title: 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.
authors.affiliation: Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan;
authors.forename: Tsung-Chuan
authors.initials: TC
authors.lastname: Ho
authors.affiliation: Department of Rehabilitation Medicine, Mackay Memorial Hospital, Taipei, Taiwan;
authors.forename: Yi-Pin
authors.initials: YP
authors.lastname: Chiang
authors.affiliation: Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan; Institute of Biotechnology, National Taipei University of Technology, Taipei, Taiwan; College of Medicine, Fu-Jen Catholic University, Taipei, Taiwan;
authors.forename: Chih-Kuang
authors.initials: CK
authors.lastname: Chuang
authors.affiliation: Department of Microbiology, School of Medicine, National Taiwan University, Taipei, Taiwan; and.
authors.forename: Show-Li
authors.initials: SL
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, Mackay Memorial Hospital, Taipei, Taiwan; Department of Medicine, Nursing and Management College, Taipei, Taiwan.
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Hsieh
authors.affiliation: Department of Ophthalmology, Mackay Memorial Hospital, Taipei, Taiwan; Department of Medicine, Nursing and Management College, Taipei, Taiwan.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Lan
authors.affiliation: Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan; Department of Ophthalmology, Mackay Memorial Hospital, Taipei, Taiwan; yptsao@yahoo.com.
authors.forename: Yeou-Ping
authors.initials: YP
authors.lastname: Tsao
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D005136:Eye Proteins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D032446:Myoblasts / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D015843:Serpins / Q000494:pharmacology*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor
keywords: myoblast; pigment epithelial-derived factor; satellite cell