Impact of exercise on the skeletal muscle in sickle cell disease: characterization of muscle fatigability and of the effects of aerobic exercise on pro/antioxidant balance

Sickle cell disease (SCD) is a group of hemoglobin disorders sharing a nucleotide mutation in the β-globin gene, such as homozygous sickle cell anaemia (SS) and sickle cell-hemoglobin C disease (SC), with various clinical severities. SCD patients are characterized by a limited exercise capacity caused by cardio-vascular abnormalities however skeletal muscle implication remains unclear. Recently, few studies characterized skeletal muscle in SS patients and showed an amyotrophy, a profound microvasculature remodelling and a decreased maximal strength however an exercise-induced skeletal muscle dysfunction are yet to described in SCD patients. It was also hypothesized that oxidative stress may be increased and participate in the skeletal muscle abnormalities observed in SCD patients. In healthy subjects, chronic aerobic exercise is known to increase the antioxidant capacity, by increasing antioxidant enzymes levels, in the skeletal muscle. However, the effects of this type exercise have not been described in the skeletal muscle of SCD patients. Hence, the aim of this thesis work is 1) to characterize skeletal muscle function during exercise in S/S et S/C patients and 2) to study the effects of chronic exercise on pro/antioxidant balance in the skeletal muscle of transgenic sickle cell mice. In a first study it was shown that S/S and S/C patients exhibit a profound skeletal muscle dysfunction characterized by a decreased maximal strength and an increased fatigability of the knee extensors. Also, the skeletal muscle dysfunction seems to be explained by intramuscular alterations specific to sickle cell disease rather than the clinical severity. In a second study, Townes sickle cell mice performed 8 weeks of moderate aerobic exercise and we observed an altered response of pro/antioxidant balance in the skeletal muscle of S/S mice. To conclude, the results of this work strengthen the idea that skeletal muscle is key therapeutic target in the exercise rehabilitation of sickle cell disease patients.

Keywords: Skeletal muscle fatigue; sickle cell disorders; oxidative stress; aerobic training.