TAK1 signaling in skeletal muscle

骨骼肌中的 TAK1 信号传导

• 批准号: 10201515
• 负责人: ASHOK KUMAR
• 金额: $ 42.97万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201515
• 关键词: Address; Adult; Aging; Atrophic; Autophagocytosis; Autophagosome; Biochemical; Biogenesis; Biological Assay; Birth; Chronic Disease; Communication; Complex; Complication; Data; Denervation; Disease; Equilibrium; Etiology; Funding; Genetic; Growth; Growth Factor; Health; Homeostasis; Human; Hypertrophy; Immobilization; Impairment; Inhibition of Apoptosis; Injury; Knockout Mice; Kyphosis deformity of spine; Lead; Life; LoxP-flanked allele; MAPK Signaling Pathway Pathway; Maintenance; Mediating; Mitochondria; Molecular; Molecular Biology; Mus; Muscle; Muscle Development; Muscle function; Muscle satellite cell; Muscular Atrophy; Muscular Dystrophies; Myoblasts; Natural regeneration; Nature; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphotransferases; Population; Prevention; Production; Protein Biosynthesis; Proteins; Reactive Oxygen Species; Regulation; Reporting; Respiratory physiology; Role; Signal Pathway; Signal Transduction; Signaling Protein; Skeletal Muscle; Starvation; Stimulus; Structure; Syndrome; TNF receptor-associated factor 6; Tamoxifen; Testing; Transforming Growth Factors; base; cell type; conditional knockout; experimental study; improved; mTOR Signaling Pathway; mitochondrial dysfunction; mouse model; muscle form; muscle hypertrophy; muscle regeneration; new therapeutic target; novel; prevent; protein degradation; response; satellite cell; self-renewal; skeletal muscle growth; skeletal muscle wasting; wasting

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.

抽象的 骨骼肌质量的丧失是多种疾病的毁灭性并发症 状况。但是，仍然没有批准的疗法来防止肌肉浪费部分，部分原因是 调节骨骼肌质量的机制仍然神秘。积累的证据表明 一系列信号通路主要通过调节来调节骨骼肌质量 蛋白质合成和降解速率。但是，涉及的上游信号传导机制 在调节肌肉中，质量的理解仍然很少。在当前的该项目资金中， 我们显示Traf6介导肌肉萎缩并抑制各种分解代谢的肌肉再生 状况。我们还证明了TRAF6和TAK1是卫星电池的重要调节剂 成人骨骼肌的稳态。与Traf6相反，激活会导致肌肉 浪费，我们发现TAK1对于骨骼肌生长和维护至关重要 成人的肌肉质量。小鼠TAK1的诱导肌纤维特异性灭活（此后TAK1MKO） 导致严重的肌肉浪费和开发性脑膜病。 TAK1在肌肉中的积极作用 我们的发现也支持增长，即tak1的激活显着增加 骨骼肌接受肥大。我们的实验还表明，tak1是必需的 特定细胞内途径的激活，这些途径促进骨骼肌生长。而且，我们的 研究表明，激活自噬/线粒体可能需要TAK1，调节 线粒体结构和功能，以及成人骨骼肌氧化还原平衡的维持。 根据我们的初步数据，我们假设（i）tak1促进骨骼肌肉的生长和 通过增强蛋白质合成并预防氧化应激，抑制萎缩。 （ii）tak1 诱导特定细胞内信号通路的激活，以增强骨骼肌质量。 （iii）tak1是激活自噬/线粒体和线粒体调节所必需的 成人骨骼肌的动力学（即生物发生，融合和裂变）和呼吸功能。测试 这些假设，在项目的下一个阶段，我们建议解决以下三个特定的特定 目的：（1）确定角色并研究TAK1促进的分子机制 骨骼肌生长并防止萎缩； （2）研究信号传导机制 TAK1调节骨骼肌质量； （3）研究tak1在调节自噬中的作用 成年骨骼肌的线粒体含量和功能。

项目成果

Estrogen-Related Receptor Gamma Gene Therapy Promotes Therapeutic Angiogenesis and Muscle Recovery in Preclinical Model of PAD.

• DOI: 10.1161/jaha.122.028880
• 发表时间: 2023-08-15
• 期刊: JOURNAL OF THE AMERICAN HEART ASSOCIATION
• 影响因子: 5.4
• 作者: Sopariwala, Danesh H. H.;Rios, Andrea S. S.;Saley, Addison;Kumar, Ashok;Narkar, Vihang A. A.
• 通讯作者: Narkar, Vihang A. A.