood flow was assessed with Doppler ultrasound of the femoral artery during both passive leg movement (PLM) and a KE graded exercise test. Muscle biopsies were taken from the vastus lateralis at baseline and after 6 weeks. Peak blood flow during PLM increased to the same extent in both the EX (∼10.5% increase, P = 0.009) and PHT groups (∼8.5% increase, P = 0.044). Peak flow during knee extension exercise increased in EX (∼19%, P = 0.005), but did not change in PHT (P = 0.523) and decreased in SHAM (∼7%, P = 0.020). Peak vascular conductance during KE increased by ∼25% in EX (P = 0.030) and PHT (P = 0.012). KE peak power increased in EX by ∼27% (P = 0.001) but did not significantly change in PHT and SHAM groups. Expression of endothelial nitric oxide synthase increased significantly in both EX (P = 0.028) and PHT (P = 0.0095), but only EX resulted in increased angiogenesis. In conclusion, 6 weeks of localized PHT improved resistance artery function at rest and during exercise to the same extent as exercise training but did not yield significant improvements in performance. KEY POINTS: Many for whom exercise would be most beneficial are either unable to exercise or have a very low exercise tolerance. In these cases, an alternative treatment to combat declines in resistance artery function is needed. We tested the hypothesis that passive heat therapy (PHT) would increase resistance artery function, improve exercise haemodynamics and enhance exercise performance compared to a sham treatment, but less than aerobic exercise training. This report shows that 6 weeks of localized PHT improved resistance artery function at rest and during exercise to the same extent as exercise training but did not improve exercise performance. Additionally, muscle biopsy analyses revealed that endothelial nitric oxide synthase expression increased in both PHT and exercise training groups, but only exercise resulted in increased angiogenesis. Our data demonstrate the efficacy of applying passive heat as an alternative treatment to improve resistance artery function for those unable to receive the benefits of regular exercise., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Sauna has been linked to a reduction of cardiovascular disease risk and is a promising nonpharmacological treatment for populations at risk of cardiovascular disease. This study examined the vascular response to an acute bout of sauna heating in young and middle-aged individuals. Ten young (25 ± 4 yr, 6 males and 4 females) and eight middle-aged adults (56 ± 4 yr, 4 males and 4 females) underwent 40 min of sauna exposure at 80°C. Esophageal and intramuscular temperatures, brachial and superficial femoral artery blood flow, artery diameter, and shear rates were recorded at baseline and following heat exposure. Brachial artery flow-mediated dilation (FMD) was measured at baseline and following 90 min of recovery. Esophageal and muscle temperatures increased similarly in the young and middle-aged adults by 1.5 ± 0.53 and 1.95 ± 0.70°C, respectively ( P < 0.05). The shear rate increased by 170-200% ( P < 0.001), while blood flow increased by 180-390% ( P < 0.001) in the superficial femoral and brachial arteries, respectively, and did not differ between age groups ( P = 0.190-0.899). Systolic blood pressure was reduced from 135 ± 17 to 122 ± 20 mmHg ( P = 0.017) in middle-aged participants. These data indicate that young and middle-aged adults have similar vascular responses to acute sauna heating. NEW & NOTEWORTHY Sauna therapy has been shown to improve cardiovascular health and function in older adults and individuals with cardiovascular disease risk factors. Specifically, improvements in vascular function have been reported and have been attributed to the increased hemodynamic stimuli on the vasculature associated with thermal stress. The present study quantified this hemodynamic response to a sauna protocol associated with improved cardiovascular health across the lifespan. Our data show that middle-aged adults have the same shear rate and blood flow response to sauna as young adults.

Few formulas have been used in exercise physiology as extensively as the Fick formula, which calculates the rate of oxygen consumption ( i.e. , V.O 2 ) as the product of cardiac output (Q.) and the difference in oxygen content in arterial and mixed venous blood (Δa v ¯ O 2 ). Unfortunately, the physiology of maximum V.O 2 (V.O 2MAX ) is often misinterpreted due to a lack of appreciation for the limitations represented by the oft-ignored superscript annotations in the Fick formula. The purpose of this perspective is to explain the meaning of the superscript annotations and highlight how such annotations influence proper interpretation of V.O 2MAX physiology with the Fick formula. First, we explain the significance of the overdots above V.O 2 and Q., which indicate a measure per unit of time. As we will show, the presence of an overdot above Q. and lack of one above Δa v ¯ O 2 denotes they are different types of ratios and should be interpreted in the context of one another-not in contrast to each other as is commonplace. Second, we discuss the significance of the overline above the " v ¯ " in Δa v ¯ O 2 , which indicates the venous sample is an average of blood that comes from mixed sources. The mixed nature of the venous sample has major implications for interpreting the influence of oxygen diffusion and blood flow heterogeneity on V.O 2MAX . Ultimately, we give recommendations and insights for using the Fick formula to calculate V.O 2 and interpret V.O 2MAX physiology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gifford, Blackmon, Hales, Hinkle and Richards.)

Ageing results in lower exercise tolerance, manifested as decreased critical power (CP). We examined whether the age-related decrease in CP occurs independently of changes in muscle mass and whether it is related to impaired vascular function. Ten older (63.1 ± 2.5 years) and 10 younger (24.4 ± 4.0 years) physically active volunteers participated. Physical activity was measured with accelerometry. Leg muscle mass was quantified with dual X-ray absorptiometry. The CP and maximum power during a graded exercise test (P GXT ) of single-leg knee-extension exercise were determined over the course of four visits. During a fifth visit, vascular function of the leg was assessed with passive leg movement (PLM) hyperaemia and leg blood flow and vascular conductance during knee-extension exercise at 10 W, 20 W, slightly below CP (90% CP) and P GXT . Despite not differing in leg lean mass (P = 0.901) and physical activity (e.g., steps per day, P = 0.735), older subjects had ∼30% lower mass-specific CP (old = 3.20 ± 0.94 W kg -1 vs. young = 4.60 ± 0.87 W kg -1 ; P < 0.001). The PLM-induced hyperaemia and leg blood flow and/or conductance were blunted in the old at 20 W, 90% CP and P GXT (P < 0.05). When normalized for leg muscle mass, CP was strongly correlated with PLM-induced hyperaemia (R 2  = 0.52; P < 0.001) and vascular conductance during knee-extension exercise at 20 W (R 2  = 0.34; P = 0.014) and 90% CP (R 2  = 0.39; P = 0.004). In conclusion, the age-related decline in CP is not only an issue of muscle quantity, but also of impaired muscle quality that corresponds to impaired vascular function., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The Tour Divide (TD) is a 4385 km ultra-endurance bicycle race that follows the continental divide from Canada to Mexico. In this case study, we performed a comprehensive molecular and physiological profile before and after the completion of the TD. Assessments were performed 35 days before the start (Pre-TD) and ∼36 h after the finish (Post-TD). Total energy expenditure was assessed during the first 9 days by doubly labelled water ( 2 H 2 18 O), abdominal and leg tissue volumes via MRI, and graded exercise tests to quantify fitness and substrate preference. Vastus lateralis muscle biopsies were taken to measure mitochondrial function via respirometry, and vascular function was assessed using Doppler ultrasound. The 47-year-old male subject took 16 days 7 h 45 min to complete the route. He rode an average of 16.8 h/day. Neither maximal O 2 uptake nor maximal power output changed pre- to post-TD. Measurement of total energy expenditure and dietary recall records suggested maintenance of energy balance, which was supported by the lack of change in body weight. The subject lost both appendicular and trunk fat mass and gained leg lean mass pre- to post-TD. Skeletal muscle mitochondrial and vascular endothelial function decreased pre- to post-TD. Overall, exercise performance was maintained despite reductions in muscle mitochondrial and vascular endothelial function post-TD, suggesting a metabolic reserve in our highly trained athlete., (© 2024 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The purpose of these experiments was to determine if the increase in vascular conductance following a single muscle contraction (50% of maximal voluntary contraction) (6 male and 6 female subjects) was altered during baroceptor loading and unloading. Rapid onset vasodilation (ROV) was determined by measuring brachial artery blood flow (Doppler ultrasound) and blood pressure (Finapress monitor). Brachial artery vascular conductance was calculated by dividing blood flow by mean arterial pressure. ROV was described by the area under the Δvascular conductance (VC)-time curve during the 30 s following muscle contraction. ROV was determined using chamber pressures of +20, +10, 0, -10, -20, and -40 mmHg (lower body positive and negative pressure, LBPP, and LBNP). We tested the hypothesis that the impact of baroreceptor loading and unloading produces a proportion change in ROV. The level of ROV following each contraction was proportional to the peak force ( r 2 = 0.393, P = 0.0001). Peak force was therefore used as a covariate in further analysis. ROV during application of -40 mmHg LBNP (0.345 ± 0.229 mL·mmHg -1 ) was lower than that observed at Control (0.532 ± 0.284 mL·mmHg -1 , P = 0.034) and +20 mmHg LBPP (0.658 ± 0.364 mL·mmHg -1 , P = 0.0008). ROV was linearly related to chamber pressure from -40 to +20 mmHg chamber pressure ( r 2 = 0.512, P = 0.022, n = 69) and from -20 to +10 mmHg chamber pressure ( r 2 = 0.973, P < 0.0425, n = 45), Overall, vasoconstrictor tone altered with physiologically relevant baroreceptor loading and unloading resulted in a proportion change in ROV. NEW & NOTEWORTHY Rapid onset vasodilation (ROV) was linearly related to the peak force of each single 1-s muscle contraction. In addition, ROV is reduced by baroreceptor unloading (LBNP: -10, -120, and -40 mmHg) and increased by baroreceptor loading (LBPP: +10 and +20 mmHg). Without accounting for peak force and the level of baroreceptor engagement makes comparison of ROV in subjects of differing muscle size or strength untenable.

This study aims to investigate the effect of the menstrual cycle (MC) on exercise performance across the power-duration relationship (PDR). We hypothesized females would exhibit greater variability in the PDR across the MC than males across a similar timespan, with critical power (CP) and work-prime ( W ') being lower during the early follicular phase than the late follicular and midluteal phases. Seven eumenorrheic, endurance-trained female adults performed multiple constant-load-to-task-failure and maximum-power tests at three timepoints across the MC (early follicular, late follicular, and midluteal phases). Ten endurance-trained male adults performed the same tests approximately 10 days apart. No differences across the PDR were observed between MC phases (CP: 186.74 ± 31.00 W, P = 0.955, CV = 0.81 ± 0.65%) ( W ': 7,961.81 ± 2,537.68 J, P = 0.476, CV = 10.48 ± 3.06%). CP was similar for male and female subjects (11.82 ± 1.42 W·kg -1 vs. 11.56 ± 1.51 W·kg -1 , respectively) when controlling for leg lean mass. However, W ' was larger ( P = 0.047) for male subjects (617.28 ± 130.10 J·kg -1 ) than female subjects (490.03 ± 136.70 J·kg -1 ) when controlling for leg lean mass. MC phase does not need to be controlled when conducting aerobic endurance performance research on eumenorrheic female subjects without menstrual dysfunction. Nevertheless, several sex differences in the power-duration relationship exist, even after normalizing for body composition. Therefore, previous studies describing the physiology of exercise performance in male subjects may not perfectly describe that of female subjects. NEW & NOTEWORTHY Females are often excluded from exercise performance research due to experimental challenges in controlling for the menstrual cycle (MC), causing uncertainty regarding how the MC impacts female performance. The present study examined the influences that biological sex and the MC have on the power-duration relationship (PDR) by comparing critical power (CP), Work-prime ( W '), and maximum power output ( P MAX ) in males and females. Our data provide evidence that the MC does not influence the PDR and that females exhibit similar reproducibility as males. Thus, when conducting aerobic endurance exercise research on eumenorrheic females without menstrual dysfunction, the phase of the MC does not need to be controlled. Although differences in body composition account for some differences between the sexes, sex differences in W ' and P MAX persisted even after normalizing for different metrics of body composition. These data highlight the necessity and feasibility of examining sex differences in performance, as previously generated male-only data within the literature may not apply to female subjects.

The mitochondria are central to skeletal muscle metabolic health. Impaired mitochondrial function is associated with various muscle pathologies, including insulin resistance and muscle atrophy. As a result, continuous efforts are made to find ways to improve mitochondrial health in the context of disuse and disease. While exercise is known to cause robust improvements in mitochondrial health, not all individuals are able to exercise. This creates a need for alternate interventions which elicit some of the same benefits as exercise. Passive heating (i.e., application of heat in the absence of muscle contractions) is one potential intervention which has been shown to increase mitochondrial enzyme content and activity, and to improve mitochondrial respiration. Associated with increases in mitochondrial content and/or function, passive heating can also improve insulin sensitivity in the context of type II diabetes and preserve muscle mass in the face of limb disuse. This area of research remains in its infancy, with many questions yet to be answered about how to maximize the benefits of passive heating and elucidate the mechanisms by which heat stress affects muscle mitochondria.

Responses to exercise at a given percentage of one's maximum rate of oxygen consumption (V̇o 2max ), or percentage of the power associated with V̇o 2max during a graded exercise test (i.e., P GXT ), vary. The purpose of this study was to determine if differences in critical power (P CRIT , maximum metabolic steady state) and work-prime (W', the amount of work tolerated above steady state) are related to training-induced changes in endurance. P CRIT , W', V̇o 2max , and other variables were determined before and after 22 adults completed 8 wk of either moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT) performed at fixed percentages of P GXT . On average, P CRIT increased to a greater extent following HIIT (MICT: 15.7 ± 3.1% vs. HIIT: 27.5 ± 4.3%; P = 0.03), but the magnitude of change varied widely within each group (MICT: 4%-36%, HIIT: 4%-61%). The intensity of the prescribed exercise relative to pretraining P CRIT , not P GXT , accounted for most of the variance in changes to P CRIT in response to a given protocol ( R 2  = 0.61-0.64; P < 0.01). Although P CRIT and V̇o 2max were related before training ( R 2  = 0.92, P < 0.01), the training-induced change in P CRIT was not significantly related to the change in V̇o 2max ( R 2  = 0.06, P = 0.26). Before training, time-to-failure at P GXT was related to W' ( R 2  = 0.52; P < 0.01), but not V̇o 2max ( R 2  = 0.13; P = 0.10) . Training-induced changes in time-to-failure at the initial P GXT were better captured by the combined changes in W' and P CRIT ( R 2  = 0.77, P < 0.01), than by the change in V̇o 2max ( R 2  = 0.24; P = 0.02). Differences in P CRIT and W' account for some of the variability in responses to endurance exercise. NEW & NOTEWORTHY As the highest percentage of V̇O 2max at which steady state conditions can be achieved, a person's critical power (P CRIT ) strongly influences the metabolic strain of a given exercise. In this study we demonstrate that training-induced changes in endurance are more strongly related to the intensity of an exercise training program, relative to P CRIT than relative to V̇o 2max . Thus, exercise may be more homogenously and effectively prescribed in relation to P CRIT than traditional factors like V̇o 2max .

AIM: Mild heat stress can improve mitochondrial respiratory capacity in skeletal muscle. However, long-term heat interventions are scarce, and the effects of heat therapy need to be understood in the context of the adaptations which follow the more complex combination of stimuli from exercise training. The purpose of this work was to compare the effects of 6 weeks of localized heat therapy on human skeletal muscle mitochondria to single-leg interval training. METHODS: Thirty-five subjects were assigned to receive sham therapy, short-wave diathermy heat therapy, or single-leg interval exercise training, localized to the quadriceps muscles of the right leg. All interventions took place 3 times per week. Muscle biopsies were performed at baseline, and after 3 and 6 weeks of intervention. Mitochondrial respiratory capacity was assessed on permeabilized muscle fibers via high-resolution respirometry. RESULTS: The primary finding of this work was that heat therapy and exercise training significantly improved mitochondrial respiratory capacity by 24.8 ± 6.2% and 27.9 ± 8.7%, respectively (p < 0.05). Fatty acid oxidation and citrate synthase activity were also increased following exercise training by 29.5 ± 6.8% and 19.0 ± 7.4%, respectively (p < 0.05). However, contrary to our hypothesis, heat therapy did not increase fatty acid oxidation or citrate synthase activity. CONCLUSION: Six weeks of muscle-localized heat therapy significantly improves mitochondrial respiratory capacity, comparable to exercise training. However, unlike exercise, heat does not improve fatty acid oxidation capacity.

New Findings: What is the central question of this study? Use of the passive leg movement (PLM) test, a non-invasive assessment of microvascular function, is on the rise. However, PLM reliability in men has not been adequately investigated, nor has such reliability data, in men, been compared to the most commonly employed vascular function assessment, flow-mediated vasodilation (FMD). What is the main finding and its importance? PLM is a reliable method to assess vascular function in men, and is comparable to values previously reported for PLM in women, and for FMD. Given the importance of vascular function as a predictor of cardiovascular disease risk, these data support the utility of PLM as a clinically relevant measurement., Abstract: Although vascular function is an independent predictor of cardiovascular disease risk, and therefore has significant prognostic value, there is currently not a single clinically accepted method of assessment. The passive leg movement (PLM) assessment predominantly reflects microvascular endothelium-dependent vasodilation and can identify decrements in vascular function with advancing age and pathology. Reliability of the PLM model was only recently determined in women, and has not been adequately investigated in men. Twenty healthy men (age: 27 ± 2 year) were studied on three separate experimental days, resulting in three within-day and three between-day trials. The hyperemic response to PLM was assessed with Doppler ultrasound, and expressed as the absolute peak in leg blood flow (LBF peak ), change from baseline to peak (ΔLBF peak ), absolute area under the curve (LBF AUC ), and change in AUC from baseline (ΔLBF AUC ). PLM-induced hyperemia yielded within-day coefficients of variation (CV) from 10.9 to 22.9%, intraclass correlation coefficients (ICC) from 0.82 to 0.90, standard error of the measurement (SEM) from 8.3 to 17.2%, and Pearson's correlation coefficients (r) from 0.56 to 0.81. Between-day assessments of PLM hyperemia resulted in CV from 14.4 to 25%, ICC from 0.75 to 0.87, SEM from 9.8 to 19.8%, and r from 0.46 to 0.75. Similar to previous reports in women, the hyperemic responses to PLM in men display moderate-to-high reliability, and are comparable to reliability data for brachial artery flow mediated vasodilation. These positive reliability findings further support the utility of PLM as a clinical measurement of vascular function and cardiovascular disease risk., (© 2022 The Authors. Experimental Physiology © 2022 The Physiological Society.)

This study examined the impact of aging on the elastic and resistive components of the work of breathing ( W b ) during locomotor exercise at a given 1 ) ventilatory rate, 2 ) metabolic rate, and 3 ) operating lung volume. Eight healthy younger (25 ± 4 yr) and 8 older (72 ± 6 yr) participants performed incremental bicycle exercise, from which retrospective analyses identified similar ventilatory rates (approximately 40, 70, and 100 L·min -1 ), similar metabolic rates (V̇o 2 : approximately 1.2, 1.6, and 1.9 L·min -1 ), and similar lung volumes [inspiratory and expiratory reserve volumes (IRV/ERV: approximately 25/34%, 16/33%, and 13-34% of vital capacity]. W b at each level was quantified by integrating the averaged esophageal pressure-volume loop, which was then partitioned into elastic and resistive components of inspiratory and expiratory work using the modified Campbell diagram. IRV was smaller in the older participants during exercise at ventilations of 70 and 100 L·min -1 and during exercise at the three metabolic rates ( P < 0.05). Mainly because of a greater inspiratory elastic and resistive W b in the older group ( P < 0.05), total W b was augmented by 40%-50% during exercise at matched ventilatory and matched metabolic rates. When examined during exercise evoking similar lung volumes, total W b was not different between the groups ( P = 0.86). Taken together, although aging exaggerates total W b during locomotor exercise at a given ventilatory or a given metabolic rate, this difference is abolished during exercise at a given operating lung volume. These findings highlight the significance of operating lung volume in determining the age-related difference in W b during locomotor exercise. NEW & NOTEWORTHY This study evaluated the impact of aging on the work of breathing ( W b ) during locomotor exercise evoking similar ventilatory rates, metabolic rates, and operating lung volumes in young and older individuals. Mainly because of a greater inspiratory elastic and resistive W b in older participants, total W b was higher during exercise at any given ventilatory and metabolic rate with aging. However, this age-related difference was abolished during exercise evoking similar operating lung volumes in both age groups. These findings highlight the significance of lung volumes in determining the age-related difference in total W b .

This study investigated the impact of dietary nitrate supplementation on peripheral hemodynamics, the development of neuromuscular fatigue, and time to task failure during cycling exercise. Eleven recreationally active male participants (27 ± 5 yr, V̇o 2max : 42 ± 2 mL/kg/min) performed two experimental trials following 3 days of either dietary nitrate-rich beetroot juice (4.1 mmol NO 3 - /day; DNS) or placebo (PLA) supplementation in a blinded, counterbalanced order. Exercise consisted of constant-load cycling at 50, 75, and 100 W (4 min each) and, at ∼80% of peak power output (218 ± 12 W), to task-failure. All participants returned to repeat the shorter of the two trials performed to task failure, but with the opposite supplementation regime (iso-time comparison; ISO). Mean arterial pressure (MAP), leg blood flow (Q L ; Doppler ultrasound), leg vascular conductance (LVC), and pulmonary gas exchange were continuously assessed during exercise. Locomotor muscle fatigue was determined by the change in pre to postexercise quadriceps twitch-torque (ΔQ tw ) and voluntary activation (ΔVA; electrical femoral nerve stimulation). Following DNS, plasma [nitrite] (∼670 vs. ∼180 nmol) and [nitrate] (∼775 vs. ∼11 μmol) were significantly elevated compared with PLA. Unlike PLA, DNS lowered both Q L and MAP by ∼8% ( P < 0.05), but did not alter LVC ( P = 0.31). V̇O 2 across work rates, as well as cycling time to task-failure (∼7 min) and locomotor muscle fatigue following the ISO-time comparison were not different between the two conditions (ΔQ tw ∼42%, ΔVA ∼4%). Thus, despite significant hemodynamic changes, DNS did not alter the development of locomotor muscle fatigue and, ultimately, cycling time to task failure. NEW & NOTEWORTHY This study sought to characterize the impact of dietary nitrate supplementation on the hemodynamic response, locomotor muscle fatigue, and time to task failure during cycling exercise. Although nitrate supplementation lowered mean arterial pressure and exercising leg blood flow, leg vascular conductance and oxygen utilization were unaffected. Despite significant hemodynamic changes, there was no effect of dietary nitrate on neuromuscular fatigue development and, ultimately, cycling time to task failure.

Purpose: Very little research has investigated the effects of ultraendurance exercise on the bioenergetic status of muscle. The primary objective of this case study was to characterize the changes that occur in skeletal muscle mitochondria in response to a 100-km ultramarathon in monozygotic twins. A second objective was to determine whether mitochondrial function is altered by consuming a periodized low-carbohydrate, high-fat diet during training compared with a high-carbohydrate diet., Methods: One pair of male monozygotic twins ran 100 km on treadmills after 4 wk of training on either a high-carbohydrate or periodized low-carbohydrate, high-fat diet. Muscle biopsies were collected 4 wk before the run, as well as 4 and 52 h postrun. Blood draws were also performed immediately before as well as 4 and 52 h after the run., Results: Four hours postrun, respiratory capacity, citrate synthase activity, and mitochondrial complex protein content were decreased. Two days later, both twins showed signs of rapid recovery in several of these measures. Furthermore, blood levels of creatine phosphokinase, C-reactive protein, and aspartate transaminase were elevated 4 h after the run but partially recovered 2 d later., Conclusion: Although there were some differences between the twins, the primary finding is that there is significant mitochondrial impairment induced by running 100 km, which rapidly recovers within 2 d. These results provide ample rationale for future investigations of the effects of ultraendurance activity on mitochondrial function., (Copyright © 2021 by the American College of Sports Medicine.)

Recently it was documented that fatiguing, high-intensity exercise resulted in a significant attenuation in maximal skeletal muscle mitochondrial respiratory capacity, potentially due to the intramuscular metabolic perturbation elicited by such intense exercise. With the utilization of intrathecal fentanyl to attenuate afferent feedback from group III/IV muscle afferents, permitting increased muscle activation and greater intramuscular metabolic disturbance, this study aimed to better elucidate the role of metabolic perturbation on mitochondrial respiratory function. Eight young, healthy males performed high-intensity cycle exercise in control (CTRL) and fentanyl-treated (FENT) conditions. Liquid chromatography-mass spectrometry and high-resolution respirometry were used to assess metabolites and mitochondrial respiratory function, respectively, pre- and postexercise in muscle biopsies from the vastus lateralis. Compared with CTRL, FENT yielded a significantly greater exercise-induced metabolic perturbation (PCr: -67% vs. -82%, Pi: 353% vs. 534%, pH: -0.22 vs. -0.31, lactate: 820% vs. 1,160%). Somewhat surprisingly, despite this greater metabolic perturbation in FENT compared with CTRL, with the only exception of respiratory control ratio (RCR) (-3% and -36%) for which the impact of FENT was significantly greater, the degree of attenuated mitochondrial respiratory capacity postexercise was not different between CTRL and FENT, respectively, as assessed by maximal respiratory flux through complex I (-15% and -33%), complex II (-36% and -23%), complex I + II (-31% and -20%), and state 3 CI+CII control ratio (-24% and -39%). Although a basement effect cannot be ruled out, this failure of an augmented metabolic perturbation to extensively further attenuate mitochondrial function questions the direct role of high-intensity exercise-induced metabolite accumulation in this postexercise response.

Limb disuse has profound negative consequences on both vascular and skeletal muscle health. The purpose of this investigation was to determine whether repeated application of passive heat, applied to the knee extensor muscles, could mitigate the detrimental effects of limb disuse on vascular function. This was a randomized, single-blinded placebo controlled trial. Twenty-one healthy volunteers (10 women, 11 men) underwent 10 days of unilateral lower limb immobilization and were randomized to receive either a daily 2 h sham (Imm) or heat treatment (Imm+H) using pulsed shortwave diathermy. Vascular function was assessed with Doppler ultrasound of the femoral artery and the passive leg movement technique. Biopsies of the vastus lateralis were also collected before and after the intervention. In Imm, femoral artery diameter (FAD) and PLM-induced hyperaemia (HYP) were reduced by 7.3% and 34.3%, respectively. Changes in both FAD (4% decrease; P = 0.0006) and HYP (7.8% increase; P = 0.003) were significantly attenuated in Imm+H. Vastus lateralis capillary density was not altered in either group. Immobilization significantly decreased expression of vascular endothelial growth factor (P = 0.006) and Akt (P = 0.001), and increased expression of angiopoietin 2 (P = 0.0004) over time, with no differences found between groups. Immobilization also upregulated elements associated with remodelling of the extracellular matrix, including matrix metalloproteinase 2 (P = 0.0046) and fibronectin (P = 0.0163), with no differences found between groups. In conclusion, limb immobilization impairs vascular endothelial function, but daily muscle heating via diathermy is sufficient to counteract this adverse effect. These are the first data to indicate that passive muscle heating mitigates disuse-induced vascular dysfunction. KEY POINTS: Limb disuse can be unavoidable for many of reasons (i.e. injury, bed rest, post-surgery), and can have significant adverse consequences for muscular and vascular health. We tested the hypothesis that declines in vascular function that result from lower limb immobilization could be mitigated by application of passive heat therapy. This report shows that 10 days of limb immobilization significantly decreases resistance artery diameter and vascular function, and that application of passive heat to the knee extensor muscle group each day for 2 h per day is sufficient to attenuate these declines. Additionally, muscle biopsy analyses showed that 10 days of heat therapy does not alter capillary density of the muscle, but upregulates multiple factors indicative of a vascular remodelling response. Our data demonstrate the utility of passive heat as a therapeutic tool to mitigate losses in lower limb vascular function that occur from disuse., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Vascular function is further attenuated in patients with chronic heart failure implanted with a continuous-flow left ventricular assist device (LVAD), likely due to decreased arterial pulsatility, and this may contribute to LVAD-associated cardiovascular complications. However, the impact of increasing pulsatility on vascular function in this population is unknown. Therefore, 15 LVAD recipients and 15 well-matched controls underwent a 45-min, unilateral, arm pulsatility treatment, evoked by intermittent cuff inflation/deflation (2-s duty cycle), distal to the elbow. Vascular function was assessed by percent brachial artery flow-mediated dilation (%FMD) and reactive hyperemia (RH) (Doppler ultrasound). Pretreatment, %FMD (LVAD: 4.0 ± 1.7; controls: 4.2 ± 1.4%) and RH (LVAD: 340 ± 101; controls: 308 ± 94 mL) were not different between LVAD recipients and controls; however, %FMD/shear rate was attenuated (LVAD: 0.10 ± 0.04; controls: 0.17 ± 0.06%/s -1 , P < 0.05). The LVAD recipients exhibited a significantly attenuated pulsatility index (PI) compared with controls prior to treatment (LVAD: 2 ± 2; controls: 15 ± 7 AU, P < 0.05); however, during the treatment, PI was no longer different (LVAD: 37 ± 38; controls: 36 ± 14 AU). Although time to peak dilation and RH were not altered by the pulsatility treatment, %FMD (LVAD: 7.0 ± 1.8; controls: 7.4 ± 2.6%) and %FMD/shear rate (LVAD: 0.19 ± 0.07; controls: 0.33 ± 0.15%/s -1 ) increased significantly in both groups, with, importantly, %FMD/shear rate in the LVAD recipients being restored to that of the controls pretreatment. This study documents that a localized pulsatility treatment in LVAD recipients and controls can recover local vascular function, an important precursor to the development of approaches to increase systemic pulsatility and reduce systemic vascular complications in LVAD recipients.

Purpose: This study aimed to determine how the speed-distance relationship, described by critical speed (CS) and distance prime (D'), is altered with aging., Methods: Official race data from the past eight World Masters Athletics Indoor Track and Field World Championships were used for this study. CS and D' were calculated for female and male athletes (35-90 yr of age) who registered times for the 800-, 1500-, and 3000-m runs during a single championship to determine the relationship between age and CS and D'. Twenty-six athletes completed sufficient races in multiple championships to retrospectively assess the change in CS and D' over time., Results: Cross-sectional data indicated that CS continuously decreases after age 35 yr in a curvilinear manner with advancing age (R2 = 0.73, P < 0.001, n = 187), with even greater decreases in CS occurring after ~70 yr of age. D' also changed in a curvilinear manner with age (R2 = 0.45, P < 0.001, n = 103), such that decreases were observed between 35 and 70 yr, followed by an increase in D' thereafter. Retrospective, longitudinal data, with an average follow-up of 6.38 ± 1.73 yr, support these findings, indicating that the annual decrease in CS grows with advancing age (e.g., ~1% vs ~3% annual decrease in CS at age 55 vs 80 yr, respectively) and that D' shifts from an annual decrease (e.g., ~2.5% annual decrease at 55 yr) to an annual increase (e.g., ~2.5% annual increase at 80 yr) around 70 yr of age. Importantly, the relationship between CS and race pace was unaffected by age, supporting the relevance of CS throughout aging., Conclusion: Even among world-class athletes, CS decreases and D' changes with aging. These adaptations may contribute to the diminished exercise ability associated with aging., (Copyright © 2020 by the American College of Sports Medicine.)

Passive leg movement (PLM) evokes a robust and predominantly nitric oxide (NO)-mediated increase in blood flow that declines with age and disease. Consequently, PLM is becoming increasingly accepted as a sensitive assessment of endothelium-mediated vascular function. However, a substantial PLM-induced hyperemic response is still evoked despite nitric oxide synthase (NOS) inhibition. Therefore, in nine young healthy men (25 ± 4 yr), this investigation aimed to determine whether the combination of two potent endothelium-dependent vasodilators, specifically prostaglandin (PG) and endothelium-derived hyperpolarizing factor (EDHF), account for the remaining hyperemic response to the two variants of PLM, PLM (60 movements) and single PLM (sPLM, 1 movement), when NOS is inhibited. The leg blood flow (LBF, Doppler ultrasound) response to PLM and sPLM following the intra-arterial infusion of N G -monomethyl-l-arginine (l-NMMA), to inhibit NOS, was compared to the combined inhibition of NOS, cyclooxygenase (COX), and cytochrome P -450 (CYP450) by l-NMMA, ketorolac tromethamine (KET), and fluconazole (FLUC), respectively. NOS inhibition attenuated the overall LBF [area under the curve (LBF AUC )] response to both PLM (control: 456 ± 194, l-NMMA: 168 ± 127 mL, P < 0.01) and sPLM (control: 185 ± 171, l-NMMA: 62 ± 31 mL, P = 0.03). The combined inhibition of NOS, COX, and CYP450 (i.e., l-NMMA+KET+FLUC) did not further attenuate the hyperemic responses to PLM (LBF AUC : 271 ± 97 mL, P > 0.05) or sPLM (LBF AUC : 72 ± 45 mL, P > 0.05). Therefore, PG and EDHF do not collectively contribute to the non-NOS-derived NO-mediated, endothelium-dependent hyperemic response to either PLM or sPLM in healthy young men. These findings add to the mounting evidence and understanding of the vasodilatory pathways assessed by the PLM and sPLM vascular function tests. NEW & NOTEWORTHY Passive leg movement (PLM) evokes a highly nitric oxide (NO)-mediated hyperemic response and may provide a novel evaluation of vascular function. The contributions of endothelium-dependent vasodilatory pathways, beyond NO and including prostaglandins and endothelium-derived hyperpolarizing factor, to the PLM-induced hyperemic response to PLM have not been evaluated. With intra-arterial drug infusion, the combined inhibition of nitric oxide synthase (NOS), cyclooxygenase, and cytochrome P -450 (CYP450) pathways did not further diminish the hyperemic response to PLM compared with NOS inhibition alone.

This study investigated the impact of HFpEF on neuromuscular fatigue and peripheral hemodynamics during small muscle mass exercise not limited by cardiac output. Eight HFpEF patients (NYHA II-III, ejection-fraction: 61 ± 2%) and eight healthy controls performed dynamic knee extension exercise (80% peak workload) to task failure and maximal intermittent quadriceps contractions (8 × 15 s). Controls repeated knee extension at the same absolute intensity as HFpEF. Leg blood flow (Q L ) was quantified using Doppler ultrasound. Pre/postexercise changes in quadriceps twitch torque (ΔQ tw ; peripheral fatigue), voluntary activation (ΔVA; central fatigue), and corticospinal excitability were quantified. At the same relative intensity, HFpEF (24 ± 5 W) and controls (42 ± 6 W) had a similar time-to-task failure (∼10 min), ΔQ tw (∼50%), and ΔVA (∼6%). This resulted in a greater exercise-induced change in neuromuscular function per unit work in HFpEF, which was significantly correlated with a slower Q L response time. Knee extension exercise at the same absolute intensity resulted in an ∼40% lower Q L and greater ΔQ tw and ΔVA in HFpEF than in controls. Corticospinal excitability remained unaltered during exercise in both groups. Finally, despite a similar ΔVA, ΔQ tw was larger in HFpEF versus controls during isometric exercise. In conclusion, HFpEF patients are characterized by a similar development of central and peripheral fatigue as healthy controls when tested at the same relative intensity during exercise not limited by cardiac output. However, HFpEF patients have a greater susceptibility to neuromuscular fatigue during exercise at a given absolute intensity, and this impairs functional capacity. The patients' compromised Q L response to exercise likely accounts, at least partly, for the patients' attenuated fatigue resistance. NEW & NOTEWORTHY The susceptibility to neuromuscular fatigue during exercise is substantially exaggerated in individuals with heart failure with a preserved ejection fraction. The faster rate of fatigue development is associated with the compromised peripheral hemodynamic response characterizing these patients during exercise. Given the role of neuromuscular fatigue as a factor limiting exercise, this impairment likely accounts for a significant portion of the exercise intolerance typical for this population.

Nitric oxide synthase (NOS) inhibition with N(G)-monomethyl-l-arginine (L-NMMA) is often used to assess the role of NO in human cardiovascular function. However, the window of effect for L-NMMA on human vascular function is unknown, which is critical for designing and interpreting human-based studies. This study utilized the passive leg movement (PLM) assessment of vascular function, which is predominantly NO-mediated, in 7 young male subjects under control conditions, immediately following intra-arterial L-NMMA infusion (0.24 mg⋅dl -1 ⋅min -1 ), and at 45-60 and 90-105 min post L-NMMA infusion. The leg blood flow (LBF) and leg vascular conductance (LVC) responses to PLM, measured with Doppler ultrasound and expressed as the change from baseline to peak (ΔLBF peak and ΔLVC peak ) and area under the curve (LBF AUC and LVC ACU ), were assessed. PLM-induced robust control ΔLBF peak (1135 ± 324 ml⋅min -1 ) and ΔLVC peak (10.7 ± 3.6 ml⋅min -1 ⋅mmHg -1 ) responses that were significantly attenuated (704 ± 196 ml⋅min -1 and 6.7 ± 2 ml⋅min -1 ⋅mmHg -1 ) immediately following L-NMMA infusion. Likewise, control condition PLM ΔLBF AUC (455 ± 202 ml) and ΔLVC AUC (4.0 ± 1.4 ml⋅mmHg -1 ) were significantly attenuated (141 ± 130 ml and 1.3 ± 1.2 ml⋅mmHg -1 ) immediately following L-NMMA infusion. However, by 45-60 min post L-NMMA infusion all PLM variables were not significantly different from control, and this was still the case at 90-105 min post L-NMMA infusion. These findings reveal that the potent reduction in NO bioavailability afforded by NOS inhibition with L-NMMA has a window of effect of less than 45-60 min in the human vasculature. These data are particularly important for the commonly employed approach of pharmacologically inhibiting NOS with L-NMMA in the human vasculature., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: While maximum blood flow influences one's maximum rate of oxygen consumption (V̇O 2 max), with so many indices of vascular function, it is still unclear if vascular function is related to V̇O 2 max in healthy, young adults. The purpose of this study was to determine if several common vascular tests of conduit artery and resistance artery function provide similar information about vascular function and the relationship between vascular function and V̇O 2 max., Methods: Twenty-two healthy adults completed multiple assessments of leg vascular function, including flow-mediated dilation (FMD), reactive hyperemia (RH), passive leg movement (PLM), and rapid onset vasodilation (ROV). V̇O 2 max was assessed with a graded exercise test on a cycle ergometer., Results: Indices associated with resistance artery function (e.g., peak flow during RH, PLM, and ROV) were generally related to each other (r = 0.47-77, p < .05), while indices derived from FMD were unrelated to other tests (p < .05). Absolute V̇O 2 max (r = 0.57-0.73, p < .05) and mass-specific V̇O 2 max (r = 0.41-0.46, p < .05) were related to indices of resistance artery function, even when controlling for factors like body mass and sex. FMD was only related to mass-specific V̇O 2 max after statistically controlling for baseline artery diameter (r = 0.44, p < .05)., Conclusion: Indices of leg resistance artery function (e.g., peak flow during RH, PLM, and ROV) relate well to each other and account for ~30% of the variance in V̇O 2 max not accounted for by other factors, like body mass and sex. Vascular interventions should focus on improving indices of resistance artery function, not conduit artery function, when seeking to improve exercise capacity., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Cerebral blood flow (CBF) is commonly inferred from blood velocity measurements in the middle cerebral artery (MCA), using nonimaging, transcranial Doppler ultrasound (TCD). However, both blood velocity and vessel diameter are critical components required to accurately determine blood flow, and there is mounting evidence that the MCA is vasoactive. Therefore, the aim of this study was to employ imaging TCD (ITCD), utilizing color flow images and pulse wave velocity, as a novel approach to measure both MCA diameter and blood velocity to accurately quantify changes in MCA blood flow. ITCD was performed at rest in 13 healthy participants (7 men/6 women; 28 ± 5 yr) with pharmaceutically induced vasodilation [nitroglycerin (NTG), 0.8 mg] and without (CON). Measurements were taken for 2 min before and for 5 min following NTG or sham delivery (CON). There was more than a fivefold, significant, fall in MCA blood velocity in response to NTG (∆-4.95 ± 4.6 cm/s) compared to negligible fluctuation in CON (∆-0.88 ± 4.7 cm/s) ( P < 0.001). MCA diameter increased significantly in response to NTG (∆0.09 ± 0.04 cm) compared with the basal variation in CON (∆0.00 ± 0.04 cm) ( P = 0.018). Interestingly, the product of the NTG-induced fall in MCA blood velocity and increase in diameter was a significant increase in MCA blood flow following NTG (∆144 ± 159 ml/min) compared with CON (∆-5 ± 130 ml/min) ( P = 0.005). These juxtaposed findings highlight the importance of measuring both MCA blood velocity and diameter when assessing CBF and document ITCD as a novel approach to achieve this goal.