Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy.
Cell Death Dis. 2010 Apr 29;1(4):e38. doi: 10.1038/cddis.2010.17.
This study shows that forcing c-Flip overexpression in undifferentiated skeletal myogenic cells in vivo results in early aging muscle phenotype. In the transgenic mice, adult muscle histology, histochemistry and biochemistry show strong alterations: reduction of fibers size and muscle mass, mitochondrial abnormalities, increase in protein oxidation and apoptosis markers and reduced AKT/GSK3β phosphorylation. In the infant, higher levels of Pax-7, PCNA, P-ERK and active-caspase-3 were observed, indicating enhanced proliferation and concomitant apoptosis of myogenic precursors. Increased proliferation correlated with NF-κB activation, detected as p65 phosphorylation, and with high levels of embryonic myosin heavy chain. Reduced regenerative potential after muscle damage in the adult and impaired fiber growth associated with reduced NFATc2 activation in the infant were also observed, indicating that the satellite cell pool is prematurely compromised. Altogether, these data show a role for c-Flip in modulating skeletal muscle phenotype by affecting the proliferative potential of undifferentiated cells. This finding indicates a novel additional mechanism through which c-Flip might possibly control tissue remodeling.
本研究表明，在体内将 c-Flip 强制过表达于未分化的骨骼肌成肌细胞中会导致早期衰老的肌肉表型。在转基因小鼠中，成年肌肉组织学、组织化学和生物化学显示出强烈的改变：纤维大小和肌肉质量减少、线粒体异常、蛋白质氧化和凋亡标志物增加以及 AKT/GSK3β 磷酸化减少。在婴儿中，观察到更高水平的 Pax-7、PCNA、P-ERK 和活性 caspase-3，表明成肌前体细胞的增殖增强和伴随的凋亡。增殖增加与 NF-κB 激活相关，检测到 p65 磷酸化，并与高水平的胚胎肌球蛋白重链相关。在成年后的肌肉损伤后再生潜力降低，以及与 NFATc2 激活减少相关的纤维生长受损也被观察到，表明卫星细胞池过早受损。总的来说，这些数据表明 c-Flip 通过影响未分化细胞的增殖潜力来调节骨骼肌表型。这一发现表明 c-Flip 可能通过一种新的附加机制来控制组织重塑。
