Indoxyl Sulfate and Soluble Prorenin Receptor Axis Contributes to Sarcopenia in Maintenance Hemodialysis Patients by Inducing Mitochondrial Damage: An Integrated Clinical and Experimental Study.

PURPOSE: This study aims to elucidate the role of indoxyl sulfate (IS) and soluble (pro)renin receptor [s(P)RR] in sarcopenia among maintenance hemodialysis (MHD) patients, integrating clinical observations with in vitro mechanistic investigations. METHODS: A single-center cross-sectional study enrolled 141 MHD patients to analyze correlations between serum IS, s(P)RR, and sarcopenia parameters. Multivariate logistic regression was conducted to determine independent predictors of sarcopenia in MHD patients. Mechanistic insights were derived from C2C12 myotube experiments, including myostatin (MSTN) knockdown and renin-angiotensin system (RAS) inhibition, to evaluate IS- and s(P)RR-induced mitochondrial dysfunction, oxidative stress, and atrophy. RESULTS: Sarcopenic patients exhibited elevated IS and s(P)RR levels and impaired physical performance. s(P)RR independently predicted sarcopenia. In vitro, IS upregulated s(P)RR, suppressed peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) and nuclear respiratory factor-1 (Nrf-1), and induced mitochondrial dysfunction, oxidative stress, and myotube atrophy, which were rescued by s(P)RR inhibition. Recombinant s(P)RR suppressed PGC1α and Nrf-1 expression, exacerbating mitochondrial damage and atrophy in C2C12 myotubes, which were reversed by PGC1α overexpression. MSTN knockdown attenuated IS-induced myotube atrophy, oxidative stress, and PGC1α downregulation, effects reversed by s(P)RR. Similarly, RAS blockade ameliorated IS-induced myotube atrophy and s(P)RR upregulation, and restored PGC1α expression. CONCLUSION: Clinical data reveal significant associations between IS, s(P)RR, and sarcopenia in MHD patients. In vitro experiments further indicate that the IS-s(P)RR-PGC1α/Nrf-1 axis, with MSTN and the RAS as key mediators, contributes to muscle atrophy via mitochondrial dysfunction and oxidative stress. s(P)RR emerges as a novel diagnostic biomarker and a modifiable target, providing a foundation for further translational studies.