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 α5β1 and activated the downstream FAK/PI3K/AKT/mTOR pathway to promote myogenic differentiation. Pharmacological inhibition of integrin α5β1 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.

中文翻译：

---

FNDC1 是一种促进肌生成和肌肉再生的肌因子。


肌生成对于受伤后骨骼肌的形成和再生至关重要，但其调节因子在很大程度上是未知的。在这里，我们将包含 1 的纤连蛋白 III 型结构域 （FNDC1） 确定为以前未表征的肌因子。体外研究表明，在成肌细胞中敲除 Fndc1 可减少肌管形成，而 Fndc1 过表达可促进肌源性分化。我们进一步生成了重组截短小鼠 FNDC1 （mFNDC1），它在体外促进成肌细胞分化方面保持了可靠的活性。功能获得和丧失研究共同表明，FNDC1 促进心脏毒素 （CTX） 诱导的成年小鼠肌肉再生。此外，重组 FNDC1 治疗改善了杜氏肌营养不良症 mdx 小鼠模型中的病理肌肉表型。机制上，FNDC1 与整合素 α5β1 结合并激活下游 FAK/PI3K/AKT/mTOR 通路以促进肌原分化。整合素 α5β1 或下游 FAK/PI3K/AKT/mTOR 通路的药理学抑制消除了 FNDC1 的促肌作用。总的来说，这些结果表明肌因子 FNDC1 可能用作调节肌源分化和肌肉再生的治疗剂，用于治疗急性和慢性肌肉疾病。