Maintaining myoprotein and redox homeostasis via an orally recharged nanoparticulate supplement potentiates sarcopenia treatment.

Sarcopenia is a progressive skeletal muscle disorder characterized by the accelerated loss of muscle mass and function, with no promising pharmacotherapies. Understanding the imbalance of myoprotein homeostasis within myotubes, which causes sarcopenia, may facilitate the development of novel treatments for clinical use. In this study, we found a strong correlation between low serum selenium levels and muscle function in elderly patients with sarcopenia. We hypothesized that supplementation with selenium might be beneficial for the management of sarcopenia. To verify this hypothesis, we developed diselenide-bridged mesoporous silica nanoparticles (Se-Se-MSNs) with ROS-responsive degradation and release to supplement selenium. Se-Se-MSNs outperformed free selenocysteine in alleviating sarcopenia in both dexamethasone (Dex)- and denervation-induced mouse models. Subsequently, Se-Se-MSNs were loaded with leucine (Leu@Se-Se-MSNs), another nutritional supplement used in sarcopenia management. Oral administration of Leu@Se-Se-MSNs restored myoprotein homeostasis by enhancing mTOR/S6K signaling and inactivating Akt/FoxO3a/MuRF1 signaling, thus exerting optimal therapeutic effects against sarcopenia and exhibiting a more favorable in vivo safety profile. This study provides a proof of concept for treating sarcopenia by maintaining myoprotein and redox homeostasis simultaneously and offers valuable insights into the development of multifunctional nanoparticle-based supplements for sarcopenia management.