TAK1/TRAF6 Signaling in Skeletal Muscle

描述（由申请人提供）：骨骼肌萎缩/萎缩是多种疾病和病症的毁灭性并发症，如衰老、废用、慢性阻塞性肺病、太空旅行、慢性心力衰竭、败血症和癌症。肌生成不仅是骨骼肌胚胎发育所需的过程，而且也是某些类型的出生后生长和修复受损肌纤维的重要因素。肌生成障碍是几种慢性疾病中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决定因素。虽然已经取得了显着的进展，了解骨骼肌的形成和消耗的过程中，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TAK 1/TRAF 6信号复合物在骨骼肌质量的获得和维持中的关键作用。我们的初步研究表明，TRAF 6和TAK 1都通过新的赖氨酸-63连接的多聚泛素化机制刺激肌原性分化。TAK 1和TRAF 6也是MyoD诱导的非肌肉细胞转化为骨骼肌所必需的。在成人骨骼肌中，TAK 1/TRAF 6的激活导致炎症、肌纤维再生受损和萎缩。为了明确TAK 1/TRAF 6复合物在骨骼肌中的作用和作用机制，我们将使用遗传方法，包括条件性基因敲除小鼠。基于我们的初步数据，我们假设通过TAK 1和TRAF 6的信号传导是骨骼肌发育所需的，但不是维持分化表型所需的。在应激条件下，TAK 1和TRAF 6的激活刺激导致骨骼肌萎缩的分解代谢途径。为了验证这一假设，我们提出了以下三个具体目标：1）研究TAK 1和TRAF 6调节成肌细胞成肌分化的信号机制; 2）研究TAK 1和TRAF 6在体内调节骨骼肌发育的作用和细胞机制;阐明TAK 1和TRAF 6调控成人骨骼肌再生和萎缩的机制。该项目的成功完成将为信号传导机制提供重要见解，并将TAK 1和TRAF 6确定为预防各种肌肉疾病中骨骼肌损失的新型分子靶点。 公共卫生相关性：骨骼肌的形成和萎缩是由自分泌、旁分泌和内分泌因子通过多种信号转导途径调控的精心协调的过程。我们的研究旨在剖析TAK 1/TRAF 6复合物调控肌肉分化的信号机制。除了肌肉形成，我们的研究还将描绘负责加速蛋白质降解的信号机制，导致成熟骨骼肌快速萎缩。这些研究的结果将有助于了解骨骼肌生物学，这将对健康相关问题产生重大影响，如肌肉减少症、疾病引起的肌肉萎缩、肌肉再生和横纹肌肉瘤。

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. PUBLIC HEALTH RELEVANCE: Skeletal muscle formation and wasting are well-orchestrated processes regulated by autocrine, paracrine, and endocrine factors via multiple signal transduction pathways. Our proposed studies are aimed to dissect the signaling mechanisms underlying the regulation of muscle differentiation with a focus on TAK1/TRAF6 complex. In addition to muscle formation, our study will also delineate the signaling mechanisms responsible for accelerated protein degradation that causes rapid atrophy of mature skeletal muscles. Results of these studies will contribute to the understanding of skeletal muscle biology, which will have a significant impact on health-related issues such as sarcopenia, disease- induced muscle atrophy, muscle regeneration, and rhabdomyosarcoma.