Daniel T. Cannon

Heart transplant recipients exhibit reduced exercise tolerance and persistently diminished aerobic capacity despite exercise training. Exercise tolerance depends on integrated oxygen transport and utilization, which are impaired in heart transplant recipients. We synthesize evidence supporting that the combined effects of impaired pulmonary gas exchange, reduced haemoglobin concentration, heart denervation, chronic calcineurin inhibition, decreased muscle capillary density, and detraining from limited physical activity contribute to: (1) reduced pulmonary diffusion and alveolar ventilation–perfusion mismatch that contribute to hypoxemia and increased ventilatory demand; (2) impaired convective oxygen delivery due to anaemia and to heart denervation that limits cardiac output; (3) deficits in endothelial function and reduced muscle capillarization that contribute to diminished convective and diffusive oxygen transport within skeletal muscle. Using Wagner's model, which describes oxygen transport from the atmosphere to muscle mitochondrion, we develop the hypothesis that the persistent reduction in aerobic capacity in heart transplant recipients reflects the combined and interactive effects of impaired convective oxygen transport and reduced muscle oxygen diffusive capacity, rather than a single dominant limitation. This basis generates testable physiological targets for interventions aimed at improving functional capacity after transplantation.

Expiratory flow limitation results in dynamic hyperinflation, dyspnoea and premature exercise intolerance. We aimed to measure whether expiratory resistance reduces locomotor power via limiting maximal voluntary motor activity, exacerbating muscle fatigue, or both. Healthy volunteers ( n = 14; 23 (3) years) performed a series of very heavy‐domain constant power cycling exercise tests with and without an imposed expiratory flow resistance (7 cmH ₂ O/L/s). The decline in maximal evocable isokinetic power at intolerance during each experimental condition was apportioned to: (1) the power equivalent from a reduction in maximum voluntary muscle activation (termed ‘activation fatigue’); and (2) the deficit in expected power at a given isokinetic muscle activity (muscle fatigue). Imposed expiratory resistance reduced exercise tolerance (487 (145) vs. 575 (137) s; 95% confidence interval of the difference (CI _diff ) 52, 125 s; P = 0.0002). At isotime‐control, imposed expiratory resistance resulted in a greater decline in inspiratory reserve volume (CI _diff 0.20, 0.94 L; P = 0.007), and increased dyspnoea (Borg CR‐10; CI _diff 0.7, 3.0; P = 0.006) than without. Muscle fatigue was unaffected (CI _diff −20, 17 W; P = 0.873), but activation fatigue was greater with expiratory resistance (CI _diff 1, 49 W; P = 0.044) and related to the reduction in inspiratory reserve volume ( r ²  = 0.53; P = 0.028). As a result, locomotor power reserve was reduced with expiratory resistance (253 (83) vs. 201 (92) W; CI _diff −10, 113; P = 0.09). Imposed expiratory resistive loading initiated a cascade of abnormal lung mechanics and symptoms. These abnormalities conflate to reduce exercise tolerance through limiting maximal voluntary motor activity.

Tolerance to high‐intensity constant power exercise can be characterized by the hyperbolic power‐duration (or velocity–duration) relationship. The hyperbola is defined by the asymptote (critical power or velocity) and the curvature constant (W′ or D′). The effects of thermoregulatory stress on middle‐distance running performance are equivocal—possibly due to the complexities of the hyperbolic velocity–duration relationship for these relatively short duration events. We aimed to measure the effects of heat stress on the velocity–duration relationship in amateur runners. Fifteen participants (23 ± 6 years) completed a series of constant‐velocity running bouts to intolerance in three heat indices (MILD: 20°C, VERY HOT: 38°C, EXTREME: 55°C). Critical velocity (CV) in MILD (3.52 ± 0.86 m/s) was higher than VERY HOT (3.39 ± 0.82 m/s) and EXTREME (3.29 ± 1.05 m/s; F[2.28] = 3.80, p < 0.035) with no effect of thermal stress on D′ (F[2.28] = 2.48, p = 0.11). In amateur competitive/recreational runners, heat stress of ≥38°C heat index negatively affected CV. Thus, even during relatively short events, such as middle‐distance running where fluid loss is not a primary concern, heat stress may negatively impact performance.

Expiratory flow limitation is a key characteristic in obstructive pulmonary diseases. To study abnormal lung mechanics isolated from heterogeneities of obstructive disease, we measured pulmonary function in healthy adults with expiratory loading. Thirty-seven volunteers (25±5 yr) completed spirometry and body plethysmography under control and threshold expiratory loading of 7, 11 cmH₂O, and a subset at 20 cmH₂O (n = 11). We analyzed the shape of the flow-volume relationship with rectangular area ratio (RAR; Ma et al., Respir Med 2010). Airway resistance was increased (p2O loading vs control (9.20±1.02 and 11.76±1.68 vs. 2.53± 0.80 cmH₂O/L/s). RAR was reduced (p = 0.0319) in loading vs control (0.45±0.07 and 0.47±0.09L vs. 0.48±0.08). FEV₁ was reduced (pp1/FVC (p2O did not result in further limitation. Expiratory loading reduced FEV₁, FVC, PEF, but there were no clinically meaningful differences in FEV₁/FVC, FRC, or RAR. Imposed expiratory loading likely leads to high airway pressures that resist dynamic airway compression. Thus, a concave expiratory flow-volume relationship was consistently absent–a key limitation for model comparison with pulmonary function in COPD. Threshold loading may be a useful strategy to increase work of breathing or induce dynamic hyperinflation.

Diaphragm dysfunction accompanies cardiopulmonary disease and impaired oxygen delivery. Vascular endothelial growth factor (VEGF) regulates oxygen delivery through angiogenesis, capillary maintenance, and contraction-induced perfusion. We hypothesized that myofiber-specific VEGF deficiency contributes to diaphragm weakness and fatigability. Diaphragm protein expression, capillarity and fiber morphology, mitochondrial respiration and hydrogen peroxide (H₂O₂) generation, and contractile function were compared between adult mice with conditional gene ablation of skeletal myofiber VEGF (SkmVEGF^−/−; n = 12) and littermate controls ( n = 13). Diaphragm VEGF protein was ~50% lower in SkmVEGF^−/−than littermate controls (1.45 ± 0.65 vs. 3.04 ± 1.41 pg/total protein; P = 0.001). This was accompanied by an ~15% impairment in maximal isometric specific force ( F[1,23] = 15.01, P = 0.001) and a trend for improved fatigue resistance ( P = 0.053). Mean fiber cross-sectional area and type I fiber cross-sectional area were lower in SkmVEGF^−/−by ~40% and ~25% ( P < 0.05). Capillary-to-fiber ratio was also lower in SkmVEGF^−/−by ~40% ( P < 0.05), and thus capillary density was not different. Sarcomeric actin expression was ~30% lower in SkmVEGF^−/−( P < 0.05), whereas myosin heavy chain and MAFbx were similar (measured via immunoblot). Mitochondrial respiration, citrate synthase activity, PGC-1α, and hypoxia-inducible factor 1α were not different in SkmVEGF^−/−( P > 0.05). However, mitochondrial-derived reactive oxygen species (ROS) flux was lower in SkmVEGF^−/−( P = 0.0003). In conclusion, myofiber-specific VEGF gene deletion resulted in a lower capillary-to-fiber ratio, type I fiber atrophy, actin loss, and contractile dysfunction in the diaphragm. In contrast, mitochondrial respiratory function was preserved alongside lower ROS generation, which may play a compensatory role to preserve fatigue resistance in the diaphragm.NEW & NOTEWORTHY Diaphragm weakness is a hallmark of diseases in which oxygen delivery is compromised. Vascular endothelial growth factor (VEGF) modulates muscle perfusion; however, it remains unclear whether VEGF deficiency contributes to the onset of diaphragm dysfunction. Conditional skeletal myofiber VEGF gene ablation impaired diaphragm contractile function and resulted in type I fiber atrophy, a lower number of capillaries per fiber, and contractile protein content. Mitochondrial function was similar and reactive oxygen species flux was lower. Diaphragm VEGF deficiency may contribute to the onset of respiratory muscle weakness.

The asymptote of the hyperbolic power-duration relationship, critical power (CP), demarcates sustainable from non-sustainable exercise. CP is a salient parameter within the theoretical framework determining exercise tolerance. However, measuring CP is time consuming – typically 4 constant-power exercise tests to intolerance, or a 3-min all-out sprint is required. To determine whether 30 s of maximal isokinetic cycling, immediately following the limit of tolerance, approximates CP. Fifteen participants (7 women, 8 men, 23±5 yr, 71±12 kg, V̇O_2peak 4.39±1.04 L·min⁻¹; 61±9 mL·kg·min⁻¹) completed 4 constant supra-CP exercise tests to intolerance. Each test was followed immediately by a 30 s maximal isokinetic effort at 80 rpm. Mean isokinetic power was compared to the known CP. Mean±SD CP was 159±47 W (CI₉₅ 133, 185 W). Maximal isokinetic power immediately following intolerance was greater (p0.07). However, this closest estimation, following the longest duration constant-power test, resulted in 21 W of mean bias and wide limits of agreement (±84 W). Isokinetic power measured immediately following intolerance consistently overestimated critical power. Thus, an adjunct of 30 s maximal isokinetic cycling immediately following the limit of tolerance does not approximate critical power. equal contribution

Purpose: We aimed to measure 1) the dynamics of locomotor fatigue during constant supra-critical power cycling and 2) the magnitude of any reserve in locomotor power at intolerance to constant and ramp-incremental cycling in recreationally active volunteers. Methods: Fifteen participants (7 women and 8 men, 22 ± 3 yr, 3.34 ± 0.67 L·min⁻¹ V˙O_2peak) completed ramp-incremental and very-heavy constant power (205 ± 46 W) exercise to the limit of tolerance. Immediately after intolerance, the ergometer was switched into the isokinetic mode, and participants completed a short (~5 s) maximal isokinetic effort at 70 rpm. The time course of locomotor fatigue during constant supra-critical power exercise was characterized with these short maximal isokinetic sprints at 30, 60, 120, and 180 s and at the limit of tolerance. Each bout was terminated after the isokinetic sprint. Results: Constant power exercise duration was 312 ± 37 s. Isokinetic power production values at 30, 60, 120, and 180 s and at the limit of tolerance (at 312 ± 37 s) was 609 ± 165, 503 ± 195, 443 ± 157, 449 ± 133, and 337 ± 94 W, respectively. Of the total decline in isokinetic power, ~36% occurred within the first minute of exercise, and significant (P < 0.05) reductions in isokinetic power occurred at all time points versus the baseline maximal isokinetic power (666 ± 158 W). In addition, a significant power reserve of 132 ± 74 W (64% of the task requirement) and 119 ± 80 W (47%) was present at the limit of constant power and ramp-incremental exercise, respectively. Conclusions: Locomotor fatigue occurred rapidly during supracritical power exercise with pseudo-exponential kinetics. Instantaneous isokinetic power production at the limit of tolerance exceeded that of the task requirement, regardless of the constant or ramp work rate profile. Thus, the perceptual and physiologic limits were dissociated at the limit of tolerance in recreationally active volunteers.

Key points: Continuous high‐intensity constant‐power exercise is unsustainable, with maximal oxygen uptake () and the limit of tolerance attained after only a few minutes. Performing the same power intermittently reduces the O₂cost of exercise and increases tolerance. The extent to which this dissociation is reflected in the intramuscular bioenergetics is unknown. We used pulmonary gas exchange and³¹P magnetic resonance spectroscopy to measure whole‐body, quadriceps phosphate metabolism and pH during continuous and intermittent exercise of different work:recovery durations. Shortening the work:recovery durations (16:32 svs. 32:64 svs. 64:128 svs. continuous) at a work rate estimated to require 110% peak aerobic power reduced, muscle phosphocreatine breakdown and muscle acidification, eliminated the glycolytic‐associated contribution to ATP synthesis, and increased exercise tolerance. Exercise intensity (i.e. magnitude of intramuscular metabolic perturbations) can be dissociated from the external power using intermittent exercise with short work:recovery durations. Compared with work‐matched high‐intensity continuous exercise, intermittent exercise dissociates pulmonary oxygen uptake () from the accumulated work. The extent to which this reflects differences in O₂storage fluctuations and/or contributions from oxidative and substrate‐level bioenergetics is unknown. Using pulmonary gas‐exchange and intramuscular³¹P magnetic resonance spectroscopy, we tested the hypotheses that, at the same power: ATP synthesis rates are similar, whereas peakamplitude is lower in intermittentvs. continuous exercise. Thus, we expected that: intermittent exercise relies less upon anaerobic glycolysis for ATP provision than continuous exercise; shorter intervals would require relatively greater fluctuations in intramuscular bioenergetics than incompared to longer intervals. Six men performed bilateral knee‐extensor exercise (estimated to require 110% peak aerobic power) continuously and with three different intermittent work:recovery durations (16:32, 32:64 and 64:128 s). Target work duration (576 s) was achieved in all intermittent protocols; greater than continuous (252 ± 174 s;P < 0.05). Mean ATP turnover rate was not different between protocols (∼43 mm min⁻¹on average). However, the intramuscular phosphocreatine (PCr) component of ATP generation was greatest (∼30 mm min⁻¹), and oxidative (∼10 mm min⁻¹) and anaerobic glycolytic (∼1 mm min⁻¹) components were lowest for 16:32 and 32:64 s intermittent protocols, compared to 64:128 s (18 ± 6, 21 ± 10 and 10 ± 4 mmmin⁻¹, respectively) and continuous protocols (8 ± 6, 20 ± 9 and 16 ± 14 mm min⁻¹, respectively). As intermittent work duration increased towards continuous exercise, ATP production relied proportionally more upon anaerobic glycolysis and oxidative phosphorylation, and less upon PCr breakdown. However, performing the same high‐intensity power intermittentlyvs. continuously reduced the amplitude of fluctuations inand intramuscular metabolism, dissociating exercise intensity from the power output and work done.

Muscle fatigue (a reduced power for a given activation) is common following exercise in chronic obstructive pulmonary disease (COPD). Whether muscle fatigue, and reduced maximal voluntary locomotor power, are sufficient to limit whole body exercise in COPD is unknown. We hypothesized in COPD: 1) exercise is terminated with a locomotor muscle power reserve; 2) reduction in maximal locomotor power is related to ventilatory limitation; and 3) muscle fatigue at intolerance is less than age-matched controls. We used a rapid switch from hyperbolic to isokinetic cycling to measure the decline in peak isokinetic power at the limit of incremental exercise (“performance fatigue”) in 13 COPD patients (FEV₁ 49 ± 17%pred) and 12 controls. By establishing the baseline relationship between muscle activity and isokinetic power, we apportioned performance fatigue into the reduction in muscle activation and muscle fatigue. Peak isokinetic power at intolerance was ~130% of peak incremental power in controls (274 ± 73 vs. 212 ± 84 W, P < 0.05), but ~260% in COPD patients (187 ± 141 vs. 72 ± 34 W, P < 0.05), greater than controls ( P < 0.05). Muscle fatigue as a fraction of baseline peak isokinetic power was not different in COPD patients vs. controls (0.11 ± 0.20 vs. 0.19 ± 0.11). Baseline to intolerance, the median frequency of maximal isokinetic muscle activity, was unchanged in COPD patients but reduced in controls (+4.3 ± 11.6 vs. −5.5 ± 7.6%, P < 0.05). Performance fatigue as a fraction of peak incremental power was greater in COPD vs. controls and related to resting (FEV₁/FVC) and peak exercise (V̇_E/maximal voluntary ventilation) pulmonary function ( r² = 0.47 and 0.55, P < 0.05). COPD patients are more fatigable than controls, but this fatigue is insufficient to constrain locomotor power and define exercise intolerance.