New role for serum response factor in postnatal skeletal muscle growth and regeneration via the interleukin 4 and insulin-like growth factor 1 pathways
New role for serum response factor in postnatal skeletal muscle growth and regeneration via the interleukin 4 and insulin-like growth factor 1 pathways
复制标题
DOI：
10.1128/mcb.00138-06
复制
发表时间：
2006-09-01
影响因子：
5.3
通讯作者：
Tuil, David
中科院分区：
文献类型：
--
作者：
Charvet, Claude;Houbron, Christophe;Tuil, David
血清反应因子（SRF）是肌肉特异性基因表达的关键转录因子。我们研究了SRF功能在成年骨骼肌，使用小鼠有丝分裂后肌纤维靶向中断的SRF基因。突变小鼠表现出严重的骨骼肌质量减少，由于出生后的肌肉生长缺陷，导致高度营养不良的成年肌纤维。SRF耗尽的肌纤维也未能在损伤后再生。缺乏SRF的肌肉具有非常低水平的肌肉肌酸激酶和骨骼α-肌动蛋白（SKA）转录物，并显示基因表达程序的其他改变，表明突变肌肉的整体不成熟。这种SKA表达的丧失，以及β-原肌球蛋白表达的减少，导致了肌纤维生长缺陷，如在突变肌肉中发现的广泛的肌节解体所示。然而，我们观察到突变型肌纤维中白细胞介素4（IL-4）和胰岛素样生长因子1（IGF-1）表达下调，这也可以解释其生长和再生缺陷。事实上，我们在体内证实SRF与白细胞介素4和IGF-1启动子结合，表明SRF在肌肉生长和再生途径中发挥了新的关键作用。
Serum response factor (SRF) is a crucial transcriptional factor for muscle-specific gene expression. We investigated SRF function in adult skeletal muscles, using mice with a postmitotic myofiber-targeted disruption of the SRF gene. Mutant mice displayed severe skeletal muscle mass reductions due to a postnatal muscle growth defect resulting in highly hypotrophic adult myofibers. SRF-depleted myofibers also failed to regenerate following injury. Muscles lacking SRF had very low levels of muscle creatine kinase and skeletal alpha-actin (SKA) transcripts and displayed other alterations to the gene expression program, indicating an overall immaturity of mutant muscles. This loss of SKA expression, together with a decrease in beta-tropomyosin expression, contributed to myofiber growth defects, as suggested by the extensive sarcomere disorganization found in mutant muscles. However, we observed a downregulation of interleukin 4 (IL-4) and insulin-like growth factor 1 (IGF-1) expression in mutant myofibers which could also account for their defective growth and regeneration. Indeed, our demonstration of SRF binding to interleukin 4 and IGF-1 promoters in vivo suggests a new crucial role for SRF in pathways involved in muscle growth and regeneration.