title: Genetic ablation of TWEAK augments regeneration and post-injury growth of skeletal muscle in mice.
abstract: Impairment in the regeneration process is a critical determinant for skeletal muscle wasting in chronic diseases and degenerative muscle disorders. Inflammatory cytokines are known to cause significant muscle wasting, however, their role in myofiber regeneration is less clear. In this study we have investigated the role of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in skeletal muscle regeneration in vivo. Our results show that expression levels of TWEAK and its receptor Fn14 are significantly increased in skeletal muscles of mice after injury. Genetic deletion of TWEAK increased the fiber cross-sectional area and levels of embryonic isoform of myosin heavy chain in regenerating tibial anterior muscle. Conversely, muscle-specific transgenic overexpression of TWEAK reduced the fiber cross-sectional area and levels of the embryonic myosin heavy chain in regenerating muscle. TWEAK induced the expression of several inflammatory molecules and increased interstitial fibrosis in regenerating muscle. Genetic ablation of TWEAK suppressed, whereas overexpression of TWEAK increased, the activation of nuclear factor-kappa B without affecting the activation of Akt or p38 kinase in regenerating myofibers. Primary myoblasts from TWEAK-null mice showed enhanced differentiation in vitro, whereas myoblasts from TWEAK-Tg mice showed reduced differentiation compared with wild-type mice. Collectively, our study suggests that TWEAK negatively regulates muscle regeneration and that TWEAK is a potential therapeutic target to enhance skeletal muscle regeneration in vivo.
authors: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
authors: Ashwani
authors: A
authors: Mittal
authors: Shephali
authors: S
authors: Bhatnagar
authors: Akhilesh
authors: A
authors: Kumar
authors: Pradyut K
authors: PK
authors: Paul
authors: Shihuan
authors: S
authors: Kuang
authors: Ashok
authors: A
authors: Kumar
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000293:injuries / Q000502:physiology*; D032446:Myoblasts / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012038:Regeneration / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000502:physiology*
chemical_list: D000074049:Cytokine TWEAK; D016328:NF-kappa B; D012333:RNA, Messenger; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D051057:Proto-Oncogene Proteins c-akt