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TAK1 signaling in skeletal muscle

骨骼肌中的 TAK1 信号传导

基本信息

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
项目类别：
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

项目摘要

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.

摘要

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.