Understanding exercise (in)tolerance in sickle cell disease: impacts of hemolysis and exercise training on skeletal muscle oxygen delivery.

Sickle cell disease (SCD) is characterized by central (cardiac) and peripheral vascular dysfunctions, significantly diminishing exercise capacity and quality of life. Although central cardiopulmonary abnormalities in SCD are known to reduce exercise capacity and quality of life; the impact of hemolysis and subsequent cell-free hemoglobin (Hb)-mediated peripheral vascular abnormalities on those outcomes are not fully understood. Despite the recognized benefits of exercise training for cardiovascular health and clinical management in chronic diseases like heart failure, there remains substantial debate on the advisability of regular physical activity for patients with SCD. This is primarily due to concerns that prolonged and/or high-intensity exercise might trigger metabolic shifts leading to vaso-occlusive crises. As a result, exercise recommendations for patients with SCD are often vague or nonexistent, reflecting a gap in knowledge about the mechanisms of exercise intolerance and the impact of exercise training on SCD-related health issues. This mini-review sheds light on recent developments in understanding how SCD affects exercise tolerance, with a special focus on the roles of hemolysis and the release of cell-free hemoglobin in altering cardiovascular and skeletal muscle function. Also highlighted here is the emerging research on the therapeutic effects and safety of exercise training in patients with SCD. In addition, the review identifies future research opportunities to fill existing gaps in our understanding of exercise (in)tolerance in SCD.

Acute Effects of High-Intensity Resistance Exercise on Recognition of Relational Memory, Lactate, and Serum and Plasma Brain-Derived Neurotrophic Factor.

ABSTRACT: Baumgartner, NW, Belbis, MD, Kargl, C, Holmes, MJ, Gavin, TP, Hirai, DM, and Kao, S-C. Acute effects of high-intensity resistance exercise on recognition of relational memory, lactate, and serum and plasma brain-derived neurotrophic factor. J Strength Cond Res XX(X): 000-000, 2024-Acute aerobic exercise improves memory, but this phenomenon is understudied in response to resistance exercise (RE) despite evidence that RE-induced increases in lactate and brain-derived neurotrophic factor (BDNF) play mechanistic roles in memory performance. To determine the acute effect of RE on lactate, BDNF, and their associations with object and relational memory, blood lactate, and serum and plasma BDNF were taken from 36 adults (average age 23.64 ± 3.89 years; 18 woman) before and immediately after 42 minutes of high-intensity RE and a rest condition on counterbalanced days. Subjects then immediately studied a series of paired objects and completed object and relational recognition tasks. Results revealed a condition by trial interaction, previously studied objects were remembered less accurately following RE (d = 0.66) but recognition occurred faster (d = 0.28), indicating a speed-accuracy tradeoff following RE. There was no effect of either intervention on relational recognition performance. Lactate (d = 3.68) and serum BDNF (d = 0.74) increased following RE, whereas there was no time-related change in lactate and serum BDNF following rest. However, changes in lactate and BDNF did not predict any measures of object (rs < 0.25, ps > 0.16) or relation recognition (rs < 0.28, ps > 0.13). Collectively, these findings suggest that acute high-intensity RE selectively improves the processing speed of recognizing objects at the cost of less accurate recognition of previously studied objects. Furthermore, changes in object and relational memory performance are unlikely driven by acute increases in lactate or BDNF following high-intensity RE.

Effects of acute phosphodiesterase type 5 inhibition on skeletal muscle interstitial PO2 during contractions and recovery.

The oxygen partial pressure within the interstitial space (PO2is; mmHg) provides the driving force for oxygen diffusion into the myocyte thereby supporting oxidative phosphorylation. We tested the hypothesis that potentiation of the nitric oxide pathway with sildenafil (phosphodiesterase type 5 inhibitor) would enhance PO2is during muscle metabolic transitions, thereby slowing PO2is on- and accelerating PO2is off-kinetics. The rat spinotrapezius muscle (n = 17) was exposed for PO2is measurements via phosphorescence quenching under control (CON), low-dose sildenafil (1 mg/kg i.a., SIL1) and high-dose sildenafil (7 mg/kg i.a., SIL7). Data were collected at rest and during submaximal twitch contractions (1 Hz, 4-6 V, 3 min) and recovery (3 min). Mean arterial blood pressure (MAP; mmHg) was reduced with both SIL1 (pre:132 ± 5; post:99 ± 5) and SIL7 (pre:111 ± 6; post:99 ± 4) (p < 0.05). SIL7 elevated resting PO2is (18.4 ± 1.1) relative to both CON (15.7 ± 0.7) and SIL1 (15.2 ± 0.7) (p < 0.05). In addition, SIL7 increased end-recovery PO2is (17.7 ± 1.6) compared to CON (12.8 ± 0.9) and SIL1 (13.4 ± 0.8) (p < 0.05). The overall PO2is response during recovery (i.e., area under the PO2is curve) was greater in SIL7 (4107 ± 444) compared to CON (3493 ± 222) and SIL1 (3114 ± 205 mmHg s) (p < 0.05). Contrary to our hypothesis, there was no impact of acute SIL (1 or 7 mg/kg) on the speed of the PO2is response during contractions or recovery (p > 0.05). However, sildenafil lowered MAP and improved skeletal muscle interstitial oxygenation in healthy rats. Specifically, SIL7 enhanced PO2is at rest and during recovery from submaximal muscle contractions. Potentiation of the nitric oxide pathway with sildenafil enhances microvascular blood-myocyte O2 transport and is expected to improve repeated bouts of contractile activity.

The Effects of Acute Caffeine Supplementation on Repeated-Sprint Ability in Healthy Young Non-Athletes.

The ergogenic effects of caffeine supplementation on repeated-sprint ability (RSA) have produced equivocal results. This study aimed to examine the effects of 200 mg of caffeine during repeated-sprint running on heart rate (HR), rating of perceived exertion (RPE), blood lactate (BLa) concentration, and sprint time (ST). Thirty-two individuals (males: n = 17, females: n = 15; age: 22 ± 1 years) participated in the study. The study followed a double-blind, randomized, placebo-controlled, crossover design, in which each participant ingested 200 mg of caffeine or placebo on separate visits 60 minutes prior to repeated-sprinting exercise. The repeated-sprint protocol consisted of three sets of six maximal-effort 30-meter sprints with 20 seconds and 5 minutes of active recovery in between sprints and sets, respectively. During each set, HR, RPE, BLa, and ST were recorded. Caffeine supplementation did not significantly (set 1: p = 0.535; set 2: p = 0.602; set 3: p = 0.189) impact HR during exercise. Similarly, RPE was not statistically (p = 0.052) altered between conditions during any of the sprint sets. The caffeine trials elicited greater BLa values after all three sets compared to the placebo trials (p < 0.001). Moreover, the caffeine trials demonstrated significantly reduced total STs during all sets compared to the placebo trials (p < 0.001). Thus, our findings suggested that 200 mg of caffeine supplementation elicited an increase in RSA in young, healthy non-athletes. These findings are accompanied by a blunted perceived exertion relative to an increase in exercise intensity during repeated-sprint exercise.

Effects of inorganic nitrate supplementation on cardiovascular function and exercise tolerance in heart failure.

Heart failure (HF) results in a myriad of central and peripheral abnormalities that impair the ability to sustain skeletal muscle contractions and, therefore, limit tolerance to exercise. Chief among these abnormalities is the lowered maximal oxygen uptake, which is brought about by reduced cardiac output and exacerbated by O2 delivery-utilization mismatch within the active skeletal muscle. Impaired nitric oxide (NO) bioavailability is considered to play a vital role in the vascular dysfunction of both reduced and preserved ejection fraction HF (HFrEF and HFpEF, respectively), leading to the pursuit of therapies aimed at restoring NO levels in these patient populations. Considering the complementary role of the nitrate-nitrite-NO pathway in the regulation of enzymatic NO signaling, this review explores the potential utility of inorganic nitrate interventions to increase NO bioavailability in the HFrEF and HFpEF patient population. Although many preclinical investigations have suggested that enhanced reduction of nitrite to NO in low Po2 and pH environments may make a nitrate-based therapy especially efficacious in patients with HF, inconsistent results have been found thus far in clinical settings. This brief review provides a summary of the effectiveness (or lack thereof) of inorganic nitrate interventions on exercise tolerance in patients with HFrEF and HFpEF. Focus is also given to practical considerations and current gaps in the literature to facilitate the development of effective nitrate-based interventions to improve exercise tolerance in patients with HF.