In:
Cellular and Molecular Life Sciences, Springer Science and Business Media LLC, Vol. 80, No. 9 ( 2023-09)
Kurzfassung:
Exposure to chronic psychological stress (CPS) is an intractable risk factor for inflammatory and metabolic diseases. Lysosomal cysteinyl cathepsins play an important role in human pathobiology. Given that cathepsin S (CTSS) is upregulated in the stressed vascular and adipose tissues, we investigated whether CTSS participates in chronic stress-induced skeletal muscle mass loss and dysfunction, with a special focus on muscle protein metabolic imbalance and apoptosis. Eight-week-old male wildtype (CTSS +/+ ) and CTSS-knockout (CTSS −/− ) mice were randomly assigned to non-stress and variable-stress groups. CTSS +/+ stressed mice showed significant losses of muscle mass, dysfunction, and fiber area, plus significant mitochondrial damage. In this setting, stressed muscle in CTSS +/+ mice presented harmful alterations in the levels of insulin receptor substrate 2 protein content (IRS-2), phospho-phosphatidylinositol 3-kinase, phospho-protein kinase B, and phospho-mammalian target of rapamycin, forkhead box-1, muscle RING-finger protein-1 protein, mitochondrial biogenesis-related peroxisome proliferator-activated receptor-γ coactivator-α, and apoptosis-related B-cell lymphoma 2 and cleaved caspase-3; these alterations were prevented by CTSS deletion. Pharmacological CTSS inhibition mimics its genetic deficiency-mediated muscle benefits. In C 2 C 12 cells, CTSS silencing prevented stressed serum- and oxidative stress-induced IRS-2 protein reduction, loss of the myotube myosin heavy chain content, and apoptosis accompanied by a rectification of investigated molecular harmful changes; these changes were accelerated by CTSS overexpression. These findings demonstrated that CTSS plays a role in IRS-2-related protein anabolism and catabolism and cell apoptosis in stress-induced muscle wasting, suggesting a novel therapeutic strategy for the control of chronic stress-related muscle disease in mice under our experimental conditions by regulating CTSS activity.
Materialart:
Online-Ressource
ISSN:
1420-682X
,
1420-9071
DOI:
10.1007/s00018-023-04888-4
Sprache:
Englisch
Verlag:
Springer Science and Business Media LLC
Publikationsdatum:
2023
ZDB Id:
1458497-9
SSG:
12
