Lillehei Heart Institute, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA.
J Cell Sci. 2012 Nov 15;125(Pt 22):5329-37. doi: 10.1242/jcs.105239. Epub 2012 Sep 6.
In response to severe injury, adult skeletal muscle exhibits a remarkable regenerative capacity due to a resident muscle stem/progenitor cell population. While a number of factors are expressed in the muscle progenitor cell (MPC) population, the molecular networks that govern this cell population remain an area of active investigation. In this study, utilizing knockdown techniques and overexpression of Foxk1 in the myogenic lineage, we observed dysregulation of Foxo and Mef2 downstream targets. Utilizing an array of technologies, we establish that Foxk1 represses the transcriptional activity of Foxo4 and Mef2 and physically interacts with Foxo4 and Mef2, thus promoting MPC proliferation and antagonizing the myogenic lineage differentiation program, respectively. Correspondingly, knockdown of Foxk1 in C2C12 myoblasts results in cell cycle arrest, and Foxk1 overexpression in C2C12CAR myoblasts retards muscle differentiation. Collectively, we have established that Foxk1 promotes MPC proliferation by repressing Foxo4 transcriptional activity and inhibits myogenic differentiation by repressing Mef2 activity. These studies enhance our understanding of the transcriptional networks that regulate the MPC population and muscle regeneration.
针对严重损伤，成体骨骼肌由于存在肌源性干细胞/前体细胞群而表现出显著的再生能力。虽然在肌源性祖细胞（MPC）群中表达了许多因子，但调控该细胞群的分子网络仍然是一个活跃的研究领域。在这项研究中，我们利用敲低技术和 Foxk1 在肌源性谱系中的过表达，观察到 Foxo 和 Mef2 下游靶标的失调。利用一系列技术，我们确定 Foxk1 抑制 Foxo4 和 Mef2 的转录活性，并与 Foxo4 和 Mef2 发生物理相互作用，从而分别促进 MPC 增殖和拮抗肌源性谱系分化程序。相应地，在 C2C12 成肌细胞中敲低 Foxk1 导致细胞周期停滞，而在 C2C12CAR 成肌细胞中过表达 Foxk1 则延迟肌肉分化。总之，我们已经确定 Foxk1 通过抑制 Foxo4 的转录活性促进 MPC 增殖，并通过抑制 Mef2 的活性抑制肌源性分化。这些研究增强了我们对调控 MPC 群体和肌肉再生的转录网络的理解。
