The dynamic response to a stimulus such as exercise can reveal valuable insights into systems control in health and disease that are not evident from the steady-state perturbation. However, the dynamic response profile and kinetics of cerebrovascular function have not been determined to date. We tested the hypotheses that bilateral middle cerebral artery blood flow mean velocity (MCA) increases exponentially following the onset of moderate-intensity exercise in 10 healthy young subjects. The MCA response profiles were well fit to a delay (TD) + exponential (time constant, τ) model with substantial agreement for baseline [left (L): 69, right (R): 64 cm/s, coefficient of variation (CV) 11%], response amplitude (L: 16, R: 13 cm/s, CV 23%), TD (L: 54, R: 52 s, CV 9%), τ (L: 30, R: 30 s, CV 22%), and mean response time (MRT) (L: 83, R: 82 s, CV 8%) between left and right MCA as supported by the high correlations (e.g., MRT = 0.82, < 0.05) and low CVs. Test-retest reliability was high with CVs for the baseline, amplitude, and MRT of 3, 14, and 12%, respectively. These responses contrasted markedly with those of three healthy older subjects in whom the MCA baseline and exercise response amplitude were far lower and the kinetics slowed. A single older stroke patient showed baseline ipsilateral MCA that was lower still and devoid of any exercise response whatsoever. We conclude that kinetics analysis of MCA during exercise has significant potential to unveil novel aspects of cerebrovascular function in health and disease. Resolution of the dynamic stimulus-response profile provides a greater understanding of the underlying the physiological control processes than steady-state measurements alone. We report a novel method of measuring cerebrovascular blood velocity (MCAv) kinetics under ecologically valid conditions from rest to moderate-intensity exercise. This technique reveals that brain blood flow increases exponentially following the onset of exercise with ) a strong bilateral coherence in young healthy individuals, and) a potential for unique age- and disease-specific profiles.

Oxygen pressure (PO2) gradients across the blood-myocyte interface are required for diffusive O transport, thereby supporting oxidative metabolism. The greatest resistance to O flux into skeletal muscle is considered to reside between the erythrocyte surface and adjacent sarcolemma, although this has not been measured during contractions. We tested the hypothesis that O gradients between skeletal muscle microvascular (PO2 mv ) and interstitial (PO2 is ) spaces would be present at rest and maintained or increased during contractions. PO2 mv and PO2 is   were determined via phosphorescence quenching (Oxyphor probes G2 and G4, respectively) in the exposed rat spinotrapezius during the rest-contraction transient (1 Hz, 6 V; n = 8). PO2 mv was higher than PO2 is in all instances from rest (34.9 ± 6.0 versus 15.7 ± 6.4) to contractions (28.4 ± 5.3 versus 10.6 ± 5.2 mmHg, respectively) such that the mean PO2 gradient throughout the transient was 16.9 ± 6.6 mmHg (P< 0.05 for all). No differences in the amplitude of PO2 fall with contractions were observed between the microvasculature and interstitium (10.9 ± 2.3 versus 9.0 ± 3.5 mmHg, respectively; P > 0.05). However, the speed of the PO2 is fall during contractions was slower than that of PO2 mv (time constant: 12.8 ± 4.7 versus 9.0 ± 5.1 s, respectively; P < 0.05). Consistent with our hypothesis, a significant transmural gradient was sustained (but not increased) from rest to contractions. This supports that the blood-myocyte interface is the site of a substantial PO2 gradient driving O diffusion during metabolic transients. Based on Fick's law, elevated O flux with contractions must thus rely primarily on modulations in effective diffusing capacity (mainly erythrocyte haemodynamics and distribution) as the PO2 gradient is not increased.

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.

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Blood velocity measured in the middle cerebral artery (MCA) increases with finite kinetics during moderate-intensity exercise, and the amplitude and dynamics of the response provide invaluable insights into the controlling mechanisms. The MCA response after exercise onset is well fit to an exponential model in young individuals but remains to be characterized in their older counterparts. The responsiveness of vasomotor control degrades with advancing age, especially in skeletal muscle. We tested the hypothesis that older subjects would evince a slower and reduced MCA response to exercise. Twenty-nine healthy young (25 ± 1 yr old) and older (69 ± 1 yr old) adults each performed a rapid transition from rest to moderate-intensity exercise on a recumbent stepper. Resting MCA was lower in older than young subjects (47 ± 2 vs. 64 ± 3 cm/s, P < 0.001), and amplitude from rest to steady-state exercise was lower in older than young subjects (12 ± 2 vs. 18 ± 3 cm/s, P = 0.04), even after subjects were matched for work rate. As hypothesized, the time constant was significantly longer (slower) in the older than young subjects (51 ± 10 vs. 31 ± 4 s, P = 0.03), driven primarily by older women. Neither age-related differences in fitness, end-tidal CO, nor blood pressure could account for this effect. Thus, MCA kinetic analyses revealed a marked impairment in the cerebrovascular response to exercise in older individuals. Kinetic analysis offers a novel approach to evaluate the efficacy of therapeutic interventions for improving cerebrovascular function in elderly and patient populations. NEW & NOTEWORTHY Understanding the dynamic cerebrovascular response to exercise has provided insights into sex-related cerebrovascular control mechanisms throughout the aging process. We report novel differences in the kinetics response of cerebrovascular blood velocity after the onset of moderate-intensity exercise. The exponential increase in brain blood flow from rest to exercise revealed that 1) the kinetics profile of the older group was blunted compared with their young counterparts and 2) the older women demonstrated a slowed response.

Whole body exercise tolerance is the consummate example of integrative physiological function among the metabolic, neuromuscular, cardiovascular, and respiratory systems. Depending on the animal selected, the energetic demands and flux through the oxygen transport system can increase two orders of magnitude from rest to maximal exercise. Thus, animal models in health and disease present the scientist with flexible, powerful, and, in some instances, purpose-built tools to explore the mechanistic bases for physiological function and help unveil the causes for pathological or age-related exercise intolerance. Elegant experimental designs and analyses of kinetic parameters and steady-state responses permit acute and chronic exercise paradigms to identify therapeutic targets for drug development in disease and also present the opportunity to test the efficacy of pharmacological and behavioral countermeasures during aging, for example. However, for this promise to be fully realized, the correct or optimal animal model must be selected in conjunction with reproducible tests of physiological function (e.g., exercise capacity and maximal oxygen uptake) that can be compared equitably across laboratories, clinics, and other proving grounds. Rigorously controlled animal exercise and training studies constitute the foundation of translational research. This review presents the most commonly selected animal models with guidelines for their use and obtaining reproducible results and, crucially, translates state-of-the-art techniques and procedures developed on humans to those animal models. Listen to this article’s corresponding podcast at: https://ajpheart.podbean.com/e/guidelines-for-animal-exercise-and-training-protocols/ .

Broxterman RM, Ade CJ, Craig JC, Wilcox SL, Schlup SJ, Barstow TJ. Influence of blood flow occlusion on muscle oxygenation characteristics and the parameters of the power-duration relationship. J Appl Physiol 118: 880 -889, 2015. First published February 6, 2015 doi:10.1152/japplphysiol.00875.2014.-It was previously (Monod H, Scherrer J. Ergonomics 8: 329 -338, 1965 postulated that blood flow occlusion during exercise would reduce critical power (CP) to 0 Watts (W), while not altering the curvature constant (W=). We empirically assessed the influence of blood flow occlusion on CP, W=, and muscle oxygenation characteristics. Ten healthy men (age: 24.8 Ϯ 2.6 yr; height: 180 Ϯ 5 cm; weight: 84.6 Ϯ 10.1 kg) completed four constant-power handgrip exercise tests during both control blood flow (control) and blood flow occlusion (occlusion) for the determination of the power-duration relationship. Occlusion CP (Ϫ0.7 Ϯ 0.4 W) was significantly (P Ͻ 0.001) lower than control CP (4.1 Ϯ 0.7 W) and significantly (P Ͻ 0.001) lower than 0 W. Occlusion W= (808 Ϯ 155 J) was significantly (P Ͻ 0.001) different from control W= (558 Ϯ 129 J), and all 10 subjects demonstrated an increased occlusion W= with a mean increase of ϳ49%. The present findings support the aerobic nature of CP. The findings also demonstrate that the amount of work that can be performed above CP is constant for a given condition, but can vary across conditions. Moreover, this amount of work that can be performed above CP does not appear to be the determinant of W=, but rather a consequence of the depletion of intramuscular energy stores and/or the accumulation of fatigue-inducing metabolites, which limit exercise tolerance and determine W=. critical power; curvature constant; oxygen delivery; muscle ischemia THE ROBUST NATURE OF THE power-duration relationship (and its equivalents for other modes of exercise) has been well established (26, 27, 52). Nevertheless, the precise physiological mechanisms of the curvature constant (W=), and to a lesser degree critical power (CP), have remained elusive. The growing body of evidence supports that CP represents the highest attainable steady state for aerobic energy production without continually drawing on W= and, as such, demarcates the boundary between the heavy-and severe-intensity exercise domains (4,12,38,39,42,51). It is also evident that W= is a constant term that determines the limit of exercise tolerance (T lim ) for severe-intensity exercise (21, 55). Intramuscular energy stores (35,36,38), the accumulation of fatigue-inducing metabolites (7,18,21,28), and/or the magnitude of the severe-intensity domain (5, 51) have all been postulated to determine W=. Building evidence supports that complete utilization of W= is associated with consistent muscle phosphocreatine ([PCr]), inorganic phosphate ([P i ]), and hydrogen ion concentration ([H ϩ ]) perturbations, which may limit the amount of work performed above CP (28,43,51). Additionally, the rate of W= utilization (but not the magnitude of W=) is influenced by mani...

Craig JC, Broxterman RM, Wilcox SL, Chen C, Barstow TJ. Effect of adipose tissue thickness, muscle site, and sex on near-infrared spectroscopy derived total-[hemoglobin + myoglobin]. J Appl Physiol 123: 1571-1578, 2017. First published September 21, 2017; doi: 10.1152/japplphysiol.00207.2017 .-Adipose tissue thickness (ATT) attenuates signals from near-infrared spectroscopy (NIRS) and diminishes the absolute quantification of underlying tissues by contemporary NIRS devices. Based on the relationship between NIRS-derived total-[hemoglobin + myoglobin] (total-[Hb + Mb]) and ATT, we tested the hypotheses that the correction factor for ATT 1) is muscle site specific; 2) does not differ between men and women; and that 3) exclusion of the shortest source-detector distance from data analysis increases total-[Hb + Mb]. Fourteen healthy subjects (7 men) rested in a neutral body position (supine or prone) while measurements of total-[Hb + Mb] and ATT were taken at four muscles common to resting and exercise studies: vastus lateralis (VL), rectus femoris (RF), gastrocnemius (GS), and flexor digitorum superficialis (FDS). ATT averaged 6.0 ± 0.4 mm across all muscles. Every muscle showed a negative slope ( r: 0.6-0.94; P < 0.01) for total-[Hb + Mb] as a function of ATT: VL (-34 μM/mm), RF (-26 μM/mm), GS (-54 μM/mm), and FDS (-33 μM/mm). The projected total-[Hb + Mb] at 0 mm ATT ( y-intercept) was 452, 372, 620, and 456 μM for VL, RF, GS, and FDS, respectively. No differences were found between the sexes within VL, RF, or FDS, but men had a greater projected total-[Hb + Mb] at 0 mm for GS (688 ± 44 vs. 552 ± 40 μM; P < 0.05). Exclusion of the shortest source-detector distance increased total-[Hb + Mb] by 12 ± 1 μM ( P < 0.05). The present findings demonstrate that total-[Hb + Mb] should be corrected for ATT using muscle site-specific factors which are not sex specific, except in the case of GS. NEW & NOTEWORTHY Near-infrared spectroscopy (NIRS) is an important tool for physiologists and clinicians. However, adipose tissue greatly attenuates the signals from these devices. Correcting for this attenuation has been suggested based on the strength of the relationship between NIRS-derived measurements and the adipose tissue thickness. We show that this relationship is unique to the muscle site of interest but may not be sex specific. Accurate quantification of underlying tissue mandates researchers correct for adipose tissue thickness.