Fn14 signaling regulates satellite cell self-renewal and expansion during adult skeletal muscle repair

Abstract

Skeletal muscle regeneration in adults is predominantly driven by satellite cells. Loss of satellite cell pool and function leads to skeletal muscle wasting in many conditions and disease states. Here, we demonstrate that the levels of fibroblast growth factor-inducible 14 (Fn14) are increased in satellite cells after muscle injury. Conditional ablation of Fn14 in Pax7-expressing satellite cells drastically reduces their expansion and skeletal muscle regeneration following injury. Fn14 is required for satellite cell self-renewal and proliferation as well as to prevent precocious differentiation. Targeted deletion of Fn14 inhibits Notch signaling but leads to the spurious activation of STAT3 signaling in regenerating skeletal muscle and in cultured muscle progenitor cells. Silencing of STAT3 improves proliferation and inhibits premature differentiation of Fn14-deficient satellite cells. Furthermore, conditional ablation of Fn14 in satellite cells exacerbates myopathy in the mdx mouse model of Duchenne muscular dystrophy (DMD) whereas its overexpression improves the engraftment of exogenous muscle progenitor cells into the dystrophic muscle of mdx mice. Altogether, our study highlights the crucial role of Fn14 in the regulation of satellite cell fate and function and suggests that Fn14 can be a potential molecular target to improve muscle regeneration in muscular disorders.