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.
Highlights
Upon injury, these quiescent satellite cells are reactivated and begin to proliferate.[1,2] Effective myogenesis depends on the daughter myoblasts successfully differentiating and fusing with each other to regenerate the characteristic multinucleated skeletal myofibers
The function of cytokines in myogenesis is relevant to our understanding of basic muscle physiology, and the diseases that negatively affect the health of muscle tissue, such as cachexia
We found that knockdown of Tnfsf[14] (Figure 1a) significantly impaired C2C12 myotube formation, as indicated by myosin heavy chain (MHC) staining of the myocytes and quantification of the fusion index (Figure 1b)
Summary
These quiescent satellite cells are reactivated and begin to proliferate.[1,2] Effective myogenesis depends on the daughter myoblasts successfully differentiating and fusing with each other to regenerate the characteristic multinucleated skeletal myofibers. This involves a number of highly regulated steps, including activation of myogenic genes, migration, cell–cell adhesion and alignment, and membrane fusion.[3,4,5] The fundamental principles underlying each step are well-conserved across species.[6] Pathologies may result from dysregulation of these processes, including the suite of muscular dystrophies, cachexia and sarcopenia. Through its receptors in the TNF receptor (TNFR) superfamily, HVEM (TNFRSF14) and lymphotoxin β receptor (LTβR), Tnfsf[14] signaling is involved in lymphoid organ development and organization, as well as innate and adaptive immune responses.[17,18,19] In recent years, Tnfsf[14]
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