TRAF6 regulates satellite stem cell self-renewal and function during regenerative myogenesis
TRAF6 regulates satellite stem cell self-renewal and function during regenerative myogenesis
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DOI：
10.1172/jci81655
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发表时间：
2016-01-01
影响因子：
15.9
通讯作者：
Kumar, Ashok
中科院分区：
文献类型：
--
作者：
Hindi, Sajedah M.;Kumar, Ashok
卫星细胞是成体肌肉中的干细胞群，负责损伤后的肌纤维再生。卫星细胞功能障碍已被证明是许多获得性和遗传性肌肉疾病中骨骼肌质量损失的基础。转录因子配对盒蛋白-7（PAX 7）对于补充卫星细胞库并驱动正常和患病肌肉的再生是不可或缺的。肿瘤坏死因子受体相关因子6（TRAF 6）是一种衔接蛋白和E3泛素连接酶，以环境依赖性方式介导多种细胞信号通路的激活。在这里，我们证明了TRAF 6介导的信号传导对卫星细胞的稳态及其在再生肌发生过程中的功能至关重要。在成年小鼠的卫星细胞中选择性缺失Traf 6导致严重的肌肉再生缺陷，并显着降低PAX 7和晚期肌生成标记物的水平。TRAF 6是激活MAPK ERK 1/2和JNK 1/2所必需的，MAPK 1/2和JNK 1/2又激活转录因子c-JUN，c-JUN结合Pax 7启动子并增强Pax 7表达。此外，TRAF 6/c-JUN信号转导抑制了促进分化的microRNA miR-1和miR-206的水平，以维持卫星细胞中的PAX 7水平。我们还确定了Traf 6的卫星细胞特异性缺失通过钝化损伤肌纤维的再生来夸大mdx（杜氏肌营养不良症的小鼠模型）小鼠中的营养不良表型。总的来说，我们的研究揭示了TRAF 6在卫星干细胞功能中的重要作用。
Satellite cells are a stem cell population within adult muscle and are responsible for myofiber regeneration upon injury. Satellite cell dysfunction has been shown to underlie the loss of skeletal muscle mass in many acquired and genetic muscle disorders. The transcription factor paired box-protein-7 (PAX7) is indispensable for supplementing the reservoir of satellite cells and driving regeneration in normal and diseased muscle. TNF receptor-associated factor 6 (TRAF6) is an adaptor protein and an E3 ubiquitin ligase that mediates the activation of multiple cell signaling pathways in a context-dependent manner. Here, we demonstrated that TRAF6-mediated signaling is critical for homeostasis of satellite cells and their function during regenerative myogenesis. Selective deletion of Traf6 in satellite cells of adult mice led to profound muscle regeneration defects and dramatically reduced levels of PAX7 and late myogenesis markers. TRAF6 was required for the activation of MAPKs ERK1/2 and JNK1/2, which in turn activated the transcription factor c-JUN, which binds the Pax7 promoter and augments Pax7 expression. Moreover, TRAF6/c-JUN signaling repressed the levels of the microRNAs miR-1 and miR-206, which promote differentiation, to maintain PAX7 levels in satellite cells. We also determined that satellite cell-specific deletion of Traf6 exaggerates the dystrophic phenotype in the mdx (a mouse model of Duchenne muscular dystrophy) mouse by blunting the regeneration of injured myofibers. Collectively, our study reveals an essential role for TRAF6 in satellite stem cell function.