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Numerous pathophysiological conditions induce hypoxemia-related cardiopulmonary perturbations, decrements in exercise capacity, and debilitating symptoms. Accordingly, this study investigated the efficacy of an allosteric hemoglobin modulator (voxelotor) to enhance arterial oxygen saturation during low-intensity exercise in hypoxia. Eight normal healthy subjects (36 ± 7 yr; 73.8 ± 9.5 kg; 3 women) completed a submaximal cycling test (60 W) under normoxic ([Formula: see text]: 0.21; O(2) partial pressure: 144 mmHg) and hypoxic ([Formula: see text]: 0.125; O(2) partial pressure: 82 mmHg) conditions before (day 1) and after (day 15) 14 days of oral drug administration. While stationary on a cycle ergometer and during exercise, ratings of perceived exertion (RPE) and dyspnea, oxygen consumption (V̇o(2)), and cardiac output (Q) were measured noninvasively, while arterial blood pressure (MAP) and blood gases ([Formula: see text] , [Formula: see text] , and [Formula: see text]) were measured invasively. The 14-day drug administration left shifted the oxygen-hemoglobin dissociation curve (ODC; p50 measured at standard pH and Pco(2); day 1: 28.0 ± 2.1 mmHg vs. day 15: 26.1 ± 1.8 mmHg, P < 0.05). RPE, dyspnea, V̇o(2), Q, and MAP were not different between day 1 and day 15. [Formula: see text] was similar during normoxia on day 1 and day 15 while stationary but higher during exercise (day 1: 95.2 ± 0.4% vs. day 15: 96.6 ± 0.3%, P < 0.05). [Formula: see text] was higher during hypoxia on day 15 while stationary (day 1: 82.9 ± 3.4% vs. day 15: 90.9 ± 1.8%, P < 0.05) and during exercise (day 1: 73.6 ± 2.5% vs. day 15: 84.8 ± 2.7%, P < 0.01). [Formula: see text] and [Formula: see text] were systematically higher and lower, respectively, after drug (P < 0.01), while the alveolar-arterial oxygen difference was unchanged suggesting hyperventilation contributed to the rise in [Formula: see text]. Oral administration of voxelotor left shifted the ODC and stimulated a mild hyperventilation, leading to improved arterial oxygen saturation without altering V̇o(2) and central hemodynamics during rest and low-intensity exercise. This effect was more pronounced during submaximal hypoxic exercise, when arterial desaturation was more evident. Additional studies are needed to determine the effects of voxelotor during maximal exercise and under chronic forms of hypoxia. NEW & NOTEWORTHY In humans, a novel allosteric hemoglobin-oxygen affinity modulator was administered to comprehensively examine the cardiopulmonary consequences of stabilizing a portion of the available hemoglobin in a high-oxygen affinity state during submaximal exercise in normoxia and hypoxia. Oral administration of voxelotor enhanced arterial oxygen saturation during submaximal exercise without altering oxygen consumption and central hemodynamics; however, the partial pressure of arterial carbon dioxide was reduced and the partial pressure of arterial oxygen was increased implying that hyperventilation also contributed to the increase in oxygen saturation. The preservation of arterial oxygen saturation and content was particularly evident during hypoxic submaximal exercise, when arterial desaturation typically occurs, but this did not influence arterial-venous oxygen difference.

Adaptations in hepatic and skeletal muscle substrate metabolism following acute and chronic (6 wk; 5 days/wk; 1 h/day) low-intensity treadmill exercise were tested in healthy male C57BL/6J mice. Low-intensity exercise maximizes lipid utilization; therefore, we hypothesized pathways involved in lipid metabolism would be most robustly affected. Acute exercise nearly depleted liver glycogen immediately postexercise (0 h), whereas hepatic triglyceride (TAG) stores increased in the early stages after exercise (0–3 h). Also, hepatic peroxisome proliferator-activated receptor-γ coactivator-1α ( PGC-1α) gene expression and fat oxidation (mitochondrial and peroxisomal) increased immediately postexercise (0 h), whereas carbohydrate and amino acid oxidation in liver peaked 24–48 h later. Alternatively, skeletal muscle exhibited a less robust response to acute exercise as stored substrates (glycogen and TAG) remained unchanged, induction of PGC-1α gene expression was delayed (up at 3 h), and mitochondrial substrate oxidation pathways (carbohydrate, amino acid, and lipid) were largely unaltered. Peroxisomal lipid oxidation exhibited the most dynamic changes in skeletal muscle substrate metabolism after acute exercise; however, this response was also delayed (peaked 3–24 h postexercise), and expression of peroxisomal genes remained unaffected. Interestingly, 6 wk of training at a similar intensity limited weight gain, increased muscle glycogen, and reduced TAG accrual in liver and muscle; however, substrate oxidation pathways remained unaltered in both tissues. Collectively, these results suggest changes in substrate metabolism induced by an acute low-intensity exercise bout in healthy mice are more rapid and robust in liver than in skeletal muscle; however, training at a similar intensity for 6 wk is insufficient to induce remodeling of substrate metabolism pathways in either tissue. NEW & NOTEWORTHY Effects of low-intensity exercise on substrate metabolism pathways were tested in liver and skeletal muscle of healthy mice. This is the first study to describe exercise-induced adaptations in peroxisomal lipid metabolism and also reports comprehensive adaptations in mitochondrial substrate metabolism pathways (carbohydrate, lipid, and amino acid). Acute low-intensity exercise induced shifts in mitochondrial and peroxisomal metabolism in both tissues, but training at this intensity did not induce adaptive remodeling of metabolic pathways in healthy mice.

Hypothermia can occur during aquatic exercise despite production of significant amounts of heat by the active muscles. Because the characteristics of human thermoregulatory responses to cold during exercise have not been fully elucidated, we investigated the effect of low-intensity exercise on the shivering response to core cooling in cool water. Eight healthy young men (24 ± 3 yr) were cooled through cool water immersion while resting (rest trial) and during loadless pedaling on a water cycle ergometer (exercise trial). Before the cooling, body temperature was elevated by hot water immersion to clearly detect a core temperature at which shivering initiates. Throughout the cooling period, mean skin temperature remained around the water temperature (25°C) in both trials, whereas esophageal temperature (Tes) did not differ between the trials ( P > 0.05). The Tes at which oxygen uptake (V̇o2) rapidly increased, an index of the core temperature threshold for shivering, was lower during exercise than rest (36.2 ± 0.4°C vs. 36.5 ± 0.4°C, P < 0.05). The sensitivity of the shivering response, as indicated by the slope of the Tes-V̇o2 relation, did not differ between the trials (−441.3 ±177.4 ml·min−1·°C−1 vs. −411.8 ± 268.1 ml·min−1·°C−1, P > 0.05). The thermal sensation response to core cooling, assessed from the slope and intercept of the regression line relating Tes and thermal sensation, did not differ between the trials ( P > 0.05). These results suggest that the core temperature threshold for shivering is delayed during low-intensity exercise in cool water compared with rest although shivering sensitivity is unaffected.

Skeletal muscle bulk and strength are becoming important therapeutic targets in medicine. To increase muscle mass, however, intensive, long-term mechanical stress must be applied to the muscles, and such stress is often accompanied by orthopedic and cardiovascular problems. We examined the effects of circulatory occlusion in resistance training combined with a very low-intensity mechanical load on enhancing muscular metabolic stress and thereby increasing muscle bulk. Muscular metabolic stress, as indicated by the increases in inorganic phosphate (Pi) and a decrease in intramuscular pH, was evaluated by31P-magnetic resonance spectroscopy during unilateral plantar-flexion at 20% of the one-repetition maximum (1-RM) with circulatory occlusion for 2 min in 14 healthy, male untrained participants (22 yr) at baseline. Participants performed two sets of the same exercise with a 30-s rest between sets, 2 times/day, 3 days/wk, for 4 wk. The muscle cross-sectional area (MCA) of the plantar-flexors and the 1-RM were measured at baseline and after 2 and 4 wk of training. MCA and 1-RM were significantly increased after 2 and 4 wk ( P < 0.05, respectively). The increase in MCA at 2 wk was significantly ( P < 0.05) correlated with the changes in Pi( r = 0.876) and intramuscular pH ( r = 0.601). Furthermore, the increases in MCA at 4 wk and 1-RM at 2 wk were also correlated with the metabolic stress. Thus enhanced metabolic stress in exercising muscle is a key mechanism for favorable effects by resistance training. Low-intensity resistance exercise provides successful outcomes when performed with circulatory occlusion, even with a short training period.

The purpose of this study was to investigate fatty acid (FA) oxidation in isolated mitochondrial vesicles (mit) and its relation to training status, fiber type composition, and whole body FA oxidation. Trained (V̇o2 peak60.7 ± 1.6, n = 8) and untrained subjects (39.5 ± 2.0 ml·min−1·kg−1, n = 5) cycled at 40, 80, and 120 W, and whole body relative FA oxidation was assessed from respiratory exchange ratio (RER). Mit were isolated from muscle biopsies, and maximal ADP stimulated respiration was measured with carbohydrate-derived substrate [pyruvate + malate (Pyr)] and FA-derived substrate [palmitoyl-l-carnitine + malate (PC)]. Fiber type composition was determined from analysis of myosin heavy-chain (MHC) composition. The rate of mit oxidation was lower with PC than with Pyr, and the ratio between PC and Pyr oxidation (MFO) varied greatly between subjects (49–93%). MFO was significantly correlated to muscle fiber type distribution, i.e., %MHC I ( r = 0.62, P = 0.03), but was not different between trained (62 ± 5%) and untrained subjects (72 ± 2%). MFO was correlated to RER during submaximal exercise at 80 ( r = −0.62, P = 0.02) and 120 W ( r = −0.71, P = 0.007) and interpolated 35% V̇o2 peak( r = −0.74, P = 0.004). ADP sensitivity of mit respiration was significantly higher with PC than with Pyr. It is concluded that MFO is influenced by fiber type composition but not by training status. The inverse correlation between RER and MFO implies that intrinsic mit characteristics are of importance for whole body FA oxidation during low-intensity exercise. The higher ADP sensitivity with PC than that with Pyr may influence fuel utilization at low rate of respiration.

We investigated the effect of acute, graded increases in plasma volume (PV) by use of dextran on substrate turnover and oxidation during exercise. Eight untrained males [peak aerobic power (VO2peak) = 45.2 +/- 2.2 (SE) ml.kg-1.min-1] performed 2 h of cycle ergometry at 46 +/- 4% of VO2peak on three occasions in a randomized order: 0% PV expansion (CON) and after 14% (LOW) and 21% (HIGH) PV expansion. Glucose and glycerol turnover were measured using primed continuous infusions of [6,6-2H2]glucose and [2H5]glycerol, respectively. Glycerol rate of appearance (Ra) was taken as a relative index of whole body lipolysis. Increases in PV had no effect on glucose Ra or disappearance (Rd) either at rest or during exercise. At the onset of exercise, both glucose Ra and Rd increased approximately 100% (P < 0.01). Glucose Ra and Rd continued to increase with exercise duration (P < 0.05) so that, at 120 min of exercise, they were > 330% higher than at rest (P < 0.01). Glycerol Ra also increased with exercise duration (P < 0.05). Total lipolysis during exercise, calculated as the area under the glycerol Ra vs. time curve, was reduced during LOW vs. CON (P < 0.01). Further expansion of PV (HIGH) had no additional effect on whole body lipolysis. No effect of hypervolemia was observed on whole body fat or carbohydrate oxidation. These results indicate that acute PV expansion can alter whole body lipolysis, possibly via a reduction in catecholamine secretion.