Affiliation:
1. Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular Disease Yanbian University Hospital Yanji P.R. China
2. Jilin Provincial Key Laboratory of Stress and Cardiovascular Disease Yanbian University Hospital Yanji P.R. China
3. Institute of Nano‐Life‐Systems, Innovation for Future Society Nagoya University Institutes of Innovation for Future Society Nagoya Japan
4. Department of Vascular Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou China
5. Department of Neurology University of Occupational and Environmental Health Kitakyushu Japan
6. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA
7. Meitetsu Hospital Nagoya Japan
Abstract
AbstractCathepsin 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 (gp91phox and p22phox,), 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.
Funder
Foundation for Innovative Research Groups of the National Natural Science Foundation of China
Subject
Genetics,Molecular Biology,Biochemistry,Biotechnology