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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.)

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) 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.)

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.)

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.)