Molecular Mechanisms that Cause Muscle Atrophy

导致肌肉萎缩的分子机制

基本信息

批准号：
8101825
负责人：
ALFRED L GOLDBERG
金额：
$ 38.75万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8101825
关键词：
Accounting Aging Applications Grants Atrophic Autophagocytosis Binding Binding Proteins Biochemical Biomedical Research Cachexia Cells Denervation Disease Exercise Family member Fasting Fiber Genes Genetic Transcription Genome Glucocorticoids Goals Grant Health Homologous Gene Human In Vitro Kidney Failure Learning Lysosomes Malignant Neoplasms Messenger RNA Methods Microarray Analysis Mitochondria Modeling Molecular Muscle Muscle Proteins Muscular Atrophy Pathway interactions Process Proteins Proteolysis Regulation of Proteolysis Relative (related person)Research Research Institute Resistance Role Sepsis Skeletal Muscle Systemic disease Testing Transcription Alteration Transcription Coactivator Translational Research Ubiquitin United States National Aeronautics and Space Administration United States National Institutes of Health base cofactor drug development falls improved in vivo inhibitor/antagonist interest multicatalytic endopeptidase complex muscle RING finger 1 muscle form nerve injury novel overexpression prevent protein degradation protein expression response transcription factor ubiquitin ligase ubiquitin-protein ligase wasting

项目摘要

DESCRIPTION (provided by applicant): Atrophy of skeletal muscle is a debilitating response to denervation, disuse, fasting, glucocorticoids, many systemic diseases (e.g. cancer cachexia, renal failure) and aging. We showed that these various types of rapid atrophy result primarily from accelerated protein breakdown, triggered by the activation of the FoxO transcription factors and alterations in the expression of a set of about 80 atrophy-related genes ("atrogenes"), including two muscle-specific ubiquitin ligases, MuRF1 and atrogin-1/MAFbx, whose dramatic induction is essential for rapid wasting. To understand the atrophy process, it will be important to learn more about MuRF1's function and cofactors in vivo and to identify the muscle proteins that MuRF1 targets for degradation during atrophy. We have identified new protein partners of MuRF1 (S5a and novel E2s) that enhance MuRF1- dependent proteolysis in vitro and protein substrates (including critical myofibrillar components) that are lost selectively during denervation atrophy. Their precise roles in the atrophy process will be elucidated. Although the accelerated proteolysis during atrophy is due primarily to activation of the ubiquitin-proteasome pathway, we recently found that FoxO3, denervation, and fasting also stimulate lysosomal proteolysis and autophagy by enhancing transcription of many autophagy-related (atg) genes. We hope to clarify how autophagy is activated and the relative importance of the autophagic and proteasomal pathways in the destruction of different muscle components, especially in the loss of mitochondria and myofibrillar proteins, during atrophy in vivo. To obtain a fuller understanding of the transcriptional changes during atrophy, we plan to use improved gene microarray technology to identify the complete set of atrogenes upregulated and down regulated similarly in various types of atrophy. These studies should also enable us to define the specific roles in activating these transcriptional changes of the three FoxO family members (FoxO1, 3, and 4) and of NFkB, which is also critical for atrophy. We hope to learn how these transcription factors influence atrogene expression, proteolysis, and cell mass and their importance in vivo in the atrophy induced by glucocorticoids, fasting, and denervation. We recently found that expression of the exercise-induced transcriptional coactivator, PGC-11, and its homolog, PGC-12 fall dramatically during various types of atrophy, but that maintaining PGC-11 expression at high levels inhibits the induction of atrogin-1 and MuRF1 and blocks atrophy. A major goal will be to elucidate the mechanisms by which PGC-11 normally inhibits atrogene expression and protein loss and is repressed during atrophy, and to learn whether PGC12 serves similar functions in preserving muscle mass. PUBLIC HEALTH RELEVANCE: The overall goal of the various studies described in this grant application is to clarify the biochemical and transcriptional mechanisms responsible for the accelerated protein degradation that causes the rapid atrophy of skeletal muscles with disuse or nerve injury and in various systemic diseases (e.g. cancer, sepsis, renal failure) and aging.

描述（由申请人提供）：骨骼肌萎缩是对去神经支配、废用、禁食、糖皮质激素、许多全身性疾病（例如癌症恶病质、肾功能衰竭）和衰老的一种衰弱反应。我们表明，这些不同类型的快速萎缩主要是由于 FoxO 转录因子的激活和一组约 80 个萎缩相关基因（“atrogenes”）表达的改变所触发的加速蛋白质分解所致，其中包括两个肌肉-特异性泛素连接酶 MuRF1 和 atrogin-1/MAFbx，其剧烈诱导对于快速消耗至关重要。为了了解萎缩过程，重要的是更多地了解 MuRF1 的体内功能和辅助因子，并确定 MuRF1 在萎缩过程中降解的目标肌肉蛋白。我们已经确定了 MuRF1 的新蛋白伴侣（S5a 和新的 E2s），它们可以增强 MuRF1 依赖性体外蛋白水解作用，以及在去神经萎缩过程中选择性丢失的蛋白底物（包括关键的肌原纤维成分）。它们在萎缩过程中的确切作用将被阐明。尽管萎缩过程中蛋白水解加速主要是由于泛素蛋白酶体途径的激活，但我们最近发现 FoxO3、去神经支配和禁食也可以通过增强许多自噬相关 (atg) 基因的转录来刺激溶酶体蛋白水解和自噬。我们希望阐明自噬是如何被激活的，以及自噬和蛋白酶体途径在体内萎缩过程中不同肌肉成分破坏中的相对重要性，特别是在线粒体和肌原纤维蛋白的丢失中。为了更全面地了解萎缩过程中的转录变化，我们计划使用改进的基因微阵列技术来鉴定在各种类型的萎缩中类似上调和下调的完整的 atrogenes。这些研究还应该使我们能够确定三个 FoxO 家族成员（FoxO1、3 和 4）和 NFkB 在激活这些转录变化中的具体作用，这对萎缩也至关重要。我们希望了解这些转录因子如何影响 atrogene 表达、蛋白水解和细胞质量，以及它们在糖皮质激素、禁食和去神经支配引起的体内萎缩中的重要性。我们最近发现，运动诱导的转录辅激活因子 PGC-11 及其同源物 PGC-12 的表达在各种类型的萎缩过程中急剧下降，但维持高水平的 PGC-11 表达会抑制 atrogin-1 和 atrogin-1 的诱导。 MuRF1 并阻止萎缩。主要目标是阐明 PGC-11 通常抑制 atrogene 表达和蛋白质损失以及在萎缩过程中受到抑制的机制，并了解 PGC12 在保持肌肉质量方面是否具有类似的功能。公共健康相关性：本拨款申请中描述的各种研究的总体目标是阐明加速蛋白质降解的生化和转录机制，这种加速蛋白质降解会导致骨骼肌因废用或神经损伤以及各种全身性疾病（例如，骨骼肌快速萎缩）而萎缩。癌症、败血症、肾衰竭）和衰老。