FNDC1 is a myokine that promotes myogenesis and muscle regeneration

Myogenesis is essential for skeletal muscle formation and regeneration after injury, yet its regulators are largely unknown. Here we identified fibronectin type III domain containing 1 (FNDC1) as a previously uncharacterized myokine. In vitro studies showed that knockdown of Fndc1 in myoblasts reduces myotube formation, while overexpression of Fndc1 promotes myogenic differentiation. We further generated recombinant truncated mouse FNDC1 (mFNDC1), which retains reliable activity in promoting myoblast differentiation in vitro. Gain- and loss-of-function studies collectively showed that FNDC1 promotes cardiotoxin (CTX)-induced muscle regeneration in adult mice. Furthermore, recombinant FNDC1 treatment ameliorated pathological muscle phenotypes in the mdx mouse model of Duchenne muscular dystrophy. Mechanistically, FNDC1 bound to the integrin alpha 5 beta 1 and activated the downstream FAK/PI3K/AKT/mTOR pathway to promote myogenic differentiation. Pharmacological inhibition of integrin alpha 5 beta 1 or of the downstream FAK/PI3K/AKT/mTOR pathway abolished the pro-myogenic effect of FNDC1. Collectively, these results suggested that myokine FNDC1 might be used as a therapeutic agent to regulate myogenic differentiation and muscle regeneration for the treatment of acute and chronic muscle disease. Muscle injury induces expression of myokines that promote muscle regeneration. This study identifies the fibronectin domain-containing protein FNDC1 as a myokine that promotes myogenesis and muscle regeneration with potential therapeutic use for treating muscle injuries and related disorders.FNDC1 is a previously uncharacterized myokine that promotes myogenesis.FNDC1 enhances myoblast differentiation and facilitates myofiber formation.Recombinant FNDC1 promotes muscle regeneration and ameliorates muscular dystrophy.FNDC1 interacts with integrin alpha 5 beta 1 to activate the FAK/PI3K/AKT/mTOR signaling pathway for muscle growth and repair. The fibronectin domain-containing protein FNDC1 promotes myogenesis via direct binding to integrin alpha 5 beta 1.