Proliferin-1 Ameliorates Cardiotoxin-Related Skeletal Muscle Repair in Mice

Abstract

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 used a CTX-induced skeletal muscle injury model in 9-week-old male mice that were administered with the recombinant PLF-1 (rPLF-1) or neutralizing PLF-1 antibody. The injured muscles exhibited increased levels of PLF-1 gene expression in a time-dependent manner. On day 14 after injury, rPLF-1 supplementation ameliorated CTX-induced alterations in muscle fiber size, interstitial fibrosis, muscle regeneration capacity, and muscle performance. On day 3 postinjury, rPLF-1 increased the levels of proteins or genes for p-Akt, p-mTOR, p-GSK3α/β, p-Erk1/2, p-p38MAPK, interleukin-10, Pax7, MyoD, and Cyclin B1, and it increased the numbers of CD34+/integrin-α7+ muscle stem cells and proliferating cells in the muscles and/or bone marrow of CTX mice. An enzyme-linked immunosorbent assay revealed that rPLF-1 suppressed the levels of plasma tumor necrosis factor-α and interleukin-1β in CTX mice. PLF-1 blocking accelerated CTX-related muscle damage and dysfunction. In C2C12 myoblasts, rPLF-1 increased the levels of proteins for p-Akt, p-mTOR, p-GSK3α/β, p-Erk1/2, and p-p38MAPK as well as cellular functions; and these effects were diminished by the depletion of PLF-1 or silencing of its mannose-6-phosphate receptor. Conclusions. These findings demonstrated that PLF-1 can improve skeletal muscle repair in response to injury, possibly via the modulation of inflammation and proliferation and regeneration, suggesting a novel therapeutic strategy for the management of skeletal muscle diseases.

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

“…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.…”

“…In addition, CTSS activity was shown to control injury‐induced experimental hyperplasia via the modulation of the p38 mitogen‐activated protein kinase (p38‐MAPK)/protein kinase B (Akt)‐histone deacetylases‐6 signaling pathway in mice 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 .…”

Human umbilical cord-derived mesenchymal stromal cells ameliorate aging-associated skeletal muscle atrophy and dysfunction by modulating apoptosis and mitochondrial damage in SAMP10 mice

“…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.…”