The novel myokine FNDC1 promotes muscle regeneration and alleviates muscular dystrophy

Myogenesis is essential for skeletal muscle formation and regeneration after injury, yet its regulators are largely unknown. Here we identified a previously uncharacterized myokine fibronectin type III domain containing 1 (FNDC1). In vitro studies showed that knockdown of Fndc1 in myoblasts reduced myotube formation, while overexpression of Fndc1 promoted myogenic differentiation. We further generated a truncated recombinant mouse FNDC1 (mFNDC1) that retains reliable activity in promoting myoblast differentiation. Gain- and loss-of-function studies collectively showed that FNDC1 promoted cardiotoxin (CTX)-induced muscle regeneration in adult mice. Furthermore, recombinant FNDC1 treatment ameliorated muscle pathological phenotypes in the mdx mouse model of Duchenne muscular dystrophy. Mechanistically, FNDC1 bound to the integrin α5β1 and activated the downstream FAK/PI3K/AKT/mTOR pathway to promote myogenic differentiation. Pharmacological inhibition of integrin α5β1 or downstream FAK/PI3K/AKT/mTOR pathway abolished the effect of FNDC1 on promoting myogenic differentiation. Collectively, these results suggested that myokine FNDC1 might be an attractive therapeutic agent to regulate myogenic differentiation and muscle regeneration for the treatment of acute and chronic muscle disease.