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Abstract Background Carbohydrates (CHOs), branched-chain amino acids (BCAAs) and caffeine are known to improve running performance. However, no information is available on the effects of a combination of these ingredients on performance and neuromuscular function during running. Methods The present study was designed as a randomized double-blind cross-over placebo-controlled trial. Thirteen trained adult males completed two protocols, each including two conditions: placebo (PLA) and Sports Drink (SPD: CHOs 68.6 g.L-1, BCAAs 4 g.L-1, caffeine 75 mg.L-1). Protocol 1 consisted of an all-out 2 h treadmill run. Total distance run and glycemia were measured. In protocol 2, subjects exercised for 2 h at 95% of their lowest average speeds recorded during protocol 1 (whatever the condition). Glycemia, blood lactate concentration and neuromuscular function were determined immediately before and after exercise. Oxygen consumption (V˙O2), heart rate (HR) and rate of perceived exertion (RPE) were recorded during the exercise. Total fluids ingested were 2 L whatever the protocols and conditions. Results Compared to PLA, ingestion of SPD increased running performance (p = 0.01), maintained glycemia and attenuated central fatigue (p = 0.04), an index of peripheral fatigue (p = 0.04) and RPE (p = 0.006). Maximal voluntary contraction, V˙O2, and HR did not differ between the two conditions. Conclusions This study showed that ingestion of a combination of CHOs, BCAAs and caffeine increased performance by about 2% during a 2-h treadmill run. The results of neuromuscular function were contrasted: no clear cut effects of SPD were observed. Trial registration ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT00799630

Transfusion-dependent β-thalassaemia (TDβT) is a genetic disorder characterised by reduced or absent β-globin chain synthesis, resulting in chronic anaemia. Treatment consists of regular blood transfusions and chelation therapy to limit iron overload and its negative effects on organs (e.g. heart, lungs and liver). Despite improved life expectancy with transfusions and chelation therapy, TDβT patients experience poor quality of life and impaired exercise capacity (mainly due to muscle deconditioning and reduced cardiac inotropism). The aims of this review are (i) to discuss the role of organ dysfunction in the impairment of exercise capacity and reduced quality of life of TDβT patients; and (ii) to discuss physical activity as a potential therapeutic strategy to alleviate the multifactorial impact of the disease., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Abstract: Although patients with homozygous sickle cell anemia (SCA) carry both significant left atrial (LA) remodeling and an increased risk of stroke, the prevalence of atrial arrhythmia (AA) has never been prospectively evaluated. The aim of this study was to identify the prevalence and predictors of atrial arrhythmia in SCA. From 2018 to 2022, consecutive adult patients with SCA were included in the DREPACOEUR prospective registry and referred to the physiology department for cardiac evaluation, including a 24-hour electrocardiogram monitoring (ECG-Holter). The primary endpoint was the occurrence of AA, defined by the presence of excessive supraventricular ectopic activity (ESVEA) on ECG-Holter (ie >720 premature atrial contractions [PACs] or any run ≥ 20 PACs) or any recent history of atrial fibrillation. Overall, 130 patients with SCA (mean age: 45±12 years, 48% of male) were included. AA was found in 34 (26%) patients. Age (52±9 vs. 42±12 years, P=0,002), LA dilation (LAVi, 71±24 vs. 52±14 mL/m², P<0.001) and history of stroke without underlying cerebral vasculopathy (26% vs. 5%, P=0.009, OR=6.6 (95%CI 1.4-30.3]) were independently associated with AA. Age and LAVi correlated with PAC load per 24 hours on ECG-Holter. An age over 47 years or a LAVi >55mL/m² could predict AA with a PPV of 33% and a NPV of 92%. AAs are frequent in middle-aged patients with SCA and increase with age and LA remodeling, leading to a major additional risk factor for ischemic stroke. This study provides arguments and means to early screen for AA and potentially prevent cerebral complications., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In track cycling, performance in the team pursuit depends on the mechanical and physiological abilities of each member of the team, but also on the choice of racing strategy. Athletes must cover the 4000 m of the race, sharing the effort between them in successive relays. This raises the question of the optimum strategy. We propose a method for resolving this question by coupling a mechanical model of the race to physiological models (digital twins) of the athletes. The mechanical model enables one to predict a theoretical finishing time for a given strategy, while the physiological model enables one to determine whether or not a given strategy is feasible. By coupling the two models and using numerical optimization, an optimal strategy for a given team can then be predicted. Simplified team composition case studies are explored. For each case studied, an optimal strategy to maximize performance is obtained and composed of a set of three variables: relay lengths, power values for each relay, and the starting order of cyclists. The proposed method can be used for real athletes and extended to other disciplines., (© 2024. The Author(s).)

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.

Patients with sickle cell disease (SCD) display lower slope coefficients of the oxygen uptake (V̇O2) versus work rate (W) relationship (delineating an O2 uptake/demand mismatch) and a poor metabolic flexibility. Because endurance training improves the microvascular network and increases the activity of oxidative enzymes, including one involved in lipid oxidation, endurance training might improve the slope coefficient of the V̇O2 versus W curve and the metabolic flexibility of SCD patients. Endurance training may also contribute to improve patients' post-exercise cardiopulmonary and metabolic recovery. Fifteen patients with SCD performed a submaximal incremental test on a cycle ergometer before (SIT1) and after (SIT2) 8 weeks of endurance training. Minute ventilation (V̇ E), ventilation rate, heart rate, V̇O2, carbon dioxide production (V̇CO2), respiratory exchange ratio, carbohydrate/lipid utilization and partitioning (including %Lipidox) and blood lactate concentration were measured during and after SIT1 and SIT2. At baseline, the slope coefficient of the V̇O2 versus W curve positively correlated with total hemoglobin, mean corpuscular hemoglobin and percentage of HbF. After training, the slope coefficient of the V̇O2 versus W curve was significantly higher and the increase in blood lactate concentration was delayed. If patients' energy metabolism apparently relied largely on carbohydrate sources during SIT1, %Lipidox tended to increase at low exercise intensities during SIT2, supporting a training-induced improvement of metabolic flexibility in patients with SCD. Post-exercise recovery of ventilation rate, V̇ E/V̇CO2, heart rate and blood lactate concentration was faster after training. We concluded that exercise training in patients with SCD: (i) ameliorated the oxygen uptake/ demand mismatch, (ii) blunted the metabolic inflexibility, and (iii) improved post-exercise cardiopulmonary and metabolic responses.

Sickle cell disease (SCD) is an hemoglobinopathy resulting in the production of an abnormal Hb (HbS) which can polymerize in deoxygenated conditions, leading to the sickling of red blood cells (RBC). These alterations can decrease the oxygen-carrying capacity leading to impaired function and energetics of skeletal muscle. Any strategy which could reverse the corresponding defects could be of interest. In SCD, endurance training is known to improve multiples muscle properties which restores patient's exercise capacity but present reduced effects in anemic patients. Hydroxyurea (HU) can increase fetal hemoglobin production which can reduce anemia in patients. The present study was conducted to determine whether HU can improve the effects of endurance training to improve muscle function and energetics. Twenty SCD Townes mice have been trained for 8 weeks with (n = 11) or without (n = 9) HU. SCD mice muscle function and energetics were analyzed during a standardized rest-exercise-recovery protocol, using Phosphorus-31 Magnetic resonance spectroscopy ( 31 P-MRS) and transcutaneous stimulation. The combination of training and HU specifically decreased fatigue index and PCr consumption while muscle oxidative capacity was improved. These results illustrate the potential synergistic effects of endurance training and HU on muscle function and energetics in sickle cell disease., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This pilot study focusing on Sickle Cell Anemia (SCA) patients offers a comprehensive and integrative evaluation of respiratory, cardiovascular, hemodynamic, and metabolic variables during exercise. Knowing that diastolic dysfunction is frequent in this population, we hypothesize that a lack of cardiac adaptation through exercise might lead to premature increase in blood lactate concentrations in SCA patients, a potential trigger for acute disease complication. SCA patients were prospectively included in PHYSIO-EXDRE study and underwent a comprehensive stress test with a standardized incremental exercise protocol up to 4 mmol L -1 blood lactate concentration (BL4). Gas exchange, capillary lactate concentration and echocardiography were performed at baseline, during stress test (at ∼ 2 mmol L -1 ) and BL4. The population was divided into two groups and compared according to the median value of percentage of theoretical peak oxygen uptake (% V ˙ O 2 p e a k t h ) at BL4. Twenty-nine patients were included (42 ± 12 years old, 48% of women). Most patients reached BL4 at low-intensity exercise [median value of predicted power output (W) was 37%], which corresponds to daily life activities. The median value of % V ˙ O 2 p e a k t h at BL4 was 39%. Interestingly, diastolic maladaptation using echocardiography during stress test along with hemoglobin concentration were independently associated to early occurrence of BL4. As BL4 occurs for low-intensity exercises, SCA patients may be subject to acidosis-related complications even during their daily life activities. Beyond assessing physical capacities, our study underlines that diastolic maladaptation during exercise is associated with an early increase in blood lactate concentration., (© 2024. The Author(s).)

Performance in many racing sports depends on the ability of the athletes to produce and maintain the highest possible work i.e., the highest power for the duration of the race. To model this energy production in an individualized way, an adaptation and a reinterpretation (including a physiological meaning of parameters) of the three-component Margaria-Morton model were performed. The model is applied to the muscles involved in a given task. The introduction of physiological meanings was possible thanks to the measurement of physiological characteristics for a given athlete. A method for creating a digital twin was therefore proposed and applied for national-level cyclists. The twins thus created were validated by comparison with field performance, experimental observations, and literature data. Simulations of record times and 3-minute all-out tests were consistent with experimental data. Considering the literature, the model provided good estimates of the time course of muscle metabolite concentrations (e.g., lactate and phosphocreatine). It also simulated the behavior of oxygen kinetics at exercise onset and during recovery. This methodology has a wide range of applications, including prediction and optimization of the performance of individually modeled athletes., (© 2024. The Author(s).)

Lactate is known to play a central role in the link between glycolytic and mitochondrial oxidative metabolism, as well as to serve as a primary gluconeogenic precursor. Blood lactate concentration is sensitive to the metabolic state of tissues and organs as lactate rates of appearance and disposal/disappearance in the circulation rise and fall in response to physical exercise and other metabolic disturbances. The highest lactate flux rates have been measured during moderate intensity exercise in endurance-trained individuals who exhibit muscular and metabolic adaptations lending to superior oxidative capacity. In contrast, a diminished ability to utilize lactate is associated with poor metabolic fitness. Given these widespread implications in exercise performance and health, we discuss the concept of lactate metabolic clearance rate, which increases at the onset of exercise and, unlike flux rates, reaches a peak just below the power output associated with the maximal lactate steady state. The metabolic clearance rate is determined by both disposal rate and blood concentration, two parameters that are mutually interdependent and thus difficult to parse during steady state exercise studies. We review the evolution of the in vivo lactate clamp methodology to control blood lactate concentration and discuss its application in the investigation of whole-body lactate disposal capacities. In conclusion, we assert that the lactate clamp is a useful research methodology for examining lactate flux, in particular the factors that drive metabolic clearance rate.

Purpose: To compare linear and curvilinear models describing the force-velocity relationship obtained in lower-limb acyclic extensions, considering experimental data on an unprecedented range of velocity conditions., Methods: Nine athletes performed lower-limb extensions on a leg-press ergometer, designed to provide a very broad range of force and velocity conditions. Previously inaccessible low inertial and resistive conditions were achieved by performing extensions horizontally and with assistance. Force and velocity were continuously measured over the push-off in six resistive conditions to assess individual force-velocity relationships. Goodness of fit of linear and curvilinear models (second-order polynomial function, Fenn and Marsh's, and Hill's equations) on force and velocity data were compared via the Akaike Information Criterion., Results: Expressed relative to the theoretical maximal force and velocity obtained from the linear model, force and velocity data ranged from 26.6 ± 6.6 to 96.0 ± 3.6% (16-99%) and from 8.3 ± 1.9 to 76.6 ± 7.0% (5-86%), respectively. Curvilinear and linear models showed very high fit (adjusted r 2  = 0.951-0.999; SEE = 17-159N). Despite curvilinear models better fitting the data, there was a ~ 99-100% chance the linear model best described the data., Conclusion: A combination between goodness of fit, degrees of freedom and common sense (e.g., rational physiologically values) indicated linear modelling is preferable for describing the force-velocity relationship during acyclic lower-limb extensions, compared to curvilinear models. Notably, linearity appears maintained in conditions approaching theoretical maximal velocity. Using horizontal and assisted lower-limb extension to more broadly explore resistive/assistive conditions could improve reliability and accuracy of the force-velocity relationship and associated parameters., (© 2023. The Author(s).)

Hydroxyurea (HU) is commonly used as a treatment for patients with sickle cell disease (SCD) to enhance fetal hemoglobin production. This increased production is expected to reduce anemia (which depresses oxygen transport) and abnormal Hb content alleviating clinical symptoms such as vaso-occlusive crisis and acute chest syndrome. The effects of HU on skeletal muscle bioenergetics in vivo are still unknown. Due to the beneficial effects of HU upon oxygen delivery, improved skeletal muscle energetics and function in response to a HU treatment have been hypothesized. Muscle energetics and function were analyzed during a standardized rest-exercise-recovery protocol, using 31 P-magnetic resonance spectroscopy in Townes SCD mice. Measurements were performed in three groups of mice: one group of 2-mo-old mice (SCD 2 m , n = 8), another one of 4-mo-old mice (SCD 4 m , n = 8), and a last group of 4-mo-old mice that have been treated from 2 mo of age with HU at 50 mg/kg/day (SCD 4 m-HU , n = 8). As compared with SCD 2 m mice, SCD 4 m mice were heavier and displayed a lower acidosis. As lower specific forces were developed by SCD 4 m compared with SCD 2 m , greater force-normalized phosphocreatine consumption and oxidative and nonoxidative costs of contraction were also reported. HU-treated mice (SCD 4 m-HU ) displayed a significantly higher specific force production as compared with untreated mice (SCD 4 m ), whereas muscle energetics was unchanged. Overall, our results support a beneficial effect of HU on muscle function. NEW & NOTEWORTHY Our results highlighted that force production decreases between 2 and 4 mo of age in SCD mice thereby indicating a decrease of muscle function during this period. Of interest, HU treatment seemed to blunt the observed age effect given that SCD 4 m-HU mice displayed a higher specific force production as compared with SCD 4 m mice. In that respect, HU treatment would help to maintain a higher capacity of force production during aging in SCD.

Hydroxyurea (HU) is a ribonucleotide reductase inhibitor most commonly used as a therapeutic agent in sickle cell disease (SCD) with the aim of reducing the risk of vaso-occlusion and improving oxygen transport to tissues. Previous studies suggest that HU may be even beneficial in mild anemia. However, the corresponding effects on skeletal muscle energetics and function have never been reported in such a mild anemia model. Seventeen mildly anemic HbAA Townes mice were subjected to a standardized rest-stimulation (transcutaneous stimulation)-protocol while muscle energetics using 31 Phosphorus magnetic resonance spectroscopy and muscle force production were assessed and recorded. Eight mice were supplemented with hydroxyurea (HU) for 6 weeks while 9 were not (CON). HU mice displayed a higher specific total force production compared to the CON, with 501.35 ± 54.12 N/mm 3 and 437.43 ± 57.10 N/mm 3 respectively (+14.6%, p < 0.05). Neither the total rate of energy consumption nor the oxidative metabolic rate were significantly different between groups. The present results illustrated a positive effect of a HU chronic supplementation on skeletal muscle function in mice with mild anemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Michel, Messonnier, Giannesini, Chatel, Vilmen, Le Fur and Bendahan.)

We previously demonstrated that 8 weeks of moderate-intensity endurance training is safe and improves muscle function and characteristics of sickle cell disease (SCD) patients. Here, we investigated skeletal muscle satellite cells (SCs) in SCD patients and their responses to a training program. Fifteen patients followed the training program while 18 control patients maintained a normal lifestyle. Biopsies of the vastus lateralis muscle were performed before and after training. After training, the cross-sectional area and myonuclear content in type I fibers were slightly increased in the training patients compared to non-training patients. The SC pool was unchanged in type I fibers while it was slightly decreased in type II fibers in the training patients compared to non-training patients. No necrotic fibers were detected in patients before or after training. Therefore, the slight myonuclear accretion in type I fibers in trained SCD patients may highlight the contribution of SCs to training-induced slight type I fiber hypertrophy without expansion of the SC pool. The low training intensity and the short duration of training sessions could explain the low SC response to the training program. However, the lack of necrotic fibers suggests that the training program seemed to be safe for patients' muscle tissue.

In elite oarsmen, the rowing ergometer is a valuable tool for both training and studying rowing performance determinants. However, the energy cost of rowing, often reported as a determinant of performance, has never been described for ergometer rowing. Therefore, this study aimed to characterize the energy cost of ergometer rowing (ECR) in elite oarsmen, its contribution to 2,000 m performance, and its determinants. This study was conducted on 21 elite oarsmen from the French national team. It included an incremental exercise test up to exhaustion and an all-out performance test over 2,000 m, both conducted on a rowing ergometer. Gas exchange analysis was performed to calculate oxygen uptake and substrate utilization rate. Whole blood lactate concentrations during the incremental test were obtained from the earlobe. During the incremental test, ECR displayed a significant linear increase up to a plateau that reached a mean rowing speed of 5.23 ± 0.02 m⋅s -1 . The ECR values at 300, 350, and 400 W were positively correlated with performance expressed as the time required to perform the 2,000 m distance on the rowing ergometer. The same ECR values were found to be significantly related to fat oxidation (expressed in percentage of total energy supply) and blood lactate concentrations. This study provides the first description of ECR and of its relationship to exercise intensity on the rowing ergometer in elite oarsmen. ECR appeared to be a factor of performance and interestingly was related to energy supply from fat and blood lactate concentrations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Blervaque, Bowen, Chatel, Corbex, Dalmais and Messonnier.)

This study investigated time-courses of physiological and psychological parameters of rowers during the first 1,500 m of a simulated race on a rowing ergometer using different pacing strategies. This provided a picture of the physiological and psychological state of the rowers at the start of the last 500 m of their race. Investigated strategies corresponded either to a degressive ( degr ), a progressive ( prog ), or a stable ( stab ) power output over the traveled distance. Thirteen French rowers (4 oarswomen and 9 oarsmen) of national and ex-international levels volunteered to participate. Handle force and velocity, oxygen uptake, heart rate, blood lactate concentration, and peripheral oxygen saturation were measured during the trials. Power output, generated energy [by O 2 consumption ( E oxi ) and blood lactate accumulation ( E non - oxi )] and efficiency were computed. Rowers also rated their perceived exertion ( RPE ) and protocol preference. In the explored strategies, no significant differences were found for E oxi . Final blood lactate concentration ([ La ] blood ) and RPE were similar for all strategies. However, the increase in [ La ] blood and RPE occurred sooner for degr than for stab and prog . Therefore, the time spent at higher [ La ] blood and RPE was longer for degr than for stab and prog . According to the questionnaire, degr was the least preferred protocol. While during 2000 m races, the first 1500 m are usually and empirically often conducted in a degr way, the present results indicate that this strategy was the least preferred by the rowers and led to a higher time spent at high [ La ] blood and RPE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Boillet, Haas, Samozino, Morel, Bowen, Cohen and Messonnier.)

It remains unclear whether sickle cell trait (SCT) should be considered a risk factor during intense physical activity. By triggering the polymerization-sickling-vaso-occlusion cascade, lactate accumulation-associated acidosis in response to high-intensity exercise is believed to be one of the causes of complications. However, our understanding of lactate metabolism in response to high-intensity exercise in SCT carriers is incomplete. Thirty male SCT carriers ( n = 15) and healthy subjects ( n = 15) with and without α-thalassemia performed a 2-min high-intensity exercise. Blood and muscle lactate concentrations were measured at exercise completion. Time courses of blood lactate and glucose concentrations were followed during the subsequent recovery. Additional biochemical analyses were performed on biopsies of the vastus lateralis muscle. SCT was associated with lower blood and muscle lactate concentrations in response to the short high-intensity exercise. Compared to controls, the muscle content among SCT carriers of lactate transporter MCT4 and β 2 -adrenergic receptor were higher and lower, respectively. During recovery, the lactate removal ability was higher in SCT carriers. In the present study, no effect of α-thalassemia was observed. The lower blood and muscle lactate accumulations in SCT carriers may, to some extent, act as protective mechanisms: (i) against exercise-related acidosis and subsequent sickling, that may explain the relatively rare complications observed in exercising SCT carriers; and (ii) against the deleterious effects of intracellular lactate and associated acidosis on muscle function, that might explain the elevated presence of SCT carriers among the best sprinters.

Lactate constitutes the primary gluconeogenic precursor in healthy humans at rest and during low-intensity exercise. Data on the interactions between lactate and glucose metabolisms during recovery after short-duration high-intensity exercise are sparse. The aim of the present study was to describe blood glucose ([glucose] b ) and lactate ([lactate] b ) concentration curves during recovery following short-duration high-intensity exercise. Fifteen healthy Cameroonian subjects took part in the study and performed successively (i) an incremental exercise to exhaustion to determine maximal work rate (P max ) and (ii) a 2-min 110% P max exercise after which blood lactate and glucose concentrations were measured during the 80-min passive recovery. In response to the 2-min 110% P max exercise, [glucose] b remained stable (from 4.93 ± 1.13 to 4.65 ± 0.74 mmol . L -1 , NS) while [lactate] b increased (from 1.35 ± 0.36 to 7.87 ± 1.66 mmol . L -1 , p < 0.0001). During recovery, blood lactate concentrations displayed the classic biphasic curve while blood glucose concentrations displayed a singular shape including a delayed and transitory rebound of glycemia. This rebound began at 27.7 ± 6.2 min and peaked at 6.78 ± 0.53 mmol . L -1 at 56.3 ± 9.7 min into recovery. The area under the curve (AUC) of [lactate] b during the rebound of glycemia was positively correlated with the peak value of glycemia and the AUC of [glucose] b during the rebound. In conclusion, the delayed rebound of glycemia observed in the present study was associated with lactate availability during this period., Competing Interests: BC was employed by Cellmade Laboratories. LM receives consulting fees from Abbott Diabetes Care. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Messonnier, Chatel, Emhoff, Blervaque and Oyono-Enguéllé.)

Background: Cancer-related fatigue (CRF) is the most common side effect of cancer and cancer treatment. CRF prevalence is up to 50% in breast cancer patients and can continue several years after cancer remission. This persistent subjective sense of exhaustion is multifactorial. Numerous parameters have been evidenced to be related to CRF across biological, physical, psychological, social and/or behavioral dimensions. Although CRF has been studied for many years, the majority of previous studies focused on only one dimension, i.e., physical function. Moreover, few studies investigated CRF longitudinally with repeated measures. These are the two main obstacles that limit the understanding of CRF mechanisms. The purpose of this study is to create a biopsychosocial model of CRF with simultaneous and longitudinal anthropometric, clinical, biological, physical, psychological and sociological parameters., Methods: BIOCARE FActory is a multicentric prospective study that will consist of an 18-month follow-up of 200 women diagnosed with breast cancer. Four visits will be scheduled at diagnosis, after treatments, and 12 and 18 months after diagnosis. The same procedure will be followed for each visit. Each session will be composed of anthropometric data collection, a semi-structured interview, cognitive tests, postural control tests, neuromuscular fatigability tests and a cardiorespiratory fitness test. Clinical and biological data will be collected during medical follow-ups. Participants will also complete questionnaires to assess psychological aspects and quality of life and wear an actigraphy device. Using a structural equation modeling analysis (SEM), collected data will build a biopsychosocial model of CRF, including the physiological, biological, psychological, behavioral and social dimensions of CRF., Discussion: This study aims to highlight the dynamics of CRF and its correlates from diagnosis to post treatment. SEM analysis could examine some relations between potential mechanisms and CRF. Thus, the biopsychosocial model will contribute to a better understanding of CRF and its underlying mechanisms from diagnosis to the aftermaths of cancer and its treatments., Trial Registration: This study is registered at ClinicalTrials.gov ( NCT04391543 ), May 2020., (© 2021. The Author(s).)

Because lactate is an important metabolic intermediate and a signalling molecule between/within cells/organs, it appears essential to be able to describe the kinetics of this central molecule, during and/or after physical exercise. The present study aimed to confront three models and their approaches [Freund and co-workers (F&co), Beneke and co-workers (B&co), and Quittmann and co-workers (Q&co)] to investigate the lactate exchange (γ 1 ) and removal (γ 2 ) abilities (min -1 ) during and/or after exercise. Nine healthy male subjects performed 3- and 6-min easy, moderate, and heavy exercise. Blood lactate concentration (BLC) was measured every 5 s over the entire period of exercise and recovery. Approaches differ depending on the domain in which the model is applied: considering exercise and part of the recovery (B&co and Q&co) or the entire period of recovery (F&co). The different approaches result in differing γ 1 and γ 2 values. Model fitting is closer to the experimental values following the method (model and approach) of F&co. Complementary analyses show that consideration of (i) exercise drastically impairs the quality of model fitting and therefore the γ 1 and γ 2 values and (ii) the entire period of recovery considerably improves the quality of fits and therefore of the γ 1 and γ 2 values. We conclude that (i) it is neither realistic nor reliable to take into account exercise and recovery in the same model and (ii) the longer the period of recovery studied, the better the quality of the γ 1 and γ 2 values., Competing Interests: LM receives consulting fees from Abbott Diabetes Care. All are outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Durand, Galli, Chenavard, Bandiera, Freund and Messonnier.)

Sickle cell anemia (SCA) is a genetic hemoglobinopathy associated with an impaired oxygen delivery to skeletal muscle that could alter ATP production processes and increase intramuscular acidosis. These alterations have been already reported in the Townes mouse model of SCA but the corresponding changes in humans have not been documented. In the present study, we used 31-phosphorus magnetic resonance spectroscopy to investigate in vivo the metabolic changes induced by a moderate-intensity exercise in twelve SCA patients, eight sickle cell trait (SCT) carriers, and twelve controls women. The rest-exercise-recovery protocol disclosed slight differences regarding phosphocreatine (PCr) consumption and lactate accumulation between SCA patients and controls but these differences did not reach a statistical significance. On that basis, the in vivo metabolic changes associated with a moderate-intensity muscle exercise were slightly altered in SCA patients and SCT carriers but within a normal range. The present results strongly support the fact that a moderate-intensity exercise is safe and could be recommended in stable SCA patients and SCT subjects. NEW & NOTEWORTHY The main finding of the present study was that the metabolic changes associated with a moderate-intensity muscle exercise were slightly modified in stable sickle cell anemia patients and sickle cell trait carriers as compared to controls but still in the normal range. The present results strongly support the safety of a moderate-intensity exercise for stable sickle cell anemia patients and sickle cell trait carriers.

The immediate postexercise/physical activity period is critical for sickle cell trait (SCT) carriers and disease (SCD) patients. Exercise-related blood acidosis is known to trigger the cascade of HbS deoxygenation and polymerization, leading to red blood cell sickling and subsequent complications. Unfortunately, two facts worsen exercise-related blood acidosis during the initial postexercise period: First, blood lactate and H + concentrations continue to increase for several minutes after exercise completion, exacerbating blood acidosis. Second, blood lactate concentration remains elevated and pH altered for 20-45 min during inactivity after intense exercise, keeping acid/base balance disturbed for a long period after exercise. Therefore, the risk of complications (including vasoocclusive crises and even sudden death) persists and even worsens several minutes after intense exercise completion in SCT carriers or SCD patients. Light physical activity following intense exercise (namely, active recovery) may, by accelerating lactate removal and acid/base balance restoration, reduce the risk of complications. Scientific evidence suggests that light exercise at or below the first lactate threshold is an appropriate strategy.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Sickle cell disease (SCD) patients display skeletal muscle hypotrophy, altered oxidative capacity, exercise intolerance and poor quality of life. We previously demonstrated that moderate-intensity endurance training is beneficial for improving muscle function and quality of life of patients. The present study evaluated the effects of this moderate-intensity endurance training program on skeletal muscle structural and metabolic properties. Of the 40 randomized SCD patients, complete data sets were obtained from 33. The training group (n = 15) followed a personalized moderate-intensity endurance training program, while the non-training (n = 18) group maintained a normal lifestyle. Biopsies of the vastus lateralis muscle and submaximal incremental cycling tests were performed before and after the training program. Endurance training increased type I muscle fiber surface area (P = .038), oxidative enzyme activity [citrate synthase, P < .001; β-hydroxyacyl-CoA dehydrogenase, P = .009; type-I fiber cytochrome c oxidase, P = .042; respiratory chain complex IV, P = .017] and contents of respiratory chain complexes I (P = .049), III (P = .005), IV (P = .003) and V (P = .002). Respiratory frequency, respiratory exchange ratio, blood lactate concentration and rating of perceived exertion were all lower at a given submaximal power output after training vs non-training group (all P < .05). The muscle content of proteins involved in glucose transport and pH regulation were unchanged in the training group relative to the non-training group. The moderate-intensity endurance exercise program improved exercise capacity and muscle structural and oxidative properties. This trial was registered at www.clinicaltrials.gov as #NCT02571088., (© 2020 Wiley Periodicals LLC.)

Context: Strength-endurance mainly depends on the power output, which is often expressed relative to the individual's maximal power capability ( P max ). However, an individual can develop the same power, but in different combinations of force and velocity (force-velocity condition). Also, at matched power output, changing the force-velocity condition results in a change of the velocity-specific relative power ( P max v ), associated with a change in the power reserve. So far, the effect of these changing conditions on strength-endurance remains unclear., Purpose: We aimed to test the effects of force-velocity condition and power output on strength-endurance., Methods: Fourteen sportsmen performed (i) force- and power-velocity relationships evaluation in squat jumps and (ii) strength-endurance evaluations during repeated squat jump tests in 10 different force-velocity-power conditions, individualized based on the force- and power-velocity relationships. Each condition was characterized by different (i) relative power (% P max ), (ii) velocity-specific relative power (% P max v ), and (iii) ratio between force and velocity ( R Fv ). Strength-endurance was assessed by the maximum repetitions ( SJ Rep ), and the cumulated mechanical work ( W tot ) performed until exhaustion during repeated squat jump tests. Intra and inter-day reliability of SJ Rep were tested in one of the 10 conditions. The effects of % P max , % P max v , and R Fv on SJ Rep and W tot were tested via stepwise multiple linear regressions and two-way ANOVAs., Results: SJ Rep exhibited almost perfect intra- and inter-day reliability (ICC=0.94 and 0.92, respectively). SJ Rep and W tot were influenced by % P max v and R Fv ( R 2 = 0.975 and 0.971; RSME=0.243 and 0.234, respectively; both p < 0.001), with the effect of R Fv increasing with decreasing % P max v (interaction effect, p = 0.03). % P max was not considered as a significant predictor of strength-endurance by the multiple regressions analysis. SJ Rep and W tot were higher at lower % P max v and in low force-high velocity conditions (i.e., lower R Fv )., Conclusion: Strength-endurance was almost fully dependent on the position of the exercise conditions relative to the individual force-velocity and power-velocity relationships (characterized by % P max v and R Fv ). Thus, the standardization of the force-velocity condition and the velocity-specific relative power should not be overlooked for strength-endurance testing and training, but also when setting fatiguing protocols., (Copyright © 2020 Rivière, Peyrot, Cross, Messonnier and Samozino.)

This study aimed to test if the non-oxidative energy supply (estimated by the accumulated oxygen deficit) is associated with an index of muscle lactate accumulation during exercise, muscle monocarboxylate transporter content and the lactate removal ability during recovery in well-trained rowers. Seventeen rowers completed a 3-min all-out exercise on rowing ergometer to estimate the accumulated oxygen deficit. Blood lactate samples were collected during the subsequent passive recovery to assess individual blood lactate curves, which were fitted to the bi-exponential time function: La(t)= [La](0)+A 1 ·(1-e -γ 1 t )+A 2 ·(1-e -γ 2 t ), where the velocity constants γ 1 and γ 2 (min -1 ) denote the lactate exchange and removal abilities during recovery, respectively. The accumulated oxygen deficit was correlated with the net amount of lactate released from the previously active muscles (r =0.58, P<0.05), the monocarboxylate transporters MCT1 and MCT4 (r=0.63, P<0.05) and γ 2 (r=0.55, P<0.05). γ 2 and the lactate release rate at exercise completion were negatively correlated with citrate synthase activity. These findings suggest that the capacity to supply non-oxidative energy during supramaximal rowing exercise is associated with muscle lactate accumulation and transport, as well as lactate removal ability., Competing Interests: The authors declare that they have no conflict of interest., (Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany.)

Introduction: The understanding of fatigue in hypoxia is limited due to: lack of control in arterial saturation, different exercise intensities and hypoxia levels, lag time between exercise cessation and fatigue evaluation. We aimed at evaluating fatigue during cycling and immediately after exhaustion (EXH) in normoxia, moderate and severe hypoxia at relative and absolute intensities., Methods: Thirteen subjects completed three sessions in normoxia, moderate, and severe hypoxia with intensity based on percentage of normoxic maximal power output (NOR, MODABS, SEVABS) plus two sessions where intensity was based on the corresponding environmental condition (MODREL, SEVREL). Arterial saturation was clamped at 85% and 70% in moderate and severe hypoxia, respectively. Before, during cycling, and at EXH, maximum voluntary contraction (MVC), peripheral fatigue (high-frequency doublet [Db100], twitch [Pt]), and central fatigue (cortical voluntary activation [VATMS]) were evaluated without delay using an innovative ergometer., Results: Time to EXH declined not only with hypoxia level at absolute but also relative intensities compared to NOR. At isotime, MVC, Pt, and Db100 were similarly depreciated in NOR, MODREL, and SEVREL. At EXH, there was a similar reduction among conditions in MVC (-26% to -31%), Db100 (-25% to -35%) and VATMS (-9% to -13%). However, Pt was less decreased in SEVREL compared with NOR (-33% ± 17% vs -46% ± 16%)., Conclusions: The shorter time to EXH in relative hypoxia and yet lower peripheral fatigue and similar central fatigue compared with normoxia suggests that hypoxia per se may affect brain areas not directly implicated in quadriceps motor function.

Sickle cell disease (SCD) is a genetic hemoglobinopathy leading to 2 major clinical manifestations: severe chronic hemolytic anemia and iterative vaso-occlusive crises. SCD is also accompanied by profound muscle microvascular remodeling. The beneficial effects of endurance training on microvasculature are widely known. The aim of this study was to evaluate the effects of an endurance training program on microvasculature of skeletal muscle in SCD patients. A biopsy of the vastus lateralis muscle and submaximal incremental exercise was performed before and after the training period. Of the 40 randomized SCD patients, complete data sets from 32 patients were obtained. The training group (n = 15) followed a personalized moderate-intensity endurance training program, while the nontraining (n = 17) group maintained a normal lifestyle. Training consisted of three 40-minute cycle ergometer exercise sessions per week for 8 weeks. Histological analysis highlighted microvascular benefits in the training SCD patients compared with nontraining patients, including increases in capillary density (P = .003), number of capillaries around a fiber (P = .015), and functional exchange surface (P < .0001). Conversely, no significant between-group difference was found in the morphology of capillaries. Indexes of physical ability also improved in the training patients. The moderate-intensity endurance exercise training program improved the muscle capillary network and partly reversed the microvascular defects commonly observed in skeletal muscle of SCD patients. This trial was registered at www.clinicaltrials.gov as #NCT02571088., (© 2019 by The American Society of Hematology.)

Purpose: Although strenuous exercise may expose sickle cell disease (SCD) patients to risks of vaso-occlusive crisis, evidence suggests that regular endurance exercise may be beneficial. This study aimed to test (i) the safety and usefulness of a submaximal incremental exercise in evaluating physical ability of SCD patients and identify a marker for the management of endurance exercise and (ii) the feasibility of endurance exercise sessions in SCD patients., Methods: Twenty adults with SCD (12 men and 8 women) performed a submaximal incremental exercise used to determine the first lactate threshold (LT1) and stopped as soon as blood lactate concentration ([lactate]b) reached ≥4 mmol·L. Fifteen of those patients (8 men and 7 women) also performed three 30-min endurance exercise sessions at ~2.5 mmol·L of [lactate]b on separate occasions., Results: LT1 occurred at 47 ± 3 and 33 ± 3 W for men and women, respectively, demonstrating the extreme deconditioning and, thus, low physical ability of adult SCD patients. During endurance exercise, peripheral oxygen saturation and [lactate]b most often remained stable and within acceptable ranges., Conclusions: The proposed strategy of submaximal incremental exercise allowed safe determination of LT1, an important parameter of patients' physical ability. The study also demonstrated the feasibility and safety of individually tailored endurance exercises at ~2.5 mmol·L of [lactate]b. These latter results suggest that endurance training programs may be considered for adult SCD patients and that the method proposed here may be helpful in that regard.

Oxidative stress is a key feature in the pathophysiology of sickle cell disease. Endurance training has been shown to reduce oxidative stress in the heart and the liver of sickle mice. However, the effects of endurance training on skeletal muscles, which are major producers of reactive oxygen species during exercise, are currently unknown. The aim of this study was to evaluate the effect of sickle genotype on prooxidant/antioxidant response to individualized endurance training in skeletal muscles of sickle mice. Healthy and homozygous Townes sickle mice were divided into trained or sedentary groups. Maximal aerobic speed and V̇O 2 peak were determined using an incremental test on a treadmill. Trained mice ran at 40% to 60% of maximal aerobic speed, 1 h/day, 5 days/week for 8 weeks. Oxidative stress markers, prooxidant/antioxidant response, and citrate synthase enzyme activities were assessed in the gastrocnemius , in the plantaris , and in the soleus muscles. Maximal aerobic speed and V̇O 2 peak were significantly reduced in sickle compared to healthy mice (-57% and -17%; p < 0.001). NADPH oxidase, superoxide dismutase, and catalase activities significantly increased after training in the gastrocnemius of sickle mice only. A similar trend was observed for citrate synthase activity in sickle mice ( p = 0.06). In this study, we showed an adaptive response to individualized endurance training on the prooxidant/antioxidant balance in the gastrocnemius, but neither in the plantaris nor in the soleus of trained sickle mice, suggesting an effect of sickle genotype on skeletal muscle response to endurance treadmill training., Competing Interests: The authors have no competing interests, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included in this manuscript.

New Findings: What is the central question of this study? The aim of this study was to evaluate the potential beneficial effects of endurance training during an ischaemia-reperfusion protocol in a mouse model of sickle cell disease (SCD). What is the main finding and its importance? Endurance training did not reverse the metabolic defects induced by a simulated vaso-occlusive crisis in SCD mice, with regard to intramuscular acidosis, mitochondrial dysfunction or anatomical properties. Our results suggest that endurance training would reduce the number of vaso-occlusive crises rather than the complications related to vaso-occlusive crises., Abstract: The aim of this study was to investigate whether endurance training could limit the abnormalities described in a mouse model of sickle cell disease (SCD) in response to an ischaemia-reperfusion (I/R) protocol. Ten sedentary (HbSS-SED) and nine endurance-trained (HbSS-END) SCD mice were submitted to a standardized protocol of I/R of the leg, during which ATP, phosphocreatine and inorganic phosphate concentrations and intramuscular pH were measured using magnetic resonance spectroscopy. Forty-eight hours later, skeletal muscles were harvested. Oxidative stress markers were then measured. Although the time course of protons accumulation was slightly different between trained and sedentary mice (P < 0.05), the extent of acidosis was similar at the end of the ischaemic period. The initial rate of phosphocreatine resynthesis measured at blood flow restoration, illustrating mitochondrial function, was not altered in trained mice compared with sedentary mice. Although several oxidative stress markers were not different between groups (P > 0.05), the I/R-related increase of uric acid concentration observed in sedentary SCD mice (P < 0.05) was not present in the trained group. The spleen weight, generally used as a marker of the severity of the disease, was not different between groups (P > 0.05). In conclusion, endurance training did not limit the metabolic consequences of an I/R protocol in skeletal muscle of SCD mice, suggesting that the reduction in the severity of the disease previously demonstrated in the basal state would be attributable to a reduction of the occurrence of vaso-occlusive crises rather than a decrease of the deleterious effects of vaso-occlusive crises., (© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.)

Sickle cell disease (SCD) is the most frequent life-threatening genetic hemoglobinopathy in the world and occurs due to the synthesis of abnormal hemoglobin S (HbS). hemoglobin S-containing red blood cells (RBC) are fragile, leading to hemolysis and anemia, and adhere to the endothelium, leading to hemorheological and hemodynamical disturbances. In its deoxygenated form, HbS may polymerize, leading to sickling of red blood cells and potentially to vasoocclusive crises. Recent findings observed that SCD patients demonstrate significant skeletal muscle remodeling and display reduced muscle functional capacities, contributing to exercise intolerance and poor quality of life. Although acute high-intensity exercise is not recommended for SCD patients because it may increase the risk of sickling, regular moderate-intensity physical activity could have beneficial effects on skeletal muscle and more generally on the well-being of SCD patients. This article reviews the literature regarding the impact of the disease on muscular tissue characteristics and function, as well as the corresponding implications for SCD patients' quality of life.

Background: Exercise could be a triggering factor for vaso-occlusive crises in patients with sickle-cell disease. We aimed to investigate whether a patient-adapted training programme of moderate endurance exercise could be safe and beneficial for patients with sickle-cell disease., Methods: We did a multicentre, prospective, open-label, randomised controlled trial at four university hospitals in France. Eligible patients were older than 18 years, with an HbSS or S/β 0 -thalassaemia genotype, and with no severe chronic complications. All patients underwent cardiopulmonary exercise tests (CPETs) on a stationary bicycle with cardiac, pulmonary, laboratory, and muscle parameter evaluations at the start and end of the study period. We randomly assigned patients (1:1) to the training group (three 45-min exercise sessions per week, for 8 weeks) or the control group (no lifestyle changes) using a central computer-generated randomisation list. During baseline evaluation, patients and researchers were masked to group assignment; randomisation was done after completion of the baseline evaluation to minimise bias. The primary outcome was difference in power output at a blood lactate concentration of 4 mmol/L during CPET between baseline and the end of the 8-week training period. Patients were analysed on a per-protocol basis, excluding those who missed more than 20% of the training sessions or had other major protocol violations. This trial is registered with ClinicalTrials.gov, number NCT02571088, and is completed., Findings: Between Sept 8, 2014, and Dec 11, 2015, 40 patients were enrolled (20 to each group). After exclusion of seven patients (one pregnancy, one appendicitis, one protocol violation, two lost to follow-up, and two incompatibilities with work schedule), 33 patients were analysed (15 in the training group, 18 in the control group). At the 8-week follow-up, the absolute change from baseline in mean power output at 4 mmol/L blood lactate was 7·2 W (SD 8·7) in trained patients (from 70·4 W [SD 16·2] at baseline to 77·6 W [15·1] at end of intervention) compared with -0·3 W (9·4) in controls (from 66·2 W [13·8] to 65·9 W [15·6]; mean difference between groups 7·3 W [95% CI 0·7-13·8], p=0·031). No adverse events requiring hospital admission occurred in the training group, whereas five occurred in the control group: four (20%) vaso-occlusive crises (one complicated by an acute chest syndrome), and one (6%) viral infection with isolated chest pain (hazard ratio 0·143 [95% CI 0·024-0·827; p=0·029)., Interpretation: Moderate-intensity endurance-exercise training seems to be safe for adults with sickle-cell disease without severe chronic complications and significantly improved their functional capacity, especially for exercise levels close to those needed for daily activities. Our findings support consideration of endurance-exercise training as a novel therapeutic strategy for patients with sickle-cell disease., Funding: Société Française de Cardiologie and Institut National du Sport, de l'Expertise et de la Performance (INSEP)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Sickle cell disease (SCD) is characterized by painful vaso-occlusive crisis. While there are several metabolic abnormalities potentially associated with muscular ischemia-reperfusion cycles that could be harmful in the context of SCD, the metabolic consequences of such events are still unknown. Ten controls (HbAA), thirteen heterozygous (HbAS), and ten homozygous (HbSS) SCD mice were submitted to a standardized protocol of rest-ischemia-reperfusion of the left leg during which adenosine triphosphate, phosphocreatine, and inorganic phosphate concentrations as well as intramuscular pH were measured using phosphorous magnetic resonance spectroscopy (MRS). Forty-eight hours later, skeletal muscles were harvested. Oxidative stress markers were then measured on the tibialis anterior. At the end of the ischemic period, HbSS mice had a lower pH value as compared with the HbAA and HbAS groups ( P <0.01). During the reperfusion period, the initial rate of phosphocreatine resynthesis was lower in HbSS mice as compared with HbAA ( P <0.05) and HbAS ( P <0.01) animals. No significant difference among groups was observed regarding oxidative stress markers. HbSS mice displayed a higher intramuscular acidosis during the ischemic period while their mitochondrial function was impaired as compared with their HbAA and HbAS counterparts. These metabolic abnormalities could worsen the complications related to the pathology of SCD., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

This study aimed to compare the effect of a 40-min submaximal rowing exercise performed on ergometers with fixed and free-floating designs. Heart rate, blood lactate concentration, force and rate of force development (RFD) at the handle, stroke rate, duty factor, movement kinematics of upper and lower limbs, and muscle activity of lumbar spine muscles iliocostalis and erector spinae (IC and ESL) were measured at the beginning and at the end of a 40-min rowing exercise at ~60% of peak power output, in eleven competitive rowers. Force of lumbar extension decreased, and blood lactate increased following submaximal exercise on both ergometers. No changes in RFD, duty factor, and muscle activity of IC occurred in response to submaximal exercise. Rowing on DYN elicited higher heart rate and modified rowing kinematics (stroke rate, acceleration of the lower limbs) without changes in temporal or force application patterns compared to rowing on STAT at the same power output. Rowing on DYN was also associated with increased activity of the lumbar spine muscle ESL, which could originate from a greater range of motion, or from an increased lumbar spine muscle activity, at the same overall power., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

New Findings: What is the topic of this review? The aim of this review is to discuss the potential involvement of exercise-induced acidosis in the commonly reported complications in sickle cell disease. What advances does it highlight? Blood acidosis appears clearly to be a risk factor for HbS polymerization, red blood cell sickling and the occurrence of vaso-occlusive crisis and could induce hyperkalaemia-related complications. It could be of great interest to try to avoid blood acidosis during exercise, which could be done using some alkalinizing solutions or adapted endurance training interventions., Abstract: Sickle cell disease (SCD) is an inherited haemoglobin (Hb) disorder and the most common monogenic disease in the world. The root cause of this pathology is the synthesis of an abnormal Hb (HbS) that polymerizes in deoxygenated conditions, leading to the sickling of red blood cells. Acidosis is well recognized as a promoter of HbS polymerization and therefore red blood cell sickling. Indeed, it has been shown in vitro that the relative amount of sickled red blood cells increases markedly from 1% at pH 7.4 to >90% at pH 7.0. Nevertheless, no study has directly tested whether exercise-induced acidosis could favour SCD complications. Greater knowledge of the effects of metabolic acidosis during exercise could be of importance given the conclusions reached in several studies that proposed regular physical exercise as a therapeutic strategy in the management of SCD. In this review, we discuss the potential consequences of exercise-induced acidosis for the pathophysiology of SCD. We also propose some potential therapeutic interventions with the aim of reducing the metabolic acidosis related to exercise., (© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.)

Sickle cell disease (SCD) mice (Townes model of SCD) presented exacerbated exercise-induced acidosis and fatigability as compared to control animals. We hypothesize that endurance training could represent a valuable approach to reverse these muscle defects. Endurance-trained HbAA (HbAA-END, n=10), HbAS (HbAS-END, n=11) and HbSS (HbSS-END, n=8) mice were compared to their sedentary counterparts (10 HbAA-SED, 10 HbAS-SED and 9 HbSS-SED mice) during two rest - exercise - recovery protocols during which muscle energetics and function were measured. In vitro analyses of some proteins involved in muscle energetics, pH regulation and oxidative stress were also performed. Exercise-induced acidosis was lower in HbSS-END mice as compared to their sedentary counterparts during both moderate (p<0.001) and intense (p<0.1) protocols. The total force production measured during both protocols was higher in trained mice compared to sedentary animals. In vitro analyses revealed that enolase/citrate synthase ratio was reduced in HbSS-END (p<0.001) and HbAS-END (p<0.01) mice compared to their sedentary counterparts. In addition, malondialdehyde concentration was reduced in trained mice (p<0.05). In conclusion, endurance training would reverse the more pronounced exercise-induced acidosis, reduce oxidative stress and ameliorate some of the muscle function parameters in SCD mice., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The present study investigated morphological and physiological factors of rowing ergometer performance over 2000 m (P 2000, W) in 70 national and international level [27 lightweight (LW) and 43 heavyweight (HW)] female rowers. Maximal oxygen uptake (V̇O 2max , L.min -1 ), maximal aerobic power (Pa max , W), power output corresponding to 4 mmol.L -1 blood lactate concentration expressed in absolute (PLa 4 , W) and relative to Pa max (PLa 4 %, %) values, peak power output (P peak , W), and rowing gross efficiency (RGE, %) were determined during an incremental rowing test. In the whole group, P peak was the best predictor of P 2000 (r=0.89, p<0.001), as it was shown in men. PLa 4 (r=0.87), V̇O 2max (r=0.83), body mass (r=0.65), and height (r=0.64) were also significantly correlated with P 2000 (p<0.001 for all). P peak was also the best predictor of P 2000 when the two sub-groups LW and HW were considered separately. It was concluded that P peak is an overall index of physiological rowing capacity in groups of high-level LW and HW female rowers. The predictive value of P peak is similar to that of PLa 4 , but P peak presents the advantage of being obtained with a simple ergometer test without biological measurements., Competing Interests: Conflict of Interest: The authors declare no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

While sickle cell disease (SCD) is characterized by frequent vaso-occlusive crisis (VOC), no direct observation of such an event in skeletal muscle has been performed in vivo. The present study reported exacerbated in vivo metabolic changes suggestive of a spontaneous muscular VOC in exercising muscle of a sickle cell mouse. Using magnetic resonance spectroscopy of phosphorus 31, phosphocreatine and inorganic phosphate concentrations and intramuscular pH were measured throughout two standardized protocols of rest - exercise - recovery at two different intensities in ten SCD mice. Among these mice, one single mouse presented divergent responses. A statistical analysis (based on confidence intervals) revealed that this single mouse presented slower phosphocreatine resynthesis and inorganic phosphate disappearance during the post-stimulation recovery of one of the protocols, what could suggest an ischemia. This study described, for the first time in a sickle cell mouse in vivo, exacerbated metabolic changes triggered by an exercise session that would be suggestive of a live observation of a muscular VOC. However, no evidence of a direct cause-effect relationship between exercise and VOC has been put forth., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The purpose of this study was to investigate the effects of a partial suppression of monocarboxylate transporter (MCT)-1 on skeletal muscle pH, energetics, and function (MCT1 +/- mice). Twenty-four MCT1 +/- and 13 wild-type (WT) mice were subjected to a rest-exercise-recovery protocol, allowing assessment of muscle energetics (by magnetic resonance spectroscopy) and function. The study included analysis of enzyme activities and content of protein involved in pH regulation. Skeletal muscle of MCT1 +/- mice had lower MCT1 (-61%; P < 0.05) and carbonic anhydrase (CA)-II (-54%; P < 0.05) contents. Although intramuscular pH was higher in MCT1 +/- mice at rest ( P < 0.001), the mice showed higher acidosis during the first minute of exercise ( P < 0.01). Then, the pH time course was similar among groups until exercise completion. MCT1 +/- mice had higher specific peak ( P < 0.05) and maximum tetanic ( P < 0.01) forces and lower fatigability ( P < 0.001) when compared to WT mice. We conclude that both MCT1 and CAII are involved in the homeostatic control of pH in skeletal muscle, both at rest and at the onset of exercise. The improved muscle function and resistance to fatigue in MCT1 +/- mice remain unexplained.-Chatel, B., Bendahan, D., Hourdé, C., Pellerin, L., Lengacher, S., Magistretti, P., Fur, Y. L., Vilmen, C., Bernard, M., Messonnier, L. A. Role of MCT1 and CAII in skeletal muscle pH homeostasis, energetics, and function: in vivo insights from MCT1 haploinsufficient mice., (© FASEB.)

Sickle cell disease (SCD) is associated with an impaired oxygen delivery to skeletal muscle that could alter ATP production processes. The present study aimed to determine the effects of sickle hemoglobin (HbS) on muscle pH homeostasis in response to exercise in homozygous (HbSS, n = 9) and heterozygous (HbAS, n = 10) SCD (Townes) mice in comparison to control (HbAA, n = 10) littermates. Magnetic resonance spectroscopy of phosphorus 31 enabled to measure intramuscular pH and phosphocreatine (PCr) concentration during rest-stimulation-recovery protocols at two different intensities. Maximal activity of some enzymes involved in muscle energetics and content of proteins involved in pH regulation were also investigated. HbSS mice presented a more pronounced exercise-induced intramuscular acidosis, whatever the intensity of exercise. Moreover, the depletion of PCr was also exacerbated in HbSS mice in response to intense exercise as compared with both HbAA and HbAS mice ( P < 0.01). While no difference was observed concerning proteins involved in muscle pH regulation, the activity of enolase (a glycolytic enzyme) was higher in both HbSS and HbAS mice as compared with controls ( P < 0.05). Interestingly, HbAS mice presented also metabolic impairments as compared with their control counterparts. This study has identified for the first time an exacerbated exercise-induced intramuscular acidosis in SCD mice. NEW & NOTEWORTHY The main finding of the present study was that the exercise-induced intramuscular acidosis was systematically more pronounced in sickle cell disease (SCD) mice as compared with their control counterparts. This result is important since it has been demonstrated in vitro that acidosis can trigger hemoglobin polymerization. From that point of view, our results tend to support the idea that high-intensity exercise may increase the risk of hemoglobin polymerization in SCD., (Copyright © 2017 the American Physiological Society.)

Skeletal muscle function has been scarcely investigated in sickle cell disease (SCD) so that the corresponding impact of sickle hemoglobin is still a matter of debate. The purpose of this study was to investigate muscle force production and fatigability in SCD and to identify whether exercise intensity could have a modulatory effect. Ten homozygous sickle cell (HbSS), ten control (HbAA) and ten heterozygous (HbAS) mice were submitted to two stimulation protocols (moderate and intense) to assess force production and fatigability. We showed that specific maximal tetanic force was lower in HbSS mice as compared to other groups. At the onset of the stimulation period, peak force was reduced in HbSS and HbAS mice as compared to HbAA mice. Contrary to the moderate protocol, the intense stimulation protocol was associated with a larger decrease in peak force and rate of force development in HbSS mice as compared to HbAA and HbAS mice. These findings provide in vivo evidence of impaired muscle force production and resistance to fatigue in SCD. These changes are independent of muscle mass. Moreover, SCD is associated with muscle fatigability when exercise intensity is high., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to investigate lactate recovery kinetics after high-intensity exercises., Methods: Six competitive middle-distance runners performed 500-, 1000-, and 1500-m trials at 90 % of their current maximal speed over 1500 m. Each event was followed by a passive recovery to obtain blood lactate recovery curves (BLRC). BLRC were fitted by the bi-exponential time function: La(t) = La(0) + A 1(1-e (-γ1t) ) + A 2(1-e (-γ2t) ), where La(0) is the blood lactate concentration at exercise completion, and γ 1 and γ 2 enlighten the lactate exchange ability between the previously active muscles and the blood and the overall lactate removal ability, respectively. Applications of the model provided parameters related to lactate release, removal and accumulation rates at exercise completion, and net amount of lactate released during recovery., Results: The increase of running distance was accompanied by (1) a continuous decrease in γ 1 (p < 0.05), (2) a primary decrease (p < 0.05) and then a stabilization of γ 2, and (3) a constant increase in blood concentrations (p < 0.05) and whole body accumulation of lactate (p < 0.05). Estimated net lactate release, removal and accumulation rates at exercise completion, as well as the net amount of lactate released during recovery were not significantly altered by distance., Conclusion: Alterations of lactate exchange and removal abilities have presumably been compensated by an increase in muscle-to-blood lactate gradient and blood lactate concentrations, respectively, so that estimated lactate release, removal and accumulation rates remained almost stable as distance increased.

The purpose of this study was to test if the lactate exchange (γ1) and removal (γ2) abilities during recovery following short all-out supramaximal exercise correlate with the muscle content of MCT1 and MCT4, the two isoforms of the monocarboxylate transporters family involved in lactate and H(+) co-transport in skeletal muscle. Eighteen lightweight rowers completed a 3-min all-out exercise on rowing ergometer. Blood lactate samples were collected during the subsequent passive recovery to assess an individual blood lactate curve (IBLC). IBLC were fitted to the bi-exponential time function: La(t) = [La](0) + A1(1 - [Formula: see text]) + A2(1 - [Formula: see text]) where [La](0) is the blood lactate concentration at exercise completion and the velocity constants γ1 and γ2 denote the lactate exchange and removal abilities, respectively. An application of the bi-compartmental model of lactate distribution space allowed estimation of the lactate removal rate at exercise completion [LRR(0)]. Biopsy of the right vastus lateralis was taken at rest to measure muscle MCT1 and MCT4 content. Fiber type distribution, activity of key enzymes and capillary density (CD) were also assessed. γ1 was correlated with [La](0) (r = -0.54, P < 0.05) but not with MCT1, MCT4 or CD. γ2 and LRR(0) were correlated with MCT4 (r = 0.63, P < 0.01 and r = 0.73, P < 0.001, respectively) but not with MCT1 or cytochrome c oxidase activity. These findings suggest that the lactate exchange ability is highly dependent on the milieu so that the importance of the muscle MCT1 and MCT4 content in γ1 was hidden in the present study. Our results also suggest that during recovery following all-out supramaximal exercise in well-trained rowers, MCT4 might play a significant role in the distribution and delivery of lactate for its subsequent removal.

Sickle cell anemia (SCA) is a hemoglobinopathy leading to major hematologic, hemorheologic, and hemodynamic disorders that induce various complications, including organ failure, and ultimately lead to death. Here, we assessed for the first time repercussions of SCA on skeletal muscle and its microvasculature. Twenty-seven sedentary Cameroonian volunteer men participated in the study. They were assigned to one of three groups according to their hemoglobin status (healthy control subjects, n = 10; sickle cell trait carriers, n = 10; and SCA patients, n = 7) and underwent muscle biopsy of the vastus lateralis. SCA was associated with microvessel rarefaction, decrease in capillary tortuosity, and widening of microvessel diameter. The absence of capillary wall reinforcement was shown by lack of wall thickening and lack of fibrous tissue or smooth muscle in their constitution. We also observed changes in fiber type distribution, muscle atrophy, an increase in satellite cell number, and a decrease in activity of creatine kinase and several oxidative enzymes. No signs of tissue necrosis, inflammatory stress, fibrosis, or segmented fibers were observed. The present study highlighted marked effects of SCA on microvascular, structural, and energetic characteristics of skeletal muscle., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)