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

Ying Wan; Limei Piao; Shengnan Xu; Aiko Inoue; Xiangkun Meng; Yanna Lei; Zhe Huang; Hailong Wang; Xueling Yue; Guo-Ping Shi; Masafumi Kuzuya; Xian Wu Cheng

doi:10.1096/fj.202300395RRR

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

FASEB J. 2023 Aug;37(8):e23086. doi: 10.1096/fj.202300395RRR.

Authors

Ying Wan^{1

2}, Limei Piao^{1

2}, Shengnan Xu^{1

2}, Aiko Inoue³, Xiangkun Meng⁴, Yanna Lei^{1

2}, Zhe Huang⁵, Hailong Wang^{1

2}, Xueling Yue^{1

2}, Guo-Ping Shi⁶, Masafumi Kuzuya^{3

7}, Xian Wu Cheng^{1

2}

Affiliations

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.

PMID: 37428652
DOI: 10.1096/fj.202300395RRR

Abstract

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.

Keywords: cathepsin Sinflammationmuscle atrophystress; oxidative stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cathepsins / metabolism
Male
Mice
Muscle Fibers, Skeletal / metabolism
Muscular Diseases* / metabolism
Oxidative Stress*

Substances

cathepsin S
Cathepsins