Cardiac output and arteriovenous oxygen difference contribute to lower peak oxygen uptake in patients with fibromyalgia.

BACKGROUND: Patients with fibromyalgia (FM) exhibit low peak oxygen uptake ([Formula: see text]O2peak). We aimed to detect the contribution of cardiac output to ([Formula: see text]) and arteriovenous oxygen difference [Formula: see text] to [Formula: see text] from rest to peak exercise in patients with FM. METHODS: Thirty-five women with FM, aged 23 to 65 years, and 23 healthy controls performed a step incremental cycle ergometer test until volitional fatigue. Alveolar gas exchange and pulmonary ventilation were measured breath-by-breath and adjusted for fat-free body mass (FFM) where appropriate. [Formula: see text] (impedance cardiography) was monitored. [Formula: see text] was calculated using Fick's equation. Linear regression slopes for oxygen cost (∆[Formula: see text]O2/∆work rate) and [Formula: see text] to [Formula: see text]O2 (∆[Formula: see text]/∆[Formula: see text]O2) were calculated. Normally distributed data were reported as mean ± SD and non-normal data as median [interquartile range]. RESULTS: [Formula: see text]O2peak was lower in FM patients than in controls (22.2 ± 5.1 vs. 31.1 ± 7.9 mL∙min-1∙kg-1, P < 0.001; 35.7 ± 7.1 vs. 44.0 ± 8.6 mL∙min-1∙kg FFM-1, P < 0.001). [Formula: see text] and C(a-v)O2 were similar between groups at submaximal work rates, but peak [Formula: see text] (14.17 [13.34-16.03] vs. 16.06 [15.24-16.99] L∙min-1, P = 0.005) and C(a-v)O2 (11.6 ± 2.7 vs. 13.3 ± 3.1 mL O2∙100 mL blood-1, P = 0.031) were lower in the FM group. No significant group differences emerged in ∆[Formula: see text]O2/∆work rate (11.1 vs. 10.8 mL∙min-1∙W-1, P = 0.248) or ∆[Formula: see text]/∆[Formula: see text]O2 (6.58 vs. 5.75, P = 0.122) slopes. CONCLUSIONS: Both [Formula: see text] and C(a-v)O2 contribute to lower [Formula: see text]O2peak in FM. The exercise responses were normal and not suggestive of a muscle metabolism pathology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03300635. Registered 3 October 2017-Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT03300635 .

Altered cardiorespiratory response to exercise in overweight and obese women with polycystic ovary syndrome.

In polycystic ovary syndrome (PCOS), cardiovascular risk is increased. Peak O2 uptake (V˙O2peak) predicts the cardiovascular risk. We were the first to examine the contribution of systemic O2 delivery and arteriovenous O2 difference to V˙O2peak in overweight and obese women with PCOS. Fifteen overweight or obese PCOS women and 15 age-, anthropometry-, and physical activity-matched control women performed a maximal incremental cycling exercise test. Alveolar gas exchange (volume turbine and mass spectrometry), arterial O2 saturation (pulse oximetry), and cardiac output (CO) (impedance cardiography) were monitored. Hb concentration was determined. Arterial O2 content and arteriovenous O2 difference (C(a-v)O2) (Fick equation) were calculated. Insulin resistance was evaluated by homeostasis model assessment (HOMA-IR). PCOS women had lower V˙O2peak than controls (40 ± 6 vs. 46 ± 5 mL/min/kg fat-free mass [FFM], P = 0.011). Arterial O2 content was similarly maintained in the groups throughout the exercise test (P > 0.05). Linear regression analysis revealed a pronounced response of CO to increasing V˙O2 in PCOS women during the exercise test: A ∆CO/∆V˙O2 slope was steeper in PCOS women than in controls (ß = 5.84 vs. ß = 5.21, P = 0.004). Eventually, the groups attained similar peak CO and peak CO scaled to FFM (P > 0.05). Instead, C(a-v)O2 at peak exercise was lower in PCOS women than in controls (13.2 ± 1.6 vs. 14.8 ± 2.4 mL O2/100 mL blood, P = 0.044). HOMA-IR was similar in the groups (P > 0.05). The altered cardiorespiratory responses to exercise in overweight and obese PCOS women indicate that PCOS per se is associated with alterations in peripheral adjustments to exercise rather than with limitations of systemic O2 delivery.

Alveolar gas exchange, oxygen delivery and tissue deoxygenation in men and women during incremental exercise.

We investigated whether leg and arm skeletal muscle, and cerebral deoxygenation, differ during incremental cycling exercise in men and women, and if women's lower capacity to deliver O2 affects tissue deoxygenation. Men (n=10) compared to women (n=10), had greater cardiac output, which with greater hemoglobin concentration produced greater absolute (QaO2) and body size-adjusted oxygen delivery (QaO2i) at peak exercise. Despite women's lower peak QaO2, their leg muscle deoxygenation was similar at a given work rate and QaO2, but less than in men at peak exercise (Δtissue saturation index -27.1 ± 13.2% vs. -11.8 ± 5.7%, P<0.01; Δ[deoxyhemoglobin] 15.03 ± 8.57 µM vs. 3.73 ± 3.98 µM, P<0.001). At peak exercise, oxygen uptake was associated both with QaO2 and leg muscle deoxygenation (both P<0.01). Arm muscle and cerebral deoxygenation did not differ between sexes at peak exercise. Thus, both high O2 delivery and severe active muscle deoxygenation are determinants of good exercise performance, and active muscle deoxygenation responses are regulated partly in a sex-specific manner with an influence of exercise capacity.

Alveolar gas exchange and tissue oxygenation during incremental treadmill exercise, and their associations with blood O(2) carrying capacity.

The magnitude and timing of oxygenation responses in highly active leg muscle, less active arm muscle, and cerebral tissue, have not been studied with simultaneous alveolar gas exchange measurement during incremental treadmill exercise. Nor is it known, if blood O(2) carrying capacity affects the tissue-specific oxygenation responses. Thus, we investigated alveolar gas exchange and tissue (m. vastus lateralis, m. biceps brachii, cerebral cortex) oxygenation during incremental treadmill exercise until volitional fatigue, and their associations with blood O(2) carrying capacity in 22 healthy men. Alveolar gas exchange was measured, and near-infrared spectroscopy (NIRS) was used to monitor relative concentration changes in oxy- (Δ[O(2)Hb]), deoxy- (Δ[HHb]) and total hemoglobin (Δ[tHb]), and tissue saturation index (TSI). NIRS inflection points (NIP), reflecting changes in tissue-specific oxygenation, were determined and their coincidence with ventilatory thresholds [anaerobic threshold (AT), respiratory compensation point (RC); V-slope method] was examined. Blood O(2) carrying capacity [total hemoglobin mass (tHb-mass)] was determined with the CO-rebreathing method. In all tissues, NIPs coincided with AT, whereas RC was followed by NIPs. High tHb-mass associated with leg muscle deoxygenation at peak exercise (e.g., Δ[HHb] from baseline walking to peak exercise vs. tHb-mass: r = 0.64, p < 0.01), but not with arm muscle- or cerebral deoxygenation. In conclusion, regional tissue oxygenation was characterized by inflection points, and tissue oxygenation in relation to alveolar gas exchange during incremental treadmill exercise resembled previous findings made during incremental cycling. It was also found out, that O(2) delivery to less active m. biceps brachii may be limited by an accelerated increase in ventilation at high running intensities. In addition, high capacity for blood O(2) carrying was associated with a high level of m. vastus lateralis deoxygenation at peak exercise.

Alveolar gas exchange and tissue deoxygenation during exercise in type 1 diabetes patients and healthy controls.

We used near-infrared spectroscopy to investigate whether leg and arm skeletal muscle and cerebral deoxygenation differ during incremental cycling exercise in men with type 1 diabetes (T1D, n=10, mean±SD age 33±7 years) and healthy control men (matched by age, anthrometry, and self-reported physical activity, CON, n=10, 32±7 years) to seek an explanation for lower aerobic capacity (˙VO2peak) often reported in T1D. T1D had lower ˙VO2peak (35±4mlkg(-1)min(-1) vs. 43±8mlkg(-1)min(-1), P<0.01) and peak work rate (219±33W vs. 290±44W, P<0.001) than CON. Leg muscle deoxygenation (↑ [deoxyhemoglobin]; ↓ tissue saturation index) was greater in T1D than CON at a given absolute submaximal work rate, but not at peak exercise, while arm muscle and cerebral deoxygenation were similar. Thus, in T1D compared with CON, faster leg muscle deoxygenation suggests limited circulatory ability to increase O(2) delivery as a plausible explanation for lower ˙VO2peak and earlier fatigue in T1D.

Effects of adenosine, exercise, and moderate acute hypoxia on energy substrate utilization of human skeletal muscle.

Glucose metabolism increases in hypoxia and can be influenced by endogenous adenosine, but the role of adenosine for regulating glucose metabolism at rest or during exercise in hypoxia has not been elucidated in humans. We studied the effects of exogenous adenosine on human skeletal muscle glucose uptake and other blood energy substrates [free fatty acid (FFA) and lactate] by infusing adenosine into the femoral artery in nine healthy young men. The role of endogenous adenosine was studied by intra-arterial adenosine receptor inhibition (aminophylline) during dynamic one-leg knee extension exercise in normoxia and acute hypoxia corresponding to ∼3,400 m of altitude. Extraction and release of energy substrates were studied by arterial-to-venous (A-V) blood samples, and total uptake or release was determined by the product of A-V differences and muscle nutritive perfusion measured by positron emission tomography. The results showed that glucose uptake increased from a baseline value of 0.2 ± 0.2 to 2.0 ± 2.2 µmol·100 g(-1)·min(-1) during adenosine infusion (P < 0.05) at rest. Although acute hypoxia enhanced arterial FFA levels, it did not affect muscle substrate utilization at rest. During exercise, glucose uptake was higher (195%) during acute hypoxia compared with normoxia (P = 0.058), and aminophylline had no effect on energy substrate utilization during exercise, despite that arterial FFA levels were increased. In conclusion, exogenous adenosine at rest and acute moderate hypoxia during low-intensity knee-extension exercise increases skeletal muscle glucose uptake, but the increase in hypoxia appears not to be mediated by adenosine.

Regulation of human skeletal muscle perfusion and its heterogeneity during exercise in moderate hypoxia.

Although many effects of both acute and chronic hypoxia on the circulation are well characterized, the distribution and regulation of blood flow (BF) heterogeneity in skeletal muscle during systemic hypoxia is not well understood in humans. We measured muscle BF within the thigh muscles of nine healthy young men using positron emission tomography during one-leg dynamic knee extension exercise in normoxia and moderate physiological systemic hypoxia (14% O(2) corresponding to approximately 3,400 m of altitude) without and with local adenosine receptor inhibition with femoral artery infusion of aminophylline. Systemic hypoxia reduced oxygen extraction of the limb but increased muscle BF, and this flow increment was confined solely to the exercising quadriceps femoris muscle. Exercising muscle BF heterogeneity was reduced from rest (P = 0.055) but was not affected by hypoxia. Adenosine receptor inhibition had no effect on capillary BF during exercise in either normoxia or hypoxia. Finally, one-leg exercise increased muscle BF heterogeneity both in the resting posterior hamstring part of the exercising leg and in the resting contralateral leg, whereas mean BF was unchanged. In conclusion, the results show that increased BF during one-leg exercise in moderate hypoxia is confined only to the contracting muscles, and the working muscle hyperemia appears not to be directly mediated by adenosine. Increased flow heterogeneity in noncontracting muscles likely reflects sympathetic nervous constraints to curtail BF increments in areas other than working skeletal muscles, but this effect is not potentiated in moderate systemic hypoxia during small muscle mass exercise.

Comparison of exogenous adenosine and voluntary exercise on human skeletal muscle perfusion and perfusion heterogeneity.

Adenosine is a widely used pharmacological agent to induce a "high-flow" control condition to study the mechanisms of exercise hyperemia, but it is not known how well an adenosine infusion depicts exercise-induced hyperemia, especially in terms of blood flow distribution at the capillary level in human muscle. Additionally, it remains to be determined what proportion of the adenosine-induced flow elevation is specifically directed to muscle only. In the present study, we measured thigh muscle capillary nutritive blood flow in nine healthy young men using PET at rest and during the femoral artery infusion of adenosine (1 mg min(-1) l thigh volume(-1)), which has previously been shown to induce a maximal whole thigh blood flow of approximately 8 l/min. This response was compared with the blood flow induced by moderate- to high-intensity one-leg dynamic knee extension exercise. Adenosine increased muscle blood flow on average to 40 +/- 7 ml x min(-1) x 100 g muscle(-1) with an aggregate value of 2.3 +/- 0.6 l/min for the whole thigh musculature. Adenosine also induced a substantial change in blood flow distribution within individuals. Muscle blood flow during the adenosine infusion was comparable with blood flow in moderate- to high-intensity exercise (36 +/- 9 ml x min(-1) x 100 g muscle(-1)), but flow heterogeneity was significantly higher during the adenosine infusion than during voluntary exercise. In conclusion, a substantial part of the flow increase in the whole limb blood flow induced by a high-dose adenosine infusion is conducted through the physiological non-nutritive shunt in muscle and/or also through tissues of the limb other than muscle. Additionally, an intra-arterial adenosine infusion does not mimic exercise hyperemia, especially in terms of muscle capillary flow heterogeneity, while the often-observed exercise-induced changes in capillary blood flow heterogeneity likely reflect true changes in nutritive flow linked to muscle fiber and vascular unit recruitment.