INTRODUCTION AND AIMS:Mitochondrial myopathies are rare genetic disorders for which no effective treatment exists. We previously showed that the pharmacological cyclophilin inhibitor cyclosporine A (CsA) extends the lifespan of fast-twitch skeletal muscle-specific mitochondrial transcription factor A knockout (Tfam KO) mice, lacking the ability to transcribe mitochondrial DNA and displaying lethal mitochondrial myopathy. Our present aim was to assess whether the positive effect of CsA was associated with improved in vivo mitochondrial energy production. METHODS:Mice were treated with CsA for 4 weeks, beginning at 12 weeks (i.e., before the terminal disease phase). Hindlimb plantar flexor muscles were fatigued by 80 contractions (40 Hz, 1.5 s on, 6 s off) while measuring force and energy metabolism using phosphorus-31 magnetic resonance spectroscopy. RESULTS:Force decreased at similar rates in Tfam KO mice with and without the CsA treatment, reaching 50% of the baseline value after ~14 ± 1 contractions, which was faster than in control mice (25 ± 1 contractions). Phosphocreatine (PCr) decreased to ~10% of the control concentration in Tfam KO mice, independent of the treatment, which was larger than the ~20% observed in control mice. The time constant of PCr recovery was higher in untreated Tfam KO than that in control muscle (+100%) and similar in untreated and CsA-treated Tfam KO mice. DISCUSSION:The results do not support improved mitochondrial energy production as a mechanism underlying the prolonged lifespan of Tfam KO mitochondrial myopathy mice treated with CsA. Thus, other mechanisms must be involved, such as the previously observed CsA-mediated protection against excessive mitochondrial Ca2+ accumulation.

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 31Phosphorus 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/mm3 and 437.43 ± 57.10 N/mm3 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.

AbstractMitochondrial myopathies are rare genetic disorders characterized by muscle weakness and exercise intolerance. Currently, no effective treatment exists for these myopathies. Interestingly, the pharmacological cyclophilin inhibitor cyclosporine A (CsA) extended lifespan and prevented loss of force and mitochondrial Ca2+overload in muscle fibers in the skeletal muscle-specificTfamknockout mouse model of lethal mitochondrial myopathy (TfamKO). The unaffected expression of proteins involved in mitochondrial energy metabolism suggests that these improvements occurred without improvement in metabolism. In this study, we aimed at investigating the effects of four weeks of CsA administration onin vivocontractile function and mitochondrial energy production inTfamKO mice. The treatment started before the terminal phase with severe muscle weakness and weight loss. Our results show that CsA treatment delayed progression into the terminal disease phase. This occurred without any obvious positive effects on mitochondrial energy production at rest or during fatigue induced by repeated contractions. In conclusion, cyclophilin inhibitors may have the potential of counteracting devastating muscle weakness in patients with mitochondrial myopathies most probably by preventing deleterious effects triggered by excessive mitochondrial Ca2+uptake rather than by improving mitochondrial energy production.

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.

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 β2-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.

Mitochondrial diseases are genetic disorders that lead to impaired mitochondrial function, resulting in exercise intolerance and muscle weakness. In patients, muscle fatigue due to defects in mitochondrial oxidative capacities commonly precedes muscle weakness. In mice, deletion of the fast-twitch skeletal muscle-specific Tfam gene (Tfam KO) leads to a deficit in respiratory chain activity, severe muscle weakness and early death. Here, we performed a time-course study of mitochondrial and muscular dysfunctions in 11-and 14-week-old Tfam KO mice, i.e. before and when mice are about to enter the terminal stage, respectively. Although force in the unfatigued state was reduced in Tfam KO mice compared to control littermates (wild type) only at 14 weeks, during repeated submaximal contractions fatigue was faster at both ages. During fatiguing stimulation, total phosphocreatine breakdown was larger in Tfam KO muscle than in wild-type muscle at both ages, whereas phosphocreatine consumption was faster only at 14 weeks. In conclusion, the Tfam KO mouse model represents a reliable model of lethal mitochondrial myopathy in which impaired mitochondrial energy production and premature fatigue occur before muscle weakness and early death.

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 (Pmax) and (ii) a 2-min 110% Pmax exercise after which blood lactate and glucose concentrations were measured during the 80-min passive recovery. In response to the 2-min 110% Pmax 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.

How to implement endurance exercise training in sickle cell diseaseA previous study demonstrated the safety and beneficial effects of moderate-intensity endurance exercise training in patients with sickle cell disease (SCD).However, this previous pilot study had several limitations.The most important constraint was the need for repeated measurements of blood lactate concentration in order to adjust training intensity.This approach considerably hinders implementation and dissemination of endurance exercise training in the general population of SCD patients.In the present study, we tested heart rate as a possible surrogate for adjustment of training intensity.Patients (n=15) successively performed an initial submaximal incremental test (SIT1), 30-min moderateintensity cycling exercises three times a week for 8 weeks, and finally another SIT (SIT2).Heart rate (HR) and blood lactate concentration ([lactate] b ) were recorded every minute during both SIT and once during training sessions.[lactate] b and HR values measured during training concurred with the correlation obtained between [lactate] b and HR during the two SIT.Provided that patients' individual [lactate] b versus HR relationship (obtained during a SIT) is known and patients are accustomed to cycling exercise, HR appears to be an acceptable surrogate to control and adjust intensity of endurance exercises.SCD is the most frequent genetic disease worldwide.Vaso-occlusion and anemia, the two main consequences of the disease, induce a myriad of complications affecting

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.

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.

ABSTRACT 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.

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 V̇O2 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 V̇O2 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.

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.

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.

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.

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.

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.

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.

The purpose of this study was to investigate the effects of a partial suppression of monocarboxylate transporter (MCT)-1 on skeletalmuscle pH, energetics, and function (MCT1(+/-) mice). Twenty-fourMCT1(+/-) and 13 wild-type (WT) mice were subjected to a rest-exercise-recovery protocol, allowing assessment of muscle energetics (bymagnetic resonance spectroscopy) and function. The study included analysis of enzyme activities and content of protein involved in pH regulation. Skeletalmuscle ofMCT1(+/-) mice had lower MCT1 (-61%; P < 0.05) and carbonic anhydrase (CA)-II (254%; 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 maximumtetanic (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., Hourd e, 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.

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.