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rPLF-1 increased the levels of proliferation-related signal proteins in the gastrocnemius muscle in response to CTX injury. Representative immunoblots and combined quantitative data show increased levels of p-Akt, p-mTOR, p-GSK3α/β, p-Erk1/2, p-p38MAKP, and IL-10 in the muscles of rPLF-1 mice. Results are mean±SE (n=3). ∗p<0.05 and ∗∗p<0.01 vs. corresponding control groups by one-way ANOVA followed by Tukey’s post hoc tests.
Source publication
Background:
We recently demonstrated that proliferin-1 (PLF-1) functions as an apoptotic cell-derived growth factor and plays an important role in vascular pathobiology. We therefore investigated its role in muscle regeneration in response to cardiotoxin injury.
Methods and results:
To determine the effects of PLF-1 on muscle regeneration, we us...
Citations
... We used a small-animal grip strength meter (Columbus Co., Largo, FL) to measure grip strength. When the forelimbs of a mouse whose tail was pulled horizontally by an examiner's hand were no longer able to grasp the strength meter, the indicated force was deemed the maximum grip strength [22]. The grip strength was measured at least three times for each mouse on Days 0, 7, and 14, and the values were averaged as the grip strength value for each of these days. ...
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 C2C12 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.
... 14 Limited previous studies reported that CTSK and CTSS were upregulated during various forms of skeletal muscle atrophy. 2,15,16,17 We also later observed that stressed atherosclerotic lesions showed increased expression of CTSS in mice that underwent carotid artery ligation surgery. 5,7 Finally, a single study reported that CTSS induction is a pathologic event that contributes to the pathogenesis of muscular dystrophy in mdx model mice. ...
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 (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.
... We have demonstrated that aging impaired bone marrow-derived CD34 + integrin α 7 + MuSC mobilization and homing to the skeletal musculature in SAMP10 mice, and these changes were rectified by long-term exercise [5]. Apoptotic cell-derived proliferin-1 has been shown to trigger bone marrow CD34 + integrin α 7 + MuSC mobilization to contribute to muscle repair in mice in response to a cardiotoxin [46]. In the present study, the expression of HGF and VEGF genes was higher in the cell-treated mice compared to the control mice, and double immunofluorescence demonstrated that UC-MSC treatment enhanced the numbers of CD34 + integrin α 7 + cells in the gastrocnemius and soleus muscles. ...
Background
Skeletal muscle mass and function losses in aging individuals are associated with quality of life deterioration and disability. Mesenchymal stromal cells exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in aging-related degenerative disease.
Methods and results
We investigated the efficacy of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) on sarcopenia-related skeletal muscle atrophy and dysfunction in senescence-accelerated mouse prone 10 (SAMP10) mice. We randomly assigned 24-week-old male SAMP10 mice to a UC-MSC treatment group and control group. At 12 weeks post-injection, the UC-MSC treatment had ameliorated sarcopenia-related muscle changes in performance, morphological structures, and mitochondria biogenesis, and it enhanced the amounts of proteins or mRNAs for myosin heavy chain, phospho-AMP-activated protein kinase, phospho-mammalian target of rapamycin, phospho-extracellular signal-regulated kinase1/2, peroxisome proliferator-activated receptor-γ coactivator, GLUT-4, COX-IV, and hepatocyte growth factor in both gastrocnemius and soleus muscles, and it reduced the levels of proteins or mRNAs for cathepsin K, cleaved caspase-3/-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, and gp91 phox mRNAs. The UC-MSC treatment retarded mitochondria damage, cell apoptosis, and macrophage infiltrations, and it enhanced desmin/laminin expression and proliferating and CD34 ⁺ /Integrin α 7 ⁺ cells in both types of skeletal muscle of the SAMP10 mice. In vitro, we observed increased levels of HGF, PAX-7, and MoyD mRNAs at the 4th passage of UC-MSCs.
Conclusions
Our results suggest that UC-MSCs can improve sarcopenia-related skeletal muscle atrophy and dysfunction via anti-apoptosis, anti-inflammatory, and mitochondrial biogenesis mechanisms that might be mediated by an AMPK-PGC1-α axis, indicating that UC-MSCs may provide a promising treatment for sarcopenia/muscle diseases.
