Cathepsin S deficiency improves muscle mass loss and dysfunction via the modulation of protein metabolism in mice under pathological stress conditions

Cathepsin S (CTSS) is a widely expressed cysteinyl protease that has garnered attention because of its enzymatic and non‐enzymatic functions under inflammatory and metabolic pathological conditions. Here, we examined whether CTSS participates in stress‐related skeletal muscle mass loss and dysfunction, focusing on protein metabolic imbalance. Eight‐week‐old male wildtype (CTSS +/+ ) and CTSS‐knockout (CTSS −/− ) mice were randomly assigned to non‐stress and variable‐stress groups for 2 weeks, and then processed for morphological and biochemical studies. Compared with non‐stressed mice, stressed CTSS +/+ mice showed significant losses of muscle mass, muscle function, and muscle fiber area. In this setting, the stress‐induced harmful changes in the levels of oxidative stress‐related (gp91 phox and p22 phox ,), inflammation‐related (SDF‐1, CXCR4, IL‐1β, TNF‐α, MCP‐1, ICAM‐1, and VCAM‐1), mitochondrial biogenesis‐related (PPAR‐γ and PGC‐1α) genes and/or proteins and protein metabolism‐related (p‐PI3K, p‐Akt, p‐FoxO3α, MuRF‐1, and MAFbx1) proteins; and these alterations were rectified by CTSS deletion. Metabolomic analysis revealed that stressed CTSS −/− mice exhibited a significant improvement in the levels of glutamine metabolism pathway products. Thus, these findings indicated that CTSS can control chronic stress‐related skeletal muscle atrophy and dysfunction by modulating protein metabolic imbalance, and thus CTSS was suggested to be a promising new therapeutic target for chronic stress‐related muscular diseases.