RIPK3 deficiency ameliorates diabetic sarcopenia through proteostasis regulation by suppressing inflammatory signaling and cellular stress pathways.

Diabetic sarcopenia is a major complication of diabetes severely impacting patient quality of life and increasing mortality risk. Its pathogenesis remains incompletely understood and effective treatments are lacking. This study reveals the critical role and molecular mechanisms of Receptor-interacting protein kinase 3 (RIPK3) in skeletal muscle atrophy during type 1 diabetes mellitus (T1DM). Using RIPK3-knockout diabetic mice, we found that RIPK3 deficiency significantly ameliorated muscle atrophy, as evidenced by increased myofiber cross-sectional area, restored muscle mass, and enhanced exercise capacity.Mechanistically, RIPK3 deletion suppressed chronic inflammation, alleviated cellular stress responses, and improved mitochondrial function. Furthermore, RIPK3 deficiency bidirectionally regulated skeletal muscle proteostasis byinhibiting overactivation of both the ubiquitin-proteasome and autophagy-lysosome systems while promoting protein synthesis pathway.In vitro experiments confirmed that the RIPK3 inhibitor GSK872 mitigated high glucose-induced atrophy in C2C12 myotubes, supporting RIPK3's direct regulatory role in muscle cells.Collectively, this work elucidates how RIPK3 contributes to T1DM-associated sarcopenia through coordinated regulation of proteostasis, inflammatory signaling, and stress responses, providing a theoretical foundation for targeting RIPK3 in the treatment of diabetic sarcopenia.