TAK1/TRAF6 Signaling in Skeletal Muscle

描述(申请人提供)：骨骼肌萎缩/萎缩是一种广泛的疾病和条件的破坏性并发症，如衰老、废用、慢性阻塞性肺疾病、太空旅行、慢性心力衰竭、败血症和癌症。肌肉发生是骨骼肌胚胎发育所必需的过程，也是某些类型的后天生长和受损肌纤维修复的重要元素。在一些慢性疾病中，肌肉生成障碍是骨骼肌萎缩的关键决定因素，也是儿童横纹肌肉瘤发生的关键因素。尽管对骨骼肌形成和消耗过程的了解已经取得了重大进展，但在各种生理和病理生理条件下调节骨骼肌质量的上游信号事件仍然知之甚少。我们已经积累了强有力的证据，支持TAK1/TRAF6信号复合体在骨骼肌群的获得和维持中起关键作用。我们的初步研究表明，TRAF6和TAK1都通过新的赖氨酸-63连接的多泛素化机制刺激肌源性分化。在MyoD诱导的非肌肉细胞向骨骼肌的转化过程中，TAK1和TRAF6也是必需的。在成人骨骼肌中，TAK1/TRAF6的激活导致炎症、肌纤维再生障碍和萎缩。为了清楚地确定TAK1/TRAF6复合体在骨骼肌中的作用和作用机制，我们将使用包括条件基因敲除小鼠在内的遗传方法。根据我们的初步数据，我们假设通过TAK1和TRAF6的信号是骨骼肌发育所必需的，但不是维持分化表型所必需的。在应激条件下，TAK1和TRAF6的激活刺激分解代谢途径，导致骨骼肌萎缩。为了验证这一假说，我们建议解决以下三个具体目标：1)研究TAK1和TRAF6调控成肌细胞分化的信号机制；2)研究TAK1和TRAF6在体内调控骨骼肌发育的作用和细胞机制；3)描述TAK1和TRAF6调控成年骨骼肌再生和萎缩的机制。该项目的成功完成将为信号机制提供关键的见解，并将TAK1和TRAF6确立为新的分子靶点，以防止各种肌肉疾病中的骨骼肌丢失。

DESCRIPTION (provided by applicant): Skeletal muscle atrophy/wasting is a devastating complication of a wide range of diseases and conditions such as aging, disuse, chronic obstructive pulmonary disease, space travel, chronic heart failure, sepsis, and cancer. Myogenesis is the process that is required not only for the embryonic development of skeletal muscle but it is also an important element of certain types of postnatal growth and repair of injured myofibers. Impairment in myogenesis is the critical determinant of skeletal muscle-wasting in several chronic diseases and also development of rhabdomyosarcoma in children. Although significant progress has been made to understanding the processes of skeletal muscle formation and wasting, the upstream signaling events regulating skeletal muscle mass in various physiological and pathophysiological conditions remain poorly understood. We have accumulated strong evidence that supports a crucial role of TAK1/TRAF6 signaling complex in the acquisition and maintenance of skeletal muscle mass. Our preliminary studies have shown that both TRAF6 and TAK1 stimulate myogenic differentiation through novel Lysine-63-linked poly-ubiquitination mechanisms. TAK1 and TRAF6 are also required for MyoD-induced transformation of non-muscle cells into skeletal muscles. In adult skeletal muscle, the activation of TAK1/TRAF6 leads to inflammation, impairment in myofiber regeneration, and atrophy. To clearly establish the role and delineate the mechanisms of action of TAK1/TRAF6 complex in skeletal muscle, we will use genetic approaches including conditional knockout mice. Based on our preliminary data, we hypothesize that signaling through TAK1 and TRAF6 is required for the development of skeletal muscle but not for maintaining differentiated phenotype. Under stress conditions, the activation of TAK1 and TRAF6 stimulates catabolic pathways leading to skeletal muscle atrophy. To test this hypothesis, we propose to address the following three specific aims: 1) Investigate the signaling mechanisms by which TAK1 and TRAF6 regulate myogenic differentiation in cultured myoblasts; 2) Investigate the role and cellular mechanisms by which TAK1 and TRAF6 regulate skeletal muscle development in vivo; and 3) Delineate the mechanisms by which TAK1 and TRAF6 regulates regeneration and atrophy in adult skeletal muscles. Successful completion of this project will provide critical insights into the signaling mechanisms and establish TAK1 and TRAF6 as novel molecular targets to prevent skeletal muscle loss in various muscular disorders.