Division of Biology, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Exp Cell Res. 2010 Oct 15;316(17):2932-44. doi: 10.1016/j.yexcr.2010.08.001. Epub 2010 Aug 6.
Muscle satellite cells are essential for muscle growth and regeneration and their morphology, behavior and gene expression have been extensively studied. However, the mechanisms involved in their proliferation and differentiation remain elusive. Six1 and Six4 proteins were expressed in the nuclei of myofibers of adult mice and the numbers of myoblasts positive for Six1 and Six4 increased during regeneration of skeletal muscles. Six1 and Six4 were expressed in quiescent, activated and differentiated muscle satellite cells isolated from adult skeletal muscle. Overexpression of Six4 and Six5 repressed the proliferation and differentiation of satellite cells. Conversely, knockdown of Six5 resulted in augmented proliferation, and that of Six4 inhibited differentiation. Muscle satellite cells isolated from Six4(+/-)Six5(-/-) mice proliferated to higher cell density though their differentiation was not altered. Meanwhile, overproduction of Six1 repressed proliferation and promoted differentiation of satellite cells. In addition, Six4 and Six5 repressed, while Six1 activated myogenin expression, suggesting that the differential regulation of myogenin expression is responsible for the differential effects of Six genes. The results indicated the involvement of Six genes in the behavior of satellite cells and identified Six genes as potential target for manipulation of proliferation and differentiation of muscle satellite cells for therapeutic applications.
肌卫星细胞对于肌肉生长和再生至关重要，其形态、行为和基因表达已得到广泛研究。然而，其增殖和分化的机制仍不清楚。Six1 和 Six4 蛋白在成年小鼠肌纤维的核内表达，在骨骼肌再生过程中，Six1 和 Six4 阳性的成肌细胞数量增加。Six1 和 Six4 在从成年骨骼肌分离的静止、激活和分化的肌卫星细胞中表达。Six4 和 Six5 的过表达抑制卫星细胞的增殖和分化。相反，Six5 的敲低导致增殖增加，Six4 的敲低则抑制分化。Six4(+/-)Six5(-/-) 小鼠的肌卫星细胞尽管分化未改变，但增殖到更高的细胞密度。同时，Six1 的过表达抑制增殖并促进卫星细胞的分化。此外，Six4 和 Six5 抑制，而 Six1 激活肌生成素表达，表明肌生成素表达的差异调节是 Six 基因产生不同作用的原因。结果表明 Six 基因参与了卫星细胞的行为，并将 Six 基因鉴定为用于治疗应用的肌肉卫星细胞增殖和分化的潜在靶标。
