The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling

Metabolic stress and changes in nutrient levels modulate many aspects of skeletal muscle function during aging and disease. Growth factors and cytokines secreted by skeletal muscle, known as myokines, are important signaling factors but it is largely unknown whether they modulate muscle growth and differentiation in response to nutrients. Here, we find that changes in glucose levels increase the activity of the glucose-responsive transcription factor MLX, which promotes and is necessary for myoblast fusion. MLX promotes myogenesis not via an adjustment of glucose metabolism but rather by inducing the expression of several myokines, including insulin like-growth factor-2 (IGF2), whereas RNAi and dominant-negative MLX reduce IGF2 expression and block myogenesis. This phenotype is rescued by conditioned media from control muscle cells and by recombinant IGF2, which activates the myogenic kinase Akt. Importantly, MLX null mice display decreased IGF2 induction and diminished muscle regeneration in response to injury, indicating that the myogenic function of MLX is conserved in vivo. Thus, glucose is a signaling molecule that regulates myogenesis and muscle regeneration via MLX/IGF2/Akt signaling. The data pproided are histome H4 acetlation data for MLX DN and MLX wt samples; 3 MLX DN H4 Ac Chip seq samples , 3 Inputs, 3 MLX WT H4 Ac samples and 3 WT inputs

代谢应激与营养水平变化，可调控衰老及疾病状态下骨骼肌功能的诸多方面。由骨骼肌分泌的生长因子与细胞因子（myokines，肌因子）是重要的信号分子，但目前尚不清楚它们是否会响应营养信号调控肌肉生长与分化。本研究发现，葡萄糖水平变化可提升葡萄糖响应性转录因子MLX的活性，该因子可促进且是成肌细胞融合所必需的。MLX并非通过调控葡萄糖代谢，而是通过诱导包括胰岛素样生长因子-2（IGF2）在内的多种肌因子的表达来促进肌发生；而RNA干扰（RNAi）与显性负效MLX则会降低IGF2的表达并阻断肌发生过程。该表型可被对照肌细胞的条件培养基以及可激活成肌激酶Akt的重组IGF2所挽救。值得注意的是，MLX敲除小鼠的IGF2诱导水平下降，且损伤后的肌肉再生能力减弱，这表明MLX的成肌功能在体内是保守的。综上，葡萄糖是一种通过MLX/IGF2/Akt信号通路调控肌发生与肌肉再生的信号分子。本次提供的数据为MLX显性负效（MLX DN）与MLX野生型（MLX WT）样本的组蛋白H4乙酰化数据：包含3份MLX DN组蛋白H4乙酰化染色质免疫共沉淀测序（ChIP-seq）样本、3份输入对照样本、3份MLX WT组蛋白H4乙酰化样本以及3份野生型输入对照样本。