PEDF-derived peptide promotes skeletal muscle regeneration through its mitogenic effect on muscle progenitor cells

Abstract

In response injury, intrinsic repair mechanisms are activated in skeletal muscle to replace the damaged muscle fibers with new muscle fibers. The regeneration process starts with the proliferation of satellite cells to give rise to myoblasts, which subsequently differentiate terminally into myofibers. Here, we investigated the promotion effect of pigment epithelial-derived factor (PEDF) on muscle regeneration. We report that PEDF and a synthetic PEDF-derived short peptide (PSP; residues Ser(93)-Leu(112)) induce satellite cell proliferation in vitro and promote muscle regeneration in vivo. Extensively, soleus muscle necrosis was induced in rats by bupivacaine, and an injectable alginate gel was used to release the PSP in the injured muscle. PSP delivery was found to stimulate satellite cell proliferation in damaged muscle and enhance the growth of regenerating myofibers, with complete regeneration of normal muscle mass by 2 wk. In cell culture, PEDF/PSP stimulated C2C12 myoblast proliferation, together with a rise in cyclin D1 expression. PEDF induced the phosphorylation of ERK1/2, Akt, and STAT3 in C2C12 myoblasts. Blocking the activity of ERK, Akt, or STAT3 with pharmacological inhibitors attenuated the effects of PEDF/PSP on the induction of C2C12 cell proliferation and cyclin D1 expression. Moreover, 5-bromo-2'-deoxyuridine pulse-labeling demonstrated that PEDF/PSP stimulated primary rat satellite cell proliferation in myofibers in vitro. In summary, we report for the first time that PSP is capable of promoting the regeneration of skeletal muscle. The signaling mechanism involves the ERK, AKT, and STAT3 pathways. These results show the potential utility of this PEDF peptide for muscle regeneration.

Pigment epithelium-derived factor promotes tumor metastasis through an interaction with laminin receptor in hepatocellular carcinomas

“…PEDF activates the ERK signaling pathway, as indicated by ERK1/2 phosphorylation in mesenchymal stem cells, primary neurons and muscle progenitor cells. 36 , 37 , 38 More importantly, there was a positive correlation between PEDF expression levels and N-cadherin in HCC tissues, and a high co-expression of PEDF and N-cadherin predicted a poorer prognosis. These data suggest that PEDF induces N-cadherin and slug expression and is coupled with E-cadherin attenuation by the activation of ERK1/2, which may be involved in promoting HCC metastasis.…”

Targeted mRNA Decay by RNA Binding Protein AUF1 Regulates Adult Muscle Stem Cell Fate, Promoting Skeletal Muscle Integrity

“…C2C12 cells can mimic the post-activated satellite cell state initiating at the progenitor myoblast level (Ho et al, 2015; Silva et al, 2015). The three largest AUF1 isoforms (p40, p42, p45) are expressed in the proliferating myoblast (Fig.…”

Pigment epithelium‐derived factor peptide promotes limbal stem cell proliferation through hedgehog pathway

“…PEDF was found to cause a striking activation of STAT3 in myoblasts, hepatocytes and LSCs; pharmacological inhibition of STAT3 blocks PEDF function in these cells. 14,23,30 Accordingly, in the present study, we (C) LSCs were exposed to the 44mer for 6 h after pretreated with STAT3 inhibitor. Gli proteins were detected by Western blot analysis.…”