SYK inhibitor fostamatinib promotes mitochondrial respiratory chain supercomplex formation and improves skeletal muscle function in aged mice

Mitochondria are major organelles involved in energy metabolism and play a crucial role in the function of muscular tissues. Mitochondrial respiratory chain (MRC) complexes are assembled to higher-order “MRC supercomplex (SC)” structures, which has been suggested to promote energy synthesis. We previously reported that inhibition of spleen tyrosine kinase (SYK) promoted SC assembly in muscles, and enhanced exercise performance in young mice. To explore the potential therapeutic relevance of SYK inhibition for age-related muscle dysfunction, we examined the effects of fostamatinib, an approved SYK inhibitor for the treatment of chronic immune thrombocytopenia (ITP), on SC formation and muscle function in aged mice and mouse-derived cells. We demonstrated that the treatment of R406, an active metabolite of fostamatinib, promoted SC formation and enhanced mitochondrial respiration in C2C12 myoblastic cells. Furthermore, administration of fostamatinib promoted SC formation and improved the scores of wire hanging test and grip strength test in aged mice. RNA sequencing analysis revealed that fostamatinib treatment upregulated the expression of genes related to actin nucleation and action potential in quadriceps femoris muscles. These findings suggest that fostamatinib may be useful in improving muscle function and developing new prevention and therapeutic strategies for age-related muscle diseases including sarcopenia.