title: Myocyte-derived Tnfsf14 is a survival factor necessary for myoblast differentiation and skeletal muscle regeneration.
abstract: Adult skeletal muscle tissue has a uniquely robust capacity for regeneration, which gradually declines with aging or is compromised in muscle diseases. The cellular mechanisms regulating adult myogenesis remain incompletely understood. Here we identify the cytokine tumor necrosis factor superfamily member 14 (Tnfsf14) as a positive regulator of myoblast differentiation in culture and muscle regeneration in vivo. We find that Tnfsf14, as well as its cognate receptors herpes virus entry mediator (HVEM) and lymphotoxin β receptor (LTβR), are expressed in both differentiating myocytes and regenerating myofibers. Depletion of Tnfsf14 or either receptor inhibits myoblast differentiation and promotes apoptosis. Our results also suggest that Tnfsf14 regulates myogenesis by supporting cell survival and maintaining a sufficient pool of cells for fusion. In addition, we show that Akt mediates the survival and myogenic function of Tnfsf14. Importantly, local knockdown of Tnfsf14 is found to impair injury-induced muscle regeneration in a mouse model, affirming an important physiological role for Tnfsf14 in myogenesis in vivo. Furthermore, we demonstrate that localized overexpression of Tnfsf14 potently enhances muscle regeneration, and that this regenerative capacity of Tnfsf14 is dependent on Akt signaling. Taken together, our findings reveal a novel regulator of skeletal myogenesis and implicate Tnfsf14 in future therapeutic development.
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Waldemer-Streyer
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival; D053259:Lymphotoxin beta Receptor / Q000378:metabolism; D051379:Mice; D032342:Muscle Cells / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000502:physiology*; D032446:Myoblasts / Q000166:cytology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism*
chemical_list: D053259:Lymphotoxin beta Receptor; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506029:Tnfrsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D051057:Proto-Oncogene Proteins c-akt