TAK1 signaling in skeletal muscle

摘要 骨骼肌质量损失是多种疾病的毁灭性并发症， 条件然而，仍然没有批准的治疗方法来防止肌肉萎缩，部分原因是 调节骨骼肌质量的机制仍然是个谜。越来越多的证据表明 一系列的信号通路主要通过调节骨骼肌的蛋白质来调节骨骼肌质量。 蛋白质合成和降解的速率。然而，涉及的上游信号传导机制 在调节肌肉质量方面的作用仍然知之甚少。在本项目目前的资助期间， 我们发现TRAF 6在多种分解代谢中介导肌肉萎缩并抑制肌肉再生， 条件我们还证明TRAF 6和TAK 1是卫星细胞的重要调节因子， 成人骨骼肌内稳态。与TRAF 6相反，TRAF 6的激活会导致肌肉 我们发现TAK 1对骨骼肌的生长和维持是必不可少的， 成人的肌肉质量。小鼠中TAK 1的诱导性肌纤维特异性失活（以下简称TAK 1 mko） 导致严重的肌肉萎缩和脊柱后凸。TAK 1在肌肉中的积极作用 我们的研究结果也支持了这种生长，即TAK 1的激活在 骨骼肌肥大。我们的实验还表明，TAK 1是必需的， 激活促进骨骼肌生长的特定细胞内途径。而且我们 研究表明，TAK 1可能是自噬/线粒体自噬激活， 线粒体结构和功能，以及维持成年人骨骼肌中的氧化还原平衡。 基于我们的初步数据，我们假设（I）TAK 1促进骨骼肌生长， 通过增加蛋白质合成和防止氧化应激来抑制萎缩;（II）TAK 1 诱导特异性细胞内信号通路的激活以增加骨骼肌质量; 和（III）TAK 1是自噬/线粒体自噬的激活和线粒体自噬的调节所必需的。 动力学（即生物发生、融合和裂变）和成人骨骼肌的呼吸功能。测试 根据这些假设，在项目的下一阶段，我们建议解决以下三个具体问题 目的：（1）研究TAK 1在人肝癌细胞中的作用及其分子机制 骨骼肌生长和防止萎缩;（2）研究信号传导机制， TAK 1调节骨骼肌质量;（3）研究TAK 1在自噬调节中的作用 以及成年骨骼肌中的线粒体含量和功能。

Abstract Loss of skeletal muscle mass is a devastating complication of a wide range of diseases and conditions. However, there is still no approved therapy to prevent muscle wasting partly because the mechanisms that regulate skeletal muscle mass remain enigmatic. Accumulating evidence suggests that an array of signaling pathways regulates skeletal muscle mass mainly through modulating the rate of protein synthesis and degradation. However, upstream signaling mechanisms that are involved in the regulation of muscle mass remain poorly understood. During the current funding of this project, we showed TRAF6 mediates muscle atrophy and inhibits muscle regeneration in a variety of catabolic conditions. We also demonstrated that TRAF6 and TAK1 are important regulators of satellite cell homeostasis in adult skeletal muscle. In contrast to TRAF6, of which activation, causes muscle wasting, we have discovered that TAK1 is essential for skeletal muscle growth and maintenance of muscle mass in adults. Inducible myofiber-specific inactivation of TAK1 in mice (henceforth TAK1mko) leads to severe muscle wasting and development of kyphosis. The positive role of TAK1 in muscle growth is also supported by our findings that the activation of TAK1 is dramatically increased in skeletal muscle undergoing hypertrophy. Our experiments also suggest that TAK1 is required for the activation of specific intracellular pathways which promote skeletal muscle growth. Moreover, our studies indicate that TAK1 may be required for the activation of autophagy/mitophagy, regulation of mitochondrial structure and function, and maintenance of redox balance in skeletal muscle of adults. Based on our preliminary data, we hypothesize that (I) TAK1 promotes skeletal muscle growth and inhibits atrophy through augmenting protein synthesis and preventing oxidative stress; (II) TAK1 induces the activation of specific intracellular signaling pathways to augment skeletal muscle mass; and (III) TAK1 is required for the activation of autophagy/mitophagy and regulation of mitochondrial dynamics (i.e. biogenesis, fusion, and fission) and respiratory function in adult skeletal muscle. To test these hypotheses, in the next phase of the project, we propose to address the following three specific aims: (1) Establish the role and investigate the molecular mechanisms by which TAK1 promotes skeletal muscle growth and prevents atrophy; (2) Investigate the signaling mechanisms by which TAK1 regulates skeletal muscle mass; and (3) Investigate the role of TAK1 in regulation of autophagy and mitochondrial content and function in adult skeletal muscle.