Cathepsin K activity controls cardiotoxin‐induced skeletal muscle repair in mice

Abstract

BackgroundCathepsin K (CatK) is a widely expressed cysteine protease that has gained attention because of its enzymatic and non‐enzymatic functions in signalling. Here, we examined whether CatK‐deficiency (CatK−/−) would mitigate injury‐related skeletal muscle remodelling and fibrosis in mice, with a special focus on inflammation and muscle cell apoptosis.MethodsCardiotoxin (CTX, 20 μM/200 μL) was injected into the left gastrocnemius muscle of male wild‐type (CatK+/+) and CatK−/− mice, and the mice were processed for morphological and biochemical studies.ResultsOn post‐injection Day 14, CatK deletion ameliorated muscle interstitial fibrosis and remodelling and performance. At an early time point (Day 3), CatK−/− reduced the lesion macrophage and leucocyte contents and cell apoptosis, the mRNA levels of monocyte chemoattractant protein‐1, toll‐like receptor‐2 and toll‐like receptor‐4, and the gelatinolytic activity related to matrix metalloproteinase‐2/‐9. CatK deletion also restored the protein levels of caspase‐3 and cleaved caspase‐8 and the ratio of the BAX to the Bcl‐2. Moreover, CatK deficiency protected muscle fibre laminin and desmin disorder in response to CTX injury. These beneficial muscle effects were mimicked by CatK‐specific inhibitor treatment. In vitro experiments demonstrated that pharmacological CatK inhibition reduced the apoptosis of C2C12 mouse myoblasts and the levels of BAX and caspase‐3 proteins induced by CTX.ConclusionsThese results demonstrate that CatK plays an essential role in skeletal muscle loss and fibrosis in response to CTX injury, possibly via a reduction of inflammation and cell apoptosis, suggesting a novel therapeutic strategy for the control of skeletal muscle diseases by regulating CatK activity.

Cysteine Cathepsins and Their Extracellular Roles: Shaping the Microenvironment

“…Recent in silico and in vitro studies reported that cathepsins K, L, and S could cleave fibrinogen and fibrin, resulting in fragments that differ from the ones produced by plasmin, which opened the door to further investigate their roles in vascular homeostasis, especially in coagulation-associated diseases [174,175]. Moreover, cathepsin K was recently demonstrated to have an essential role in skeletal muscle remodeling, dysfunction, and fibrosis following injury [176]. The roles of cysteine cathepsins in tissue remodeling are diverse and can be both detrimental and beneficial; therefore, cysteine cathepsins are emerging as possible targets in therapeutic strategies.…”

Lycopene restores the effect of ischemic postconditioning on myocardial ischemia‑reperfusion injury in hypercholesterolemic rats

“…In this model, the ischemic heart was only subjected to 60-120 min reperfusion and then harvested (44). Therefore, cardiac fibrosis or remodeling, including changes in histology and protein biomarkers (matrix metallopeptidase-2/-9 and cathepsins S/K) (45-48), could not be observed in this model within this short period of time. Finally, considerable evidence indicates that reactive oxygen species (ROS) have a predominant role in myocardial damage induced by reperfusion (49,50).…”

Palmitoyl Protein Thioesterase 1 Is Essential for Myogenic Autophagy of C2C12 Skeletal Myoblast

“…Phosphorylation of TFEB, a well-known master controller of lysosomal biogenesis ( Vega-Rubin-De-Celis et al, 2017 ), was also elevated and translocated from the cytosol to the nucleus during muscle differentiation ( Figure 4A ). In addition, as number of increased lysosome, we investigated activity of Cathepsin B, D, and K, well-known represented lysosomal hydrolase ( Kirschke et al, 1983 ; Colella et al, 1986 ; Bechet et al, 1991 ; Ebisui et al, 1994 ; Ogasawara et al, 2018 ). Cathepsin B, D, and K activities were elevated during muscle differentiation ( Figure 4B ).…”