Ex vivo characterization of skeletal muscle contractility in Townes sickle cell mice

Sickle cell disease is a genetic disorder characterized by the production of mutated hemoglobin, hemoglobin S, which is prone to polymerize under deoxygenated conditions. Polymerization of hemoglobin S causes a mechanical distortion of red blood cells into a crescent-like shape, i.e. sickling. These sickled red blood cells are very fragile and rigid, which may lead to multi-organic complications. Several studies performed in our laboratory, including my PhD work, showed a severe muscle dysfunction characterize by a decrease capacity to generate strength and a higher fatigability. However, the intracellular modifications responsible for the alterations in skeletal muscle function are currently not described in sickle cell disease. It was previously shown that transgenic sickle cell mice exhibited a marked intramuscular acidosis compared to healthy mice during exercise, but it cannot explain solely the skeletal muscle dysfunction. An alteration of calcium homeostasis, which could be the consequence of an elevated oxidative stress, seems to be an interesting hypothesis to explain the skeletal muscle dysfunction in sickle cell disease but such modifications are yet to be described. Hence, my research project as research and teaching assistant is to characterize skeletal muscle contractility ex vivo and the effects of oxidative stress on it in Townes transgenic sickle cell mice, a severe model of the disease. During this project, the contractility of two muscles, the extensor digitum longus and soleus, will be described thanks to force-frequency relation ship followed by a fatiguing protocol. Also, markers of skeletal muscle oxidative stress will be studied before and after this fatiguing protocol.