GBT1118 voxelotor analog improves skeletal muscle function, phenotype and significantly reduced serum myopathy biomarker GDF15 in sickle cell disease mice

We examined the effect of GBT1118, a sickle hemoglobin polymerization inhibitor on skeletal muscle grip strength and phenotype in Townes sickle cell disease (SCD) mouse model. Control male and female mice were fed with control Vehicle-chow for 2-months, while SCD male and female mice were fed with Vehicle-chow or 2-hydroxy-6-(2S)-1-(pyridine-3-carbonyl)piperidin-2ylmethoxy (GBT1118)-chow for 2-months. We first confirmed significantly reduced hematocrit in both SCD males and females, that was significantly improved with GBT1118. Analysis of muscle function by grip strength measurement revealed significantly decreased grip strength in both SCD male and female mice that was significantly rescued by GBT1118. To assess whether there was phenotypic evidence of damaged skeletal muscle, histologic analysis of tibialis anterior muscle was performed. Muscle size determined using Laminin 2a stained muscle sections revealed significantly decreased fiber cross-sectional area in SCD females that was significantly increased by GBT1118. However, fiber size was similar in Control and SCD male mice and was not modulated by GBT1118. Hematoxylin Eosin staining revealed markedly increased fibrosis and inflammatory cells in tibialis anterior muscle of both sexes of SCD mice that was not reduced by GBT1118. Picrosirius-red staining revealed markedly increased collagen accumulation in muscle of both sexes that was reduced with GBT1118. Interestingly Oil red-O staining revealed markedly increased fat accumulation in tibialis muscle of SCD mice of both sexes that was markedly reduced with GBT1118. We made the novel observation that Growth and Differentiation Factor 15 (GDF15) a serum biomarker of muscle pathology that was significantly increased in serum of SCD mice of both sexes was significantly reduced by GBT1118. We conclude that GBT1118 might has the potential to enhance certain parameters of skeletal muscle dysfunction in older SCD mice. • GBT1118 increases hematocrit in male and female SCD mice. • GBT1118 improves skeletal muscle grip strength in SCD mice. • GBT1118 rescues reduced muscle fiber size in SCD females. • GBT1118 reduces muscle fibrosis, fat accumulation, and macrophages. • GBT1118 lowers circulating GDF15, a novel SCD myopathy biomarker.