ARNT调控低氧通路促进小鼠骨骼肌再生的实验研究

Study on aryl hydrocarbon receptor nuclear translocator regulating hypoxic pathway to promote skeletal muscle regeneration in mice

目的探索芳香烃受体核转运子(aryl hydrocarbon receptornuclear translocator,ARNT)对骨骼肌再生的调控作用,为提高老龄人口骨骼肌再生能力提供方向。方法构建小鼠骨骼肌冰冻损伤模型,观察幼龄鼠与老龄鼠、骨骼肌特异性ARNT基因敲除小鼠与野生鼠、加入低氧通路激活剂(ML228)与DMSO老龄鼠间骨骼肌再生能力差别;分析ARNT、低氧通路、肌再生因子表达含量及小鼠下肢血流差异。结果衰老导致骨骼肌再生能力减弱;敲除ARNT基因后,小鼠骨骼肌的再生能力显著下降,低氧通路因子及相关基因表达下调;ML228可使受损的骨骼肌再生能力得到恢复。结论衰老引起的ARNT含量下降抑制低氧通路是导致老龄骨骼肌再生能力降低的主要原因。低氧通路激活剂可改善受损骨骼肌的再生能力,有望成为药物重塑衰老骨骼肌再生能力的新靶点。

Objective To explore the regulatory role of aryl hydrocarbon receptor nuclear transporter(ARNT)on skeletal muscle regeneration and to provide theories for improving muscle regeneration in aging population.Methods Mice skeletal muscle injury model was constructed.Skeletal muscle regeneration ability was explored between young and old mice,transgenic and wild-type mice,old hypoxia pathway activator(ML228)and DMSO mice following cryoinjury.Whole muscle was obtained and analyzed to evaluate the expressions of ARNT,hypoxia pathway and skeletal muscle regeneration related protein/genes,as well as the blood flow in the lower limbs of mice.Results The regeneration ability of skeletal muscle decreased in aging mice.ARNT gene knockout in young mice hindered skeletal muscle regeneration,as well as down-regulated hypoxia pathway factor and the expressions of related genes.ML228 could restore the regenerative ability of damaged skeletal muscle.Conclusions The inhibition of hypoxia pathway by the decreasing of ARNT content caused by aging is the main reason for the decreasing of skeletal muscle regeneration ability.The pharmacological activator of hypoxia signal improves the regeneration ability of skeletal muscle in the elderly is promising.