Characterizing FDA-Approved Drugs Targeting Staufen1 as Therapeutics Against Skeletal Muscle Atrophy

Abstract

Skeletal muscle atrophy is a debilitating condition characterized by progressive muscle mass loss and functional decline, commonly associated with aging, physical inactivity, denervation, cachexia, and various chronic diseases. Previous work from our laboratory demonstrated that transgenic overexpression of STAU1 in mouse skeletal muscle induces muscle atrophy, suggesting that STAU1 functions as a novel atrogene. More recently, we observed an early and transient increase in STAU1 expression across multiple models of muscle atrophy, including starvation-induced atrophy in C2C12 myotubes, muscle samples in a denervation model, and human participants undergoing bed rest or dry immersion. Importantly, genetic knockdown of STAU1 during atrophic condition preserved myofiber diameter, supporting a causal role for STAU1 in the initiation of muscle wasting. However, whether STAU1 can be effectively targeted using pharmacological approaches remains unknown. To explore potential therapeutic strategies, we aimed to identify FDA-approved compounds capable of reducing STAU1 expression during atrophy. A high-throughput ELISA-based screen of 770 FDA-approved drugs was conducted in myoblasts to assess their ability to downregulate STAU1 protein levels. Using our established in vitro atrophy model, three candidate drugs (11, 12, and 15) were identified that significantly reduced STAU1 mRNA and protein expression and preserved myotube diameter, thereby attenuating atrophy. Subsequently, Drugs 12 and 15 were evaluated both in vitro and in vivo using C2C12 myotubes and male and female mice subjected to sciatic nerve denervation followed by daily drug administration. STAU1 inhibition preserves myotube integrity during acute atrophic stress in vitro. However, in vivo treatment following denervation did not significantly prevent muscle loss, indicating that while STAU1 contributes to early atrophic responses, its inhibition alone is insufficient to mitigate denervation-induced skeletal muscle atrophy. Collectively, these findings indicate that although STAU1 inhibition is protective in vitro, it does not confer significant protection against denervation-induced muscle atrophy in vivo. Further studies are warranted to identify more effective modulators of STAU1 or complementary pathways to mitigate skeletal muscle atrophy.