https://ror.org/048sx0r50 Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX, USA.
https://ror.org/048sx0r50 Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
Life Sci Alliance. 2023 Oct 9;6(12). doi: 10.26508/lsa.202302312. Print 2023 Dec.
Skeletal muscle regeneration involves coordinated activation of an array of signaling pathways. Fibroblast growth factor-inducible 14 (Fn14) is a bona fide receptor for the TWEAK cytokine. Levels of Fn14 are increased in the skeletal muscle of mice after injury. However, the cell-autonomous role of Fn14 in muscle regeneration remains unknown. Here, we demonstrate that global deletion of the Fn14 receptor in mice attenuates muscle regeneration. Conditional ablation of Fn14 in myoblasts but not in differentiated myofibers of mice inhibits skeletal muscle regeneration. Fn14 promotes myoblast fusion without affecting the levels of myogenic regulatory factors in the regenerating muscle. Fn14 deletion in myoblasts hastens initial differentiation but impairs their fusion. The overexpression of Fn14 in myoblasts results in the formation of myotubes having an increased diameter after induction of differentiation. Ablation of Fn14 also reduces the levels of various components of canonical Wnt and calcium signaling both in vitro and in vivo. Forced activation of Wnt signaling rescues fusion defects in Fn14-deficient myoblast cultures. Collectively, our results demonstrate that Fn14-mediated signaling positively regulates myoblast fusion and skeletal muscle regeneration.
骨骼肌再生涉及一系列信号通路的协调激活。成纤维细胞生长因子诱导 14（Fn14）是 TWEAK 细胞因子的真正受体。损伤后，小鼠骨骼肌中 Fn14 的水平增加。然而，Fn14 在肌肉再生中的细胞自主作用尚不清楚。在这里，我们证明了小鼠中 Fn14 受体的全局缺失会减弱肌肉再生。在小鼠中，成肌细胞中 Fn14 的条件性缺失而不是分化的肌纤维中 Fn14 的缺失抑制了骨骼肌再生。Fn14 促进成肌细胞融合，而不影响再生肌肉中肌生成调节因子的水平。成肌细胞中 Fn14 的缺失会加速初始分化，但会损害它们的融合。成肌细胞中 Fn14 的过表达导致分化诱导后形成的肌管直径增加。Fn14 的缺失还会降低体外和体内各种经典 Wnt 和钙信号成分的水平。Wnt 信号的强制激活可挽救 Fn14 缺陷的成肌细胞培养物中的融合缺陷。总之，我们的结果表明，Fn14 介导的信号正向调节成肌细胞融合和骨骼肌再生。
