Muscle Function and Its Biological and Physiological Determinants in Sickle Cell Disease (DREPAMUSCLE)

Background : Sickle cell patients have profound remodeling of their muscle microcirculation networks with signs of amyotrophy. However, the consequences of these muscle alterations on the functional status of muscles are unknown. In addition, whether the poor physical fitness of sickle cell patients can be attributed, at least partly, to an hypothetical muscle dysfunction has never been tested. Purpose : this study will compare the muscle function of legs between sickle cell patients (SS and SC genotypes) and healthy individuals (AA genotype) before, during and after a short localized muscle endurance exercise. Abstract : Very recently, a study reported large differences between the muscle microcirculation networks of sickle cell patients compared to healthy individuals with decreased capillary density and higher proportion of large capillaries in the former population. In addition, the same study showed signs of amyotrophy in sickle cell patients. However, the muscle function of sickle cell patients has not been investigated and one may suggest that muscle dysfunction could participate in the decrease of physical fitness, in association with the hematological and hemorheological disorders, already reported in this population. The hypothesis is that muscle fatigue during a short localized muscle endurance exercise should be higher in sickle cell patients compared to healthy individuals, due to a greater recruitment of glycolytic fibers and a faster decrease of muscle oxygenation during exercise.

Sickle cell patients with SS genotype. Each subject will undergo the following : Blood sample Maximum Voluntary Contraction (MVC) test force before and after a localized muscle endurance test Localized muscle endurance test: 4 series of 20 submaximal dynamic contractions at 50% of the MVC interspaced with 1 min recovery. Self-paced six-minute walk test will be conducted according to the guidelines of the American Thoracic Society

Sickle cell patients with SC genotype. Each subject will undergo the following : Blood sample Maximum Voluntary Contraction (MVC) test force before and after a localized muscle endurance test Localized muscle endurance test: 4 series of 20 submaximal dynamic contractions at 50% of the MVC interspaced with 1 min recovery. Self-paced six-minute walk test will be conducted according to the guidelines of the American Thoracic Society

Healthy subjects. Each subject will undergo the following : Blood sample Maximum Voluntary Contraction (MVC) test force before and after a localized muscle endurance test Localized muscle endurance test: 4 series of 20 submaximal dynamic contractions at 50% of the MVC interspaced with 1 min recovery. Self-paced six-minute walk test will be conducted according to the guidelines of the American Thoracic Society

Maximum Voluntary Contraction (MVC) test force will be performed before and after a localized muscle endurance test

Subject will perform 4 series of 20 submaximal dynamic contractions at 50% of the MVC interspaced with 1 min recovery.

Self-paced six-minute walk test will be conducted according to the guidelines of the American Thoracic Society

Isometric muscular strength will be determined by Maximum Voluntary Contraction (MVC) test force on dominant leg. Muscular function will be evaluated using Maximum Voluntary Contraction (MVC) test force and the muscle endurance ability, which will be highlighted by the degree of decline of MVC after a short localized muscle effort using the formula: ((post MVC force - pre MVC force) / pre MVC force)x100. Muscle weakness will be determined by a loss of maximum isometric strength ≥ 20 % compared with control group.

oxyhemoglobin (HbO2) and deoxyhemoglobin (HHb) levels will be measured using Near-Infrared spectroscopy on the dominant leg.

In order to investigate the association between muscle endurance ability and physical fitness in sickle cell patients, patients will realize a six-minute walk test (6MWT). 6MWD will be measured = the distance that a patient has walked on a flat, hard surface in a period of 6 minutes (6MWT).

CBC will be performed in order to evaluate the role of hematological disorders in the muscle fatigue of sickle cell patients.

Hematocrit will be measured in order to evaluate the role of hematological disorders in the muscle fatigue of sickle cell patients.

Blood viscosity will be measured by using viscosimetry, in order to evaluate the role of hemorheological disorders in the muscle fatigue of sickle cell patients.

RBC deformability will be assessed by using ektacytometry, in order to evaluate the role of hemorheological disorders in the muscle fatigue of sickle cell patients.

Aggregation properties will be assessed by using syllectometry, in order to evaluate the role of hemorheological disorders in the muscle fatigue of sickle cell patients.

Hemoglobin oxygenation level will be measured in order to evaluate the role of hemorheological disorders in the muscle fatigue of sickle cell patients.

Number of vaso-occlusive crises and acute chest syndrome reflects of clinical severity of the sickle cell disease. Clinical severity will be retrospectively (5 years) collected in clinical record of sickle cell patients. These clinical data will be used to study the relationships between the degree of muscle dysfunction and the degree of clinical severity in sickle cell patients.

Inclusion Criteria: For Sickle cell patients : age ≥ 15 and < 60 years old, SS homozygote or SC heterozygote in clinical steady state (i.e. without vaso-occlusive crisis or recent blood transfusion) identified by systematic neonatal screening programs, registered in the French medical social security national program For Healthy and non sickle cell subjects: age ≥ 18 and < 60 years old without cardiovascular/respiratory/muscle disease, registered in the French medical social security national program. Exclusion Criteria: other hemoglobinopathies, stroke or vasculopathy history, presence of leg ulcers or osteonecrosis, recent infectious episode (less than 1 month), chronic transfusion therapy programs, recent blood transfusion or phlebotomies (less than 3 months), patients not at steady state, pregnancy or breast feeding