Effects of hydroxyurea on skeletal muscle energetics and force production in a sickle cell disease murine model

Abstract

Hydroxyurea (HU) is commonly used as a treatment for Sickle Cell Disease (SCD) patients in order to produce fetal hemoglobin beneficial to compensate anemia (reduced oxygen transport), to reduce abnormal Hb content, which alleviate clinical symptoms such as vaso-occlusives crisis and acute chest syndrome. The effects of HU on skeletal muscle bioenergetics in vivo are still unknown. Due to the beneficial effects of HU upon oxygen delivery, we hypothesized that skeletal muscle might be improved by HU. Muscle energetics and function were analyzed during a standardized rest-exercise-recovery protocol, using 31P-Magnetic resonance spectroscopy in Townes SCD mice. Measurements were performed in three groups of mice i.e. SCD2m (2-month-old, n = 8), SCD4m (4-month-old, n = 8) and SCD4m-HU (4-month-old mice which has been treated from 2 months of age with HU at 50 mg/kg/day, n = 8). The 4-month-old untreated mice (SCD4m) were heavier, developed a lower specific force, displayed lower acidosis and force-normalized PCr decrease during stimulation and demonstrated lower cost of contraction than SCD2m mice. Specific force production (from minute 1 to 5.25 of stimulation) was significantly higher in SCD4m-HU than in SCD4m mice whereas muscle energetics was unchanged. Overall, our results support a beneficial effect of HU on muscle function.